FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Copeland, LA Zeber, JE Wang, CP Parchman, ML Lawrence, VA Valenstein, M Miller, AL AF Copeland, Laurel A. Zeber, John E. Wang, Chen-Pin Parchman, Michael L. Lawrence, Valerie A. Valenstein, Marcia Miller, Alexander L. TI Patterns of primary care and mortality among patients with schizophrenia or diabetes: a cluster analysis approach to the retrospective study of healthcare utilization SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID SERIOUS MENTAL-ILLNESS; OF-VETERANS-AFFAIRS; EXCESS MORTALITY; SYSTEM; MANAGEMENT; RETENTION; QUALITY; RISK AB Background: Patients with schizophrenia have difficulty managing their medical healthcare needs, possibly resulting in delayed treatment and poor outcomes. We analyzed whether patients reduced primary care use over time, differentially by diagnosis with schizophrenia, diabetes, or both schizophrenia and diabetes. We also assessed whether such patterns of primary care use were a significant predictor of mortality over a 4-year period. Methods: The Veterans Healthcare Administration (VA) is the largest integrated healthcare system in the United States. Administrative extracts of the VA's all-electronic medical records were studied. Patients over age 50 and diagnosed with schizophrenia in 2002 were age-matched 1:4 to diabetes patients. All patients were followed through 2005. Cluster analysis explored trajectories of primary care use. Proportional hazards regression modelled the impact of these primary care utilization trajectories on survival, controlling for demographic and clinical covariates. Results: Patients comprised three diagnostic groups: diabetes only (n = 188,332), schizophrenia only (n = 40,109), and schizophrenia with diabetes (Scz-DM, n = 13,025). Cluster analysis revealed four distinct trajectories of primary care use: consistent over time, increasing over time, high and decreasing, low and decreasing. Patients with schizophrenia only were likely to have low-decreasing use (73% schizophrenia-only vs 54% Scz-DM vs 52% diabetes). Increasing use was least common among schizophrenia patients (4% vs 8% Scz-DM vs 7% diabetes) and was associated with improved survival. Low-decreasing primary care, compared to consistent use, was associated with shorter survival controlling for demographics and case-mix. The observational study was limited by reliance on administrative data. Conclusion: Regular primary care and high levels of primary care were associated with better survival for patients with chronic illness, whether psychiatric or medical. For schizophrenia patients, with or without comorbid diabetes, primary care offers a survival benefit, suggesting that innovations in treatment retention targeting at-risk groups can offer significant promise of improving outcomes. C1 [Copeland, Laurel A.; Zeber, John E.; Wang, Chen-Pin; Parchman, Michael L.; Lawrence, Valerie A.] S Texas Vet Hlth Care Syst, VERDICT Res, San Antonio, TX USA. [Copeland, Laurel A.; Zeber, John E.; Miller, Alexander L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Wang, Chen-Pin] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Parchman, Michael L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Family & Community Med, San Antonio, TX 78229 USA. [Lawrence, Valerie A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Valenstein, Marcia] Vet Adm Ann Arbor Healthcare Syst, SMITREC Res, Ann Arbor, MI USA. [Valenstein, Marcia] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Copeland, LA (reprint author), S Texas Vet Hlth Care Syst, VERDICT Res, San Antonio, TX USA. EM copelandl@uthscsa.edu; zeber@uthscsa.edu; chen-pin.wang@va.gov; parchman@uthscsa.edu; vlawrence@uthscsa.edu; marciav@umich.edu; millera@uthscsa.edu OI Copeland, Laurel/0000-0002-9478-0209 FU Department of Veterans Affairs; Veterans Health Administration, Health Services Research and Development Service [IIR 05-326]; South Texas Veterans Health Care System, San Antonio, TX; University of Texas Health Science Center at San Antonio; Serious Mental Illness Treatment Research & Evaluation Center; VA Ann Arbor Healthcare System, Ann Arbor, MI; Merit Review Entry Program [MRP-05145]; VA Health Services Research and Development program; VA HSRD [IIR05-326] FX This research was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service ( IIR 05-326; PI: Copeland). This work was completed with the additional support of the VERDICT Research Program at the South Texas Veterans Health Care System, San Antonio, TX, the University of Texas Health Science Center at San Antonio, and the Serious Mental Illness Treatment Research & Evaluation Center, VA Ann Arbor Healthcare System, Ann Arbor, MI. LAC is funded by Merit Review Entry Program grant MRP-05145 from the VA Health Services Research and Development program. CPW, VAL, ALM, MV and JEZ are co-investigators on grant VA HSRD IIR05-326 [Copeland-PI]. The authors gratefully acknowledge the contributions of Brandon J Hosek in extracting, aggregating, and managing the data. NR 30 TC 35 Z9 36 U1 2 U2 8 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 JUL 26 PY 2009 VL 9 AR 127 DI 10.1186/1472-6963-9-127 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 490SW UT WOS:000269525900001 PM 19630997 ER PT J AU Raab, MS Podar, K Breitkreutz, I Richardson, PG Anderson, KC AF Raab, Marc S. Podar, Klaus Breitkreutz, Iris Richardson, Paul G. Anderson, Kenneth C. TI Multiple myeloma SO LANCET LA English DT Review ID STEM-CELL TRANSPLANTATION; PEGYLATED LIPOSOMAL DOXORUBICIN; THALIDOMIDE PLUS DEXAMETHASONE; HIGH-DOSE THERAPY; PROTEASOME INHIBITOR BORTEZOMIB; BONE-MARROW TRANSPLANTATION; PREVIOUSLY TREATED PATIENTS; NEWLY-DIAGNOSED MYELOMA; NF-KAPPA-B; PHASE-II AB Multiple myeloma is characterised by clonal proliferation of malignant plasma cells, and mounting evidence indicates that the bone marrow microenvironment of tumour cells has a pivotal role in myeloma pathogenesis. This knowledge has already expanded treatment options for patients with multiple myeloma. Prototypic drugs thalidomide, bortezomib, and lenalidomide have each been approved for the treatment of this disease by targeting both multiple myeloma cells and the bone marrow microenvironment. Although benefit was first shown in relapsed and refractory disease, improved overall response, duration of response, and progression-free and overall survival can be achieved when these drugs are part of first-line regimens. This treatment framework promises to improve outcome not only for patients with multiple myeloma, but also with other haematological malignancies and solid tumours. C1 [Raab, Marc S.; Podar, Klaus; Breitkreutz, Iris; Richardson, Paul G.; Anderson, Kenneth C.] Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Raab, Marc S.; Podar, Klaus; Breitkreutz, Iris; Richardson, Paul G.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Boston, MA 02115 USA. [Raab, Marc S.] Heidelberg Univ, Med Ctr, Dept Med 5, Heidelberg, Germany. [Raab, Marc S.; Breitkreutz, Iris] Natl Ctr Tumor Dis, Heidelberg, Germany. [Raab, Marc S.; Breitkreutz, Iris] German Canc Res Ctr, D-6900 Heidelberg, Germany. RP Anderson, KC (reprint author), Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, 44 Binney St, Boston, MA 02115 USA. EM Kenneth_Anderson@dfci.harvard.edu NR 148 TC 347 Z9 370 U1 8 U2 55 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 25 PY 2009 VL 374 IS 9686 BP 324 EP 339 DI 10.1016/S0140-6736(09)60221-X PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 477GW UT WOS:000268508200030 PM 19541364 ER PT J AU Joussen, AM Doehmen, S Le, ML Koizumi, K Radetzky, S Krohne, TU Poulaki, V Semkova, I Kociok, N AF Joussen, Antonia M. Doehmen, Sven Le, Minh L. Koizumi, Kan Radetzky, Sven Krohne, Tim U. Poulaki, Vassiliki Semkova, Irina Kociok, Norbert TI TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations SO MOLECULAR VISION LA English DT Article ID NF-KAPPA-B; CELL-DEATH; RHEUMATOID-ARTHRITIS; ENDOTHELIAL-CELLS; TRANSCRIPTIONAL REGULATION; ADHESION MOLECULES; VASCULAR LEAKAGE; IN-VIVO; EXPRESSION; RETINA AB Purpose: The pathophysiology of diabetic retinopathy involves leukocyte adhesion to retinal vasculature, early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell death. We investigated the involvement of tumor necrosis factor alpha (TNF-alpha) in diabetes-related histopathological changes in two relevant rodent models. Methods: In short-term studies, Long-Evans rats with streptozotocin-induced diabetes were treated with or without the TNF-alpha inhibitor, etanercept. For long-term studies, tumor necrosis factor receptor I (TNF-RI)-deficient mice and TNF-RII-deficient mice, as well as C57/Bl6 wild-type mice, were fed 30% galactose for up to 20 months. The retinal histopathological alterations of hypergalactosemia were analyzed in trypsin digest preparations. Endothelial cell injury and apoptosis in rat retinas were evaluated by propidium iodide, TUNEL, CytoDeath staining, and DNA fragmentation ELISA. Caspase 3 and 8 activity was evaluated by immunoblotting and quantitative enzymatic activity assay. Results: Etanercept suppressed caspase activation, retinal cell injury, and apoptosis in short-term diabetic rats. Pericyte and endothelial cell loss were also reduced in long-term hypergalactosemic mice. Long-term studies demonstrated that pericyte loss and endothelial cell loss were reduced in comparison to wild-type diabetic controls. Conclusions: Our study identifies an important role for TNF-alpha in the pathogenesis of signature diabetic retinopathy pathologies and demonstrates that etanercept can inhibit retinal cell death and long-term complication of diabetes. Taken together, our results suggest that etanercept could prove beneficial in preventing both early and late vascular diabetic complications. C1 [Joussen, Antonia M.; Semkova, Irina; Kociok, Norbert] Univ Dusseldorf, Dept Ophthalmol, D-40225 Dusseldorf, Germany. [Joussen, Antonia M.; Doehmen, Sven; Le, Minh L.; Koizumi, Kan; Radetzky, Sven; Krohne, Tim U.; Semkova, Irina; Kociok, Norbert] Univ Cologne, Dept Vitreoretinal Surg, Ctr Ophthalmol, D-5000 Cologne 41, Germany. [Joussen, Antonia M.; Doehmen, Sven] Univ Cologne, Ctr Mol Med, D-5000 Cologne 41, Germany. [Poulaki, Vassiliki] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Joussen, AM (reprint author), Univ Dusseldorf, Dept Ophthalmol, Moorenstr 5, D-40225 Dusseldorf, Germany. EM JoussenA@googlemail.com RI Krohne, Tim/D-1497-2013 OI Krohne, Tim/0000-0003-2280-925X FU Deutsche Forschungsgemeinschaft DFG [JO 324/6-1, JO 324/4-1, JO 324/10-1] FX This study was funded by the Deutsche Forschungsgemeinschaft DFG JO 324/6-1 (ENP), DFG JO 324/4-1, DFG JO 324/10-1, Ernst und Berta Grimmke Stiftung, Meyer-Schwarting Stiftung, Gertrud und Werner Muller Stiftung, and the Foundation Fighting Blindness (to V.P.). We thank Christina Esser, Claudia Gavranic, and Heimke Bucken for professional technical assistance and Silke Coburger, PhD, Department of Medical Informatics, University of Cologne for statistical advice. There is no financial or other connection to the manufacturer of etanercept. NR 44 TC 108 Z9 115 U1 1 U2 5 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 JUL 25 PY 2009 VL 15 IS 151 BP 1418 EP 1428 PG 11 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 493LZ UT WOS:000269739600001 PM 19641635 ER PT J AU Taboada, E Solanas, R Rodriguez, E Weissleder, R Roig, A AF Taboada, Elena Solanas, Raul Rodriguez, Elisenda Weissleder, Ralph Roig, Anna TI Supercritical-Fluid-Assisted One-Pot Synthesis of Biocompatible Core(gamma-Fe2O3)/Shell(SiO2) Nanoparticles as High Relaxivity T-2-Contrast Agents for Magnetic Resonance Imaging SO ADVANCED FUNCTIONAL MATERIALS LA English DT Article ID SILICA PARTICLES; DELIVERY-SYSTEM; MRI; AEROGELS AB Monodisperse iron oxide/microporous silica core/shell composite nanoparticles, core(gamma-Fe2O3)/shell(SiO2), with a diameter of approximately 100 nm and a high magnetization are synthesized by combining sol-gel chemistry and supercritical fluid technology. This one-step processing method, which is easily scalable, allows quick fabrication of materials with controlled properties and in high yield. The particles have a specific magnetic moment (per kg of iron) comparable to that of the bulk maghemite and show superparamagnetic behavior at room temperature. The nanocomposites are proven to be useful as T-2 MRI imaging agent. They also have potential to be used in NMR proximity sensing, theranostic drug delivery, and bioseparation. C1 [Taboada, Elena; Solanas, Raul; Roig, Anna] CSIC, ICMAB, Bellaterra 08193, Spain. [Solanas, Raul] MATGAS 2000 AIE, Bellaterra 08193, Spain. [Rodriguez, Elisenda; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02129 USA. [Rodriguez, Elisenda; Weissleder, Ralph] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Taboada, E (reprint author), CSIC, ICMAB, Campus UAB, Bellaterra 08193, Spain. EM roig@icmab.es RI ROIG, ANNA/E-7616-2011 OI ROIG, ANNA/0000-0001-6464-7573 FU Ministerio de Ciencia e Innovacion [MAT2006-13572-C02-01]; CONSOLIDER-NANOSELECT [CSD2007-00041]; Fundacion Domingo Martinez (2009); EC-NoE FAME; CNRS FX This work has been partially financed by the Ministerio de Ciencia e Innovacion (MAT2006-13572-C02-01 and CONSOLIDER-NANOSELECT-CSD2007-00041), the Fundacion Domingo Martinez (2009), and the EC-NoE FAME. We thank M.-H. Delville from CNRS Bordeaux for early discussions on the materials and D. X. Chen (ICREA-UAB), A. Goni (ICREA-CSIC), and A. Slawska-Waniewska (I F-PAS) for fruitful discussions on the magnetic properties. E. R. kindly acknowledges the EC-Marie Curie grant OIF (Molecular Imaging 39639). NR 33 TC 82 Z9 82 U1 5 U2 46 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1616-301X J9 ADV FUNCT MATER JI Adv. Funct. Mater. PD JUL 24 PY 2009 VL 19 IS 14 BP 2319 EP 2324 DI 10.1002/adfm.200801681 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 478RR UT WOS:000268606500018 ER PT J AU Kelly, TJ Lerin, C Haas, W Gygi, SP Puigserver, P AF Kelly, Timothy J. Lerin, Carles Haas, Wilhelm Gygi, Steven P. Puigserver, Pere TI GCN5-mediated Transcriptional Control of the Metabolic Coactivator PGC-1 beta through Lysine Acetylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PPAR-GAMMA COACTIVATOR-1; FATTY-ACID OXIDATION; MITOCHONDRIAL BIOGENESIS; SKELETAL-MUSCLE; RECEPTOR-ALPHA; ERR-ALPHA; ENERGY-EXPENDITURE; INSULIN-RESISTANCE; PGC-1-ALPHA; ACTIVATION AB Changes in expression levels of genes encoding for proteins that control metabolic pathways are essential to maintain nutrient and energy homeostasis in individual cells as well as in organisms. An important regulated step in this process is accomplished through covalent chemical modifications of proteins that form complexes with the chromatin of gene promoters. The peroxisome proliferators gamma co-activator 1 (PGC-1) family of transcriptional co-activators comprises important components of a number of these complexes and participates in a large array of glucose and lipid metabolic adaptations. Here, we show that PGC-1 beta is acetylated on at least 10 lysine residues distributed along the length of the protein by the acetyl transferase general control of amino-acid synthesis (GCN5) and that this acetylation reaction is reversed by the deacetylase sirtuin 1 (SIRT1). GCN5 strongly interacts with PGC-1 beta and represses its transcriptional activity associated with transcription factors such as ERR alpha, NRF-1, and HNF4 alpha, however acetylation and transcriptional repression do not occur when a catalytically inactive GCN5 is co-expressed. Transcriptional repression coincides with PGC-1 beta redistribution to nuclear foci where it co-localizes with GCN5. Furthermore, knockdown of GCN5 ablates PGC-1 beta acetylation and increases transcriptional activity. In primary skeletal muscle cells, PGC-1 beta induction of endogenous target genes, including MCAD and GLUT4, is largely repressed by GCN5. Functionally, this translates to a blunted response to PGC-1 beta-induced insulin-mediated glucose transport. These results suggest that PGC-1 beta acetylation by GCN5 might be an important step in the control of glucose and lipid pathways and its dysregulation could contribute to metabolic diseases. C1 [Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Kelly, Timothy J.; Lerin, Carles; Haas, Wilhelm; Gygi, Steven P.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kelly, Timothy J.] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. RP Puigserver, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 1 Jimmy Fund Way,Smith 932C, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu FU National Institutes of Health [RO1 DK069966]; Ellison Medical Foundation New Scholar Award; American Diabetes Association; U.S. Dept. of Defense FX This work was supported, in whole or in part, by National Institutes of Health Grant RO1 DK069966 (to P. P.). This work was also supported by an Ellison Medical Foundation New Scholar Award, by the American Diabetes Association, and by the U.S. Dept. of Defense. NR 46 TC 52 Z9 55 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 24 PY 2009 VL 284 IS 30 BP 19945 EP 19952 DI 10.1074/jbc.M109.015164 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471ZO UT WOS:000268097400021 PM 19491097 ER PT J AU Bains, M Florez-McClure, ML Heidenreich, KA AF Bains, Mona Florez-McClure, Maria L. Heidenreich, Kim A. TI Insulin-like Growth Factor-I Prevents the Accumulation of Autophagic Vesicles and Cell Death in Purkinje Neurons by Increasing the Rate of Autophagosome-to-lysosome Fusion and Degradation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHAPERONE-MEDIATED AUTOPHAGY; CEREBELLAR GRANULE NEURONS; PROTEIN-KINASE; ALZHEIMERS-DISEASE; SIGNALING PATHWAYS; GLUTAMATE-RECEPTOR; TRANSGENIC MICE; LURCHER MICE; APOPTOSIS; MACROAUTOPHAGY AB Continuous macroautophagic activity is critical for the maintenance of neuronal homeostasis; however, unchecked or dysregulated autophagy can lead to cell death. Cultured Purkinje neurons die by an autophagy-associated cell death mechanism when deprived of trophic support. Here, we report that insulin-like growth factor-I ( IGF-I) completely blocked the autophagy-associated cell death of Purkinje neurons. To examine the mechanism by which IGF-I influences autophagy, neurons were infected with adeno-RFP-LC3 and subjected to trophic factor withdrawal, and the size and number of autophagosomes were analyzed by live-cell fluorescence imaging. In control neurons, autophagy occurred at a constitutive low level with most autophagosomes measuring less than 0.75 mu m. Trophic factor withdrawal increased the number and size of autophagosomes with most autophagosomes ranging between 0.75 and 1.5 mu m and some reaching 1.5-2.25 mu m. IGF-I added at the time of trophic factor withdrawal prevented the accumulation of the larger autophagosomes; however, it had no effect on the conversion of LC3, an indicator of autophagy induction. Instead, the rate of autophagosome-to-lysosome fusion measured by colocalization of RFP-LC3 and LysoSensor Green was accelerated by IGF-I. Treating the neurons with bafilomycin A(1) in the presence of IGF-I led to the accumulation of autophagosomes even larger than those induced by trophic factor withdrawal alone, indicating that IGF-I regulates autophagic vesicle turnover. Finally, the effect of IGF-I on autophagy was mediated by an Akt/mTOR-dependent and an ERK-independent pathway. These data suggest a novel role for IGF-I in protecting Purkinje neurons from autophagy-associated cell death by increasing autophagy efficiency downstream of autophagy induction. C1 [Bains, Mona; Heidenreich, Kim A.] Univ Colorado Denver, Dept Pharmacol, Aurora, CO 80045 USA. [Florez-McClure, Maria L.] Discovery Martek Biosci Corp, Neurosci Res, Boulder, CO 80301 USA. [Heidenreich, Kim A.] Denver Vet Affairs Med Ctr, Denver, CO 80262 USA. RP Heidenreich, KA (reprint author), Univ Colorado Denver, Dept Pharmacol, MS 8303,POB 6511, Aurora, CO 80045 USA. EM Kim.Heidenreich@ucdenver.edu FU National Institutes of Health [NS045560, 1F32NS062534-01A1]; Department of Veterans Affairs merit awards; Department of Defense [03281009] FX This work was supported, in whole or in part, by National Institutes of Health Grants NS045560 and 1F32NS062534-01A1 (NINDS). This work was also supported by a Department of Veterans Affairs merit awards and Department of Defense Grant 03281009 (United States Army Medical Research and Material Command). NR 55 TC 31 Z9 32 U1 3 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 24 PY 2009 VL 284 IS 30 BP 20398 EP 20407 DI 10.1074/jbc.M109.011791 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471ZO UT WOS:000268097400065 PM 19509289 ER PT J AU Barabasi, AL AF Barabasi, Albert-Laszlo TI Scale-Free Networks: A Decade and Beyond SO SCIENCE LA English DT Editorial Material ID SMALL-WORLD NETWORKS; COMPLEX NETWORKS; INTERNET AB For decades, we tacitly assumed that the components of such complex systems as the cell, the society, or the Internet are randomly wired together. In the past decade, an avalanche of research has shown that many real networks, independent of their age, function, and scope, converge to similar architectures, a universality that allowed researchers from different disciplines to embrace network theory as a common paradigm. The decade-old discovery of scale-free networks was one of those events that had helped catalyze the emergence of network science, a new research field with its distinct set of challenges and accomplishments. C1 [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys Biol & Comp Sci, Ctr Complex Network Res, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. RP Barabasi, AL (reprint author), Northeastern Univ, Dept Phys Biol & Comp Sci, Ctr Complex Network Res, Boston, MA 02115 USA. EM alb@neu.edu RI Xie, Jianjun/D-9838-2012 NR 26 TC 547 Z9 597 U1 12 U2 156 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 JUL 24 PY 2009 VL 325 IS 5939 BP 412 EP 413 DI 10.1126/science.1173299 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 474AR UT WOS:000268255100038 PM 19628854 ER PT J AU Richardson, P Jagannath, S Hussein, M Berenson, J Singhal, S Irwin, D Williams, SF Bensinger, W Badros, AZ Vescio, R Kenvin, L Yu, ZN Olesnyckyj, M Zeldis, J Knight, R Anderson, KC AF Richardson, Paul Jagannath, Sundar Hussein, Mohamad Berenson, James Singhal, Seema Irwin, David Williams, Stephanie F. Bensinger, William Badros, Ashraf Z. Vescio, Robert Kenvin, Laurie Yu, Zhinuan Olesnyckyj, Marta Zeldis, Jerome Knight, Robert Anderson, Kenneth C. TI Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma SO BLOOD LA English DT Article ID EXTENDED FOLLOW-UP; PLUS DEXAMETHASONE; DRUG-RESISTANCE; THALIDOMIDE; CANCER; THROMBOEMBOLISM; BORTEZOMIB; THERAPY; PHASE-2; TRIAL AB Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351. (Blood. 2009; 114: 772-778) C1 [Richardson, Paul] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Jagannath, Sundar] St Vincents Comprehens Canc Ctr, New York, NY USA. [Hussein, Mohamad] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Hussein, Mohamad] Res Inst, Tampa, FL USA. [Berenson, James] Inst Myeloma & Bone Canc Res, W Hollywood, CA USA. [Singhal, Seema] Robert H Lurie Canc Ctr, Chicago, IL USA. [Irwin, David] Alta Bates Canc Ctr, Berkeley, CA USA. [Williams, Stephanie F.] Hematol Oncol Associates Illinois, Chicago, IL USA. [Bensinger, William] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Badros, Ashraf Z.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Vescio, Robert] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Kenvin, Laurie; Yu, Zhinuan; Olesnyckyj, Marta; Zeldis, Jerome; Knight, Robert] Hoechst Celanese Corp, Summit, NJ 07901 USA. RP Richardson, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Dana 1B02, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu FU Celgene Corporation FX The authors gratefully acknowledge the work performed by individual research teams at all participating study sites; Caitlin Conant and Nicole Carreau for their administrative support with the paper; and a special thank you to all of our patients and their families for their participation.; This study was supported by research funding from Celgene Corporation. The authors received editorial support in the preparation of this paper funded by Celgene; the authors were fully responsible for all content and editorial decisions, and received no financial support or other form of compensation related to the development of the paper. NR 28 TC 84 Z9 87 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 23 PY 2009 VL 114 IS 4 BP 772 EP 778 DI 10.1182/blood-2008-12-196238 PG 7 WC Hematology SC Hematology GA 474BO UT WOS:000268257400010 PM 19471019 ER PT J AU Wang, QB Li, W Zhang, Y Yuan, X Xu, KX Yu, JD Chen, Z Beroukhim, R Wang, HY Lupien, M Wu, T Regan, MM Meyer, CA Carroll, JS Manrai, AK Janne, OA Balk, SP Mehra, R Han, B Chinnaiyan, AM Rubin, MA True, L Fiorentino, M Fiore, C Loda, M Kantoff, PW Liu, XS Brown, M AF Wang, Qianben Li, Wei Zhang, Yong Yuan, Xin Xu, Kexin Yu, Jindan Chen, Zhong Beroukhim, Rameen Wang, Hongyun Lupien, Mathieu Wu, Tao Regan, Meredith M. Meyer, Clifford A. Carroll, Jason S. Manrai, Arjun Kumar Janne, Olli A. Balk, Steven P. Mehra, Rohit Han, Bo Chinnaiyan, Arul M. Rubin, Mark A. True, Lawrence Fiorentino, Michelangelo Fiore, Christopher Loda, Massimo Kantoff, Philip W. Liu, X. Shirley Brown, Myles TI Androgen Receptor Regulates a Distinct Transcription Program in Androgen-Independent Prostate Cancer SO CELL LA English DT Article ID KALLIKREIN 2; HUMAN GENOME; HISTONE H3; CHIP-CHIP; CYCLIN-A; COMPLEX; PROGRESSION; EXPRESSION; SIGNATURES; MODEL AB The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth. C1 [Wang, Qianben; Xu, Kexin; Beroukhim, Rameen; Lupien, Mathieu; Fiorentino, Michelangelo; Fiore, Christopher; Loda, Massimo; Kantoff, Philip W.; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wu, Tao] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Wang, Qianben; Chen, Zhong] Ohio State Univ, Coll Med, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. [Wang, Qianben; Chen, Zhong] Ohio State Univ, Coll Med, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Li, Wei] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA. [Li, Wei] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Zhang, Yong; Regan, Meredith M.; Meyer, Clifford A.; Manrai, Arjun Kumar; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Zhang, Yong; Regan, Meredith M.; Meyer, Clifford A.; Manrai, Arjun Kumar; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Yuan, Xin; Wang, Hongyun; Balk, Steven P.] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Canc Biol Program, Boston, MA 02215 USA. [Yu, Jindan; Mehra, Rohit; Han, Bo; Chinnaiyan, Arul M.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Beroukhim, Rameen] Harvard & MIT, Broad Inst, Cambridge, MA 02139 USA. [Carroll, Jason S.] Cambridge Res Inst, Canc Res UK, Cambridge CB2 0RE, England. [Janne, Olli A.] Univ Helsinki, Inst Biomed Physiol, Biomedicum, FI-00014 Helsinki, Finland. [Rubin, Mark A.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10021 USA. [True, Lawrence] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. RP Wang, QB (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM qianben.wang@osumc.edu; xsliu@jimmy.harvard.edu; myles_brown@dfci.harvard.edu RI Li, Wei/A-8544-2009; Zhang, Yong/B-4838-2011; Wang, Qianben/E-4267-2011; Wu, Tao/C-7533-2013; OI Zhang, Yong/0000-0001-6316-2734; Brown, Myles/0000-0002-8213-1658; Rubin, Mark/0000-0002-8321-9950 FU National Institutes of Health [P50 CA090381, K99 CA126160, R01 HG004069, K99 CA129565]; The Prostate Cancer Foundation; Department of Defense [W81XWH-07-1-0037, PC080665] FX This work was supported by grants from National Institutes of Health (P50 CA090381 to M. B., K99 CA126160 to Q. W., and R01 HG004069 to X. S. L., and K99 CA129565 to J.Y., The Prostate Cancer Foundation (to M. B), and Department of Defense (W81XWH-07-1-0037 to X. S. L., and PC080665 to J.Y.). We thank Drs. Roland Schule for providing KDM1 constructs; and Michael Rape for UBE2C constructs. We also thank Drs. James DeCaprio, Gustavo Leone, Tim Huang, Yun Li, and Shengjun Ren for helpful discussions; and Dr. Chunpeng Zhang and Anna Rorick for technical assistance. NR 48 TC 418 Z9 428 U1 4 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 23 PY 2009 VL 138 IS 2 BP 245 EP 256 DI 10.1016/j.cell.2009.04.056 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474IM UT WOS:000268277000008 PM 19632176 ER PT J AU Kalaszczynska, I Geng, Y Iino, T Mizuno, SI Choi, Y Kondratiuk, I Silver, DP Wolgemuth, DJ Akashi, K Sicinski, P AF Kalaszczynska, Ilona Geng, Yan Iino, Tadafumi Mizuno, Shin-ichi Choi, Yoon Kondratiuk, Ilona Silver, Daniel P. Wolgemuth, Debra J. Akashi, Koichi Sicinski, Piotr TI Cyclin A Is Redundant in Fibroblasts but Essential in Hematopoietic and Embryonic Stem Cells SO CELL LA English DT Article ID DEPENDENT KINASES; C-MYC; EXPRESSION; PROGRESSION; GENE; MICE; MOUSE; PROLIFERATION; ACCUMULATION; PROGENITOR AB Cyclins are regulatory subunits of cyclin-dependent kinases. Cyclin A, the first cyclin ever cloned, is thought to be an essential component of the cell-cycle engine. Mammalian cells encode two A-type cyclins, testis-specific cyclin A1 and ubiquitously expressed cyclin A2. Here, we tested the requirement for cyclin A function using conditional knockout mice lacking both A-type cyclins. We found that acute ablation of cyclin A in fibroblasts did not affect cell proliferation, but led to prolonged expression of another cyclin, cyclin E, across the cell cycle. However, combined ablation of all A- and E-type cyclins extinguished cell division. In contrast, cyclin A function was essential for cell-cycle progression of hematopoietic and embryonic stem cells. Expression of cyclin A is particularly high in these compartments, which might render stem cells dependent on cyclin A, whereas in fibroblasts cyclins A and E play redundant roles in cell proliferation. C1 [Kalaszczynska, Ilona; Geng, Yan; Choi, Yoon; Kondratiuk, Ilona; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Iino, Tadafumi; Mizuno, Shin-ichi; Akashi, Koichi] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Silver, Daniel P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kalaszczynska, Ilona; Geng, Yan; Iino, Tadafumi; Mizuno, Shin-ichi; Choi, Yoon; Kondratiuk, Ilona; Akashi, Koichi; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Silver, Daniel P.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Wolgemuth, Debra J.] Columbia Univ, Ctr Med, Dept Genet & Dev, New York, NY 10032 USA. [Wolgemuth, Debra J.] Columbia Univ, Ctr Med, Dept Obstet & Gynecol, New York, NY 10032 USA. RP Sicinski, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM peter_sicinski@dfci.harvard.edu OI Kalaszczynska, Ilona/0000-0001-6698-1372 FU National Institutes of Health [R01CA132740, R01CA108950, R01 HD34915] FX We thank members of the Sicinski lab, R. Bronson, E. Sicinska, M. A. Ciemerych-Litwinienko, A. Minamishima, S. Kobayashi, and B. Will for help and advice, B. Clurman for anti-cyclin E1 antibody, and F. Liu for anti-phospho Smad3 antibodies. This work was supported by R01CA132740 and R01CA108950 grants from the National Institutes of Health (to P. S.) and R01 HD34915 (to D. J. W.). P. S. is a Scholar of The Leukemia and Lymphoma Society. NR 48 TC 101 Z9 104 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 23 PY 2009 VL 138 IS 2 BP 352 EP 365 DI 10.1016/j.cell.2009.04.062 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474IM UT WOS:000268277000016 PM 19592082 ER PT J AU Vlopp, KG Das, A AF Vlopp, Kevin G. Das, Anup TI Comparative Effectiveness - Thinking beyond Medication A versus Medication B SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SMOKING-CESSATION C1 [Vlopp, Kevin G.; Das, Anup] Univ Penn, Philadelphia, PA 19104 USA. [Vlopp, Kevin G.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Vlopp, KG (reprint author), Univ Penn, Philadelphia, PA 19104 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 23 PY 2009 VL 361 IS 4 BP 331 EP 333 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 473DC UT WOS:000268184500003 ER PT J AU Plotkin, SR Stemmer-Rachamimov, AO Barker, FG Halpin, C Padera, TP Tyrrell, A Sorensen, AG Jain, RK di Tomaso, E AF Plotkin, Scott R. Stemmer-Rachamimov, Anat O. Barker, Fred G., II Halpin, Chris Padera, Timothy P. Tyrrell, Alex Sorensen, A. Gregory Jain, Rakesh K. di Tomaso, Emmanuelle TI Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; FACIAL-NERVE FUNCTION; PHASE-II TRIAL; VESTIBULAR-SCHWANNOMA; TUMOR VASCULATURE; ACOUSTIC NEUROMAS; KINASE INHIBITOR; ANGIOGENESIS; EXPRESSION; MANAGEMENT AB Background Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. Methods We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. Results VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. Conclusions VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas. C1 [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat O.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Padera, Timothy P.; Tyrrell, Alex; Jain, Rakesh K.; di Tomaso, Emmanuelle] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. [Sorensen, A. Gregory] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Halpin, Chris] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Dept Neurol, Yawkey 9E,55 Fruit St, Boston, MA 02114 USA. EM splotkin@partners.org RI Tyrrell, James/A-6359-2010; OI Padera, Timothy/0000-0002-3453-9384 FU Harvard Medical School Center for Neurofibromatosis and Allied Disorders; Neurofibromatosis, Inc., New England; Children's Tumor Foundation [NF050202]; Neurofibromatosis Research Program of the Department of Defense [P01NS024279, P01CA80124]; National Institutes of Health; Federal Share/National Cancer Institute Proton Beam Program FX Supported by the Harvard Medical School Center for Neurofibromatosis and Allied Disorders; Neurofibromatosis, Inc., New England; the Children's Tumor Foundation; a grant (NF050202, to Dr. Plotkin) from the Neurofibromatosis Research Program of the Department of Defense; a Claflin Award (to Dr. di Tomaso); grants (P01NS024279, to Dr. Stemmer- Rachamimov; and P01CA80124, to Dr. Jain) from the National Institutes of Health; and grants from the Federal Share/National Cancer Institute Proton Beam Program (to Drs. di Tomaso and Jain). NR 30 TC 166 Z9 168 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 23 PY 2009 VL 361 IS 4 BP 358 EP 367 DI 10.1056/NEJMoa0902579 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 473DC UT WOS:000268184500006 PM 19587327 ER PT J AU Somers, MJG Sharma, A Grant, PE Guimaraes, AR Schneeberger, EE AF Somers, Michael J. G. Sharma, Amita Grant, P. Ellen Guimaraes, Alexander R. Schneeberger, Eveline E. TI A Boy with Headache, Nausea, Seizures, and Hypertension Atypical hemolytic-uremic syndrome with complement factor H mutation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CRESCENTIC GLOMERULONEPHRITIS; THROMBOTIC MICROANGIOPATHY; THROMBOCYTOPENIC PURPURA; MALIGNANT HYPERTENSION; CHILDREN; SURFACE C1 [Somers, Michael J. G.] Childrens Hosp, Div Nephrol, Boston, MA 02115 USA. [Sharma, Amita] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Grant, P. Ellen; Guimaraes, Alexander R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Schneeberger, Eveline E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Somers, Michael J. G.; Sharma, Amita] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Grant, P. Ellen; Guimaraes, Alexander R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Schneeberger, Eveline E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Somers, MJG (reprint author), Childrens Hosp, Div Nephrol, Boston, MA 02115 USA. FU AstraZeneca FX Dr. Guimaraes reports receiving grant support from AstraZeneca. No other potential conflict of interest relevant to this article was reported. NR 25 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 23 PY 2009 VL 361 IS 4 BP 389 EP 400 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 473DC UT WOS:000268184500011 PM 19625720 ER PT J AU Budin, I Bruckner, RJ Szostak, JW AF Budin, Itay Bruckner, Raphael J. Szostak, Jack W. TI Formation of Protocell-like Vesicles in a Thermal Diffusion Column SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TEMPERATURE; SEPARATION C1 [Budin, Itay; Bruckner, Raphael J.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Budin, Itay; Bruckner, Raphael J.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. [Budin, Itay] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Bruckner, Raphael J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU Harvard Origins Initiative [EXB02-0031-0018] FX R.J.B. was supported by a fellowship from the Harvard Origins Initiative. This work was supported in part by Grant EXB02-0031-0018 from the NASA Exobiology Program. J.W.S. is an Investigator of the Howard Hughes Medical Institute. The authors thank Dr. H. Stone, Dr. J. Higgins, and S. Tobe for helpful discussions and Dr. A. Ricardo, M. Elenko. T. Zhu. and Q. Dufton for comments on the manuscript. NR 13 TC 54 Z9 56 U1 5 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 22 PY 2009 VL 131 IS 28 BP 9628 EP 9629 DI 10.1021/ja9029818 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 475XG UT WOS:000268399800014 PM 19601679 ER PT J AU Volberding, P AF Volberding, Paul TI Cohorts, Trials, and Evidence: Expanding Our Confidence in Guidelines for Antiretroviral Resistance Testing SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID HIV-INFECTED PATIENTS; SOCIETY-USA PANEL; 2008 RECOMMENDATIONS; DRUG-RESISTANCE; THERAPY C1 [Volberding, Paul] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Volberding, Paul] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Volberding, P (reprint author), Vet Affairs Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM paul.volberding@med.va.gov NR 13 TC 1 Z9 1 U1 0 U2 1 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 JUL 21 PY 2009 VL 151 IS 2 BP 135 EP 136 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 478RH UT WOS:000268605300008 PM 19620166 ER PT J AU Schlueter, PJ Peterson, RT AF Schlueter, Peter J. Peterson, Randall T. TI Systematizing Serendipity for Cardiovascular Drug Discovery SO CIRCULATION LA English DT Article ID ZINC-FINGER NUCLEASES; EMBRYONIC STEM-CELLS; SMALL MOLECULES; GENE-EXPRESSION; IN-VIVO; CAENORHABDITIS-ELEGANS; TRANSGENIC ZEBRAFISH; CHEMICAL GENETICS; SIGNALING PATHWAY; CONNECTIVITY MAP C1 [Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Broad Inst, Cambridge, MA USA. RP Peterson, RT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM peterson@cvrc.mgh.harvard.edu FU NHLBI NIH HHS [T32 HL007208-32, R01 HL079267, T32 HL07208, R01 HL079267-03, T32 HL007208] NR 82 TC 6 Z9 6 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 JUL 21 PY 2009 VL 120 IS 3 BP 255 EP 263 DI 10.1161/CIRCULATIONAHA.108.824177 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 472EA UT WOS:000268110900011 PM 19620524 ER PT J AU Pagani, FD Miller, LW Russell, SD Aaronson, KD John, R Boyle, AJ Conte, JV Bogaev, RC MacGillivray, TE Naka, Y Mancini, D Massey, HT Chen, L Klodell, CT Aranda, JM Moazami, N Ewald, GA Farrar, DJ Frazier, OH AF Pagani, Francis D. Miller, Leslie W. Russell, Stuart D. Aaronson, Keith D. John, Ranjit Boyle, Andrew J. Conte, John V. Bogaev, Roberta C. MacGillivray, Thomas E. Naka, Yoshifumi Mancini, Donna Massey, H. Todd Chen, Leway Klodell, Charles T. Aranda, Juan M. Moazami, Nader Ewald, Gregory A. Farrar, David J. Frazier, O. Howard CA HeartMate II Investigators TI Extended Mechanical Circulatory Support With a Continuous-Flow Rotary Left Ventricular Assist Device SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE heart failure; left ventricular assist device; heart transplantation ID AWAITING HEART-TRANSPLANTATION; DESTINATION THERAPY; CLINICAL-TRIAL; BLOOD-PUMPS; SYSTEM; BRIDGE; RELIABILITY; CANDIDATES AB Objectives This study sought to evaluate the use of a continuous-flow rotary left ventricular assist device (LVAD) as a bridge to heart transplantation. Background LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. Methods In a prospective, multicenter study, 281 patients urgently listed (United Network of Organ Sharing status 1A or 1B) for heart transplantation underwent implantation of a continuous-flow LVAD. Survival and transplantation rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. Results Of 281 patients, 222 (79%) underwent transplantation, LVAD removal for cardiac recovery, or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval: 65% to 79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-min walk test (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-min walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. Conclusions A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplantation, with improved functional status and quality of life. (Thoratec HeartMate II Left Ventricular Assist System [LVAS] for Bridge to Cardiac Transplantation; NCT00121472) (J Am Coll Cardiol 2009; 54: 312-21) (C) 2009 by the American College of Cardiology Foundation C1 [Pagani, Francis D.; Aaronson, Keith D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Miller, Leslie W.] Washington Hosp Ctr, Washington, DC 20010 USA. [Russell, Stuart D.; Conte, John V.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [John, Ranjit; Boyle, Andrew J.] Univ Minnesota, Minneapolis, MN USA. [Bogaev, Roberta C.; Frazier, O. Howard] Texas Heart Inst, Houston, TX 77025 USA. [MacGillivray, Thomas E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Naka, Yoshifumi; Mancini, Donna] Columbia Univ, New York, NY USA. [Massey, H. Todd; Chen, Leway] Univ Rochester, Rochester, NY USA. [Klodell, Charles T.; Aranda, Juan M.] Univ Florida, Gainesville, FL USA. [Moazami, Nader; Ewald, Gregory A.] Barnes Jewish Hosp, St Louis, MO 63110 USA. [Farrar, David J.] Thoratec Corp, Pleasanton, CA USA. RP Pagani, FD (reprint author), Univ Michigan Hlth Syst, Sect Cardiac Surg, Ctr Cardiovasc, Room 5161,1500 E Med Ctr Dr,SPC 5864, Ann Arbor, MI 48109 USA. EM fpagani@umich.edu NR 24 TC 452 Z9 457 U1 2 U2 18 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 JUL 21 PY 2009 VL 54 IS 4 BP 312 EP 321 DI 10.1016/j.jacc.2009.03.055 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 471AW UT WOS:000268025200004 PM 19608028 ER PT J AU Barnes, DE Covinsky, KE Whitmer, RA Kuller, LH Lopez, OL Yaffe, K AF Barnes, D. E. Covinsky, K. E. Whitmer, R. A. Kuller, L. H. Lopez, O. L. Yaffe, K. TI Predicting risk of dementia in older adults The late-life dementia risk index SO NEUROLOGY LA English DT Article ID CARDIOVASCULAR HEALTH COGNITION; INCIDENT ALZHEIMER-DISEASE; PROGNOSTIC INDEX; BREAST-CANCER; PREVALENCE; VALIDATION; MORTALITY; PEOPLE; SCORE AB Objective: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years. Methods: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients. Results: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), >= 1 apolipoprotein E epsilon 4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores. Conclusions: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals. Neurology (R) 2009; 73: 173-179 C1 [Barnes, D. E.; Yaffe, K.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Covinsky, K. E.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Yaffe, K.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, K.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA USA. [Barnes, D. E.; Covinsky, K. E.; Whitmer, R. A.; Yaffe, K.] Kaiser Div Res, Oakland, CA USA. [Kuller, L. H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Lopez, O. L.] Univ Pittsburgh, Dept Neurol & Psychiat, Pittsburgh, PA 15260 USA. RP Barnes, DE (reprint author), Univ Calif San Francisco, Dept Psychiat, 4150 Clement St,151R, San Francisco, CA 94121 USA. EM Deborah.Barnes@ucsf.edu FU National Heart, Lung, and Blood Institute [N01-HC85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295]; National Institute on Aging [AG15928]; National Institute of Neurological Disorders and Stroke; NIH [K01 AG024069]; NIH/NCRR [UL1 RR024131] FX The research reported in this article was supported by contracts N01-HC85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, grant U01 HL080295 from the National Heart, Lung, and Blood Institute, and grant AG15928 from the National Institute on Aging with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. Dr. Barnes is funded through a K01 Career Development Award (K01 AG024069) from the NIH. This project also was supported by NIH/NCRR UCSF-CTSI grant UL1 RR024131. The Biostatistics, Research Design, Ethics and Data Management program of UCSF's Clinical and Translational Sciences Institute (NIH/NCRR UCSF-CTSI grant UL1 RR024131) provided preliminary data analyses and statistical advice. NR 35 TC 86 Z9 88 U1 2 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 JUL 21 PY 2009 VL 73 IS 3 BP 173 EP 179 DI 10.1212/WNL.0b013e3181a81636 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 472QO UT WOS:000268147100004 PM 19439724 ER PT J AU Paganetti, H AF Paganetti, Harald TI Dose to water versus dose to medium in proton beam therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MONTE-CARLO SIMULATIONS; STOPPING POWERS; CT NUMBERS; NUCLEAR-INTERACTIONS; HOUNSFIELD UNITS; CROSS-SECTIONS; DISTRIBUTIONS; DOSIMETRY; ENERGY; VERIFICATION AB Dose in radiation therapy is traditionally reported as the water-equivalent dose, or dose to water. Monte Carlo dose calculations report dose to medium and thus a methodology is needed to convert dose to medium into dose to water (or vice versa) for comparison of Monte Carlo results with results from planning systems. This paper describes the development of a formalism to convert dose to medium into dose to water for proton fields when simulating the dose with Monte Carlo techniques. The conversion is based on relative stopping power but also considers energy transferred via nuclear interactions. The influence of different interaction mechanisms of proton beams (electromagnetic versus nuclear) is demonstrated. Further, an approximate method for converting doses retroactively is presented. Based on the outlined formalism, five proton therapy patients with a total of 33 fields were analyzed. Dose distributions, dose volume histograms and absolute doses to assess the clinical significance of differences between dose to medium and dose to water are presented. We found that the difference between the two dose reporting definitions can be up to 10% for high CT numbers if analyzing the mean dose to the target. The difference is clinically insignificant for soft tissues. For the structures analyzed, the mean dose to water could be converted to dose to medium by applying a correction factor increasing linearly with increasing average CT number in the volume. We determined that an approximate conversion method, done retroactively with an energy-independent stopping power ratio and without considering nuclear interaction events separately (as compared to on-the-fly conversion during simulation), is sufficiently accurate to compute mean doses. It is insufficient, however, when analyzing the beam range. For proton beams stopping in bony anatomy, the predicted beam range can differ by 2-3 mm when comparing dose to tissue and dose to water. C1 [Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Paganetti, Harald] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Paganetti, H (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM hpaganetti@partners.org FU [NIH/NCI6-PO1 CA 21239] FX This work was supported by NIH/NCI6-PO1 CA 21239 ('Proton Therapy Research'). NR 32 TC 42 Z9 43 U1 0 U2 10 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 21 PY 2009 VL 54 IS 14 BP 4399 EP 4421 DI 10.1088/0031-9155/54/14/004 PG 23 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 467VB UT WOS:000267770100004 PM 19550004 ER PT J AU Seco, J Robertson, D Trofimov, A Paganetti, H AF Seco, Joao Robertson, Daniel Trofimov, Alexei Paganetti, Harald TI Breathing interplay effects during proton beam scanning: simulation and statistical analysis SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID ORGAN MOTION; IMRT TREATMENTS; RADIOTHERAPY; LUNG AB Treatment delivery with active beam scanning in proton radiation therapy introduces the problem of interplay effects when pencil beam motion occurs on a similar time scale as intra-fractional tumor motion. In situations where fractionation may not provide enough repetition to blur the effects of interplay, repeated delivery or 'repainting' of each field several times within a fraction has been suggested. The purpose of this work was to investigate the effectiveness of different repainting strategies in proton beam scanning. To assess the dosimetric impact of interplay effects, we performed a series of simulations considering the following parameters: tumor motion amplitude, breathing period, asymmetry in the motion trajectory for the target and time required to change the beam energy for the delivery system. Several repainting strategies were compared in terms of potential vulnerability to a dose delivery error. Breathing motion perpendicular to the beam direction (representing superior-inferior type tumor motion in patients) was considered and modeled as an asymmetric sine function with a peak-to-peak amplitude of between 10 and 30 mm. The results show that motion effects cause a narrowing of the high-dose profile and widening of the penumbra. The 90% isodose area was reduced significantly when considering a large motion amplitude of 3 cm. The broadening of the penumbra appears to depend only on the amplitude of tumor motion (assuming harmonic motion). The delivered dose exhibits a shift of 10-15% of the tumor amplitude (or 1-5 mm) in the caudal direction due to breathing asymmetry observed for both sin(4)(x) and sin(6)(x) motion. Of the five repainting techniques studied, so-called 'breath sampling' turned out to be most effective in reducing dose errors with a minimal increase in treatment time. In this method, each energy level is repainted at several evenly spaced times within one breathing period. To keep dose delivery errors below 5% while minimizing treatment time, it is recommended that breath sampling repainting be employed using 5-10 paintings per field for an assumed tumor volume of 8.5 x 8.5 x 10 cm(3).For smaller tumor volumes more repaintings will be required, while for larger volumes five repaintings should be sufficient to achieve the required dose accuracy. C1 [Seco, Joao; Robertson, Daniel; Trofimov, Alexei; Paganetti, Harald] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Seco, Joao; Robertson, Daniel; Trofimov, Alexei; Paganetti, Harald] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Robertson, Daniel] Brigham Young Univ, Dept Phys & Astron, Provo, UT 84602 USA. RP Seco, J (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. RI Seco, Joao/J-4451-2012 FU NIH [P01 CA021239- 29A1]; American Association of Physicists in Medicine (AAPM) FX This work was sponsored by NIH grant P01 CA021239- 29A1. One of the authors (DR) was supported by the Summer Undergraduate Fellowship Program of the American Association of Physicists in Medicine (AAPM). NR 14 TC 54 Z9 56 U1 0 U2 10 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 21 PY 2009 VL 54 IS 14 BP N283 EP N294 DI 10.1088/0031-9155/54/14/N01 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 467VB UT WOS:000267770100016 PM 19550002 ER PT J AU Britschgi, M Olin, CE Johns, HT Takeda-Uchimura, Y LeMieux, MC Rufibach, K Rajadas, J Zhang, H Tomooka, B Robinson, WH Clark, CM Fagan, AM Galasko, DR Holtzman, DM Jutel, M Kaye, JA Lemere, CA Leszek, J Li, G Peskind, ER Quinn, JF Yesavage, JA Ghiso, JA Wyss-Coray, T AF Britschgi, M. Olin, C. E. Johns, H. T. Takeda-Uchimura, Y. LeMieux, M. C. Rufibach, K. Rajadas, J. Zhang, H. Tomooka, B. Robinson, W. H. Clark, C. M. Fagan, A. M. Galasko, D. R. Holtzman, D. M. Jutel, M. Kaye, J. A. Lemere, C. A. Leszek, J. Li, G. Peskind, E. R. Quinn, J. F. Yesavage, J. A. Ghiso, J. A. Wyss-Coray, T. TI Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID A-BETA ANTIBODIES; MOUSE MODEL; IN-VITRO; PROTEIN; AUTOANTIBODIES; OLIGOMERS; PLAQUES; IMMUNOTHERAPY; MICROARRAYS; DEPOSITION AB A number of distinct beta-amyloid (A beta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural A beta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic A beta and amyloidogenic non-A beta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of A beta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of A beta 1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant A beta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from A beta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with A beta the monkeys developed high titers not only against A beta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of A beta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD. C1 [Britschgi, M.; Olin, C. E.; Johns, H. T.; Takeda-Uchimura, Y.; Rajadas, J.; Zhang, H.; Yesavage, J. A.; Wyss-Coray, T.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [LeMieux, M. C.] Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA. [Rufibach, K.] Univ Zurich, Biostat Unit, Inst Social & Prevent Med, CH-8001 Zurich, Switzerland. [Robinson, W. H.; Yesavage, J. A.; Wyss-Coray, T.] Vet Affairs Palo Alto Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Palo Alto, CA 94304 USA. [Clark, C. M.] Univ Penn, Alzheimers Dis Ctr, Dept Neurol, Philadelphia, PA 19104 USA. [Clark, C. M.] Univ Penn, Inst Aging, Philadelphia, PA 19104 USA. [Fagan, A. M.; Holtzman, D. M.] Washington Univ, Dept Neurol, St Louis, MO 63110 USA. [Galasko, D. R.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Jutel, M.] Wroclaw Med Univ, Dept Internal Med & Allergol, PL-50417 Wroclaw, Poland. [Kaye, J. A.; Quinn, J. F.] Oregon Hlth & Sci Univ, Layton Aging & Alzheimers Dis Ctr, Portland, OR 97201 USA. [Lemere, C. A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Lemere, C. A.] Harvard Univ, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Leszek, J.] Wroclaw Med Univ, Dept Psychiat, PL-51622 Wroclaw, Poland. [Li, G.; Peskind, E. R.] Univ Washington, Alzheimers Dis Res Ctr, Seattle, WA 98108 USA. [Li, G.; Peskind, E. R.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Ghiso, J. A.] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10016 USA. [Ghiso, J. A.] NYU, Langone Med Ctr, Dept Psychiat, New York, NY 10016 USA. RP Wyss-Coray, T (reprint author), Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. EM twc@stanford.edu RI Rufibach, Kaspar/F-1163-2010 OI Kaye, Jeffrey/0000-0002-9971-3478; FU John Douglas French Alzheimer's Foundation; Department of Veterans Affairs; National Institute on Aging [AG20603, AG10491, AG030539, P50 AG005136, AG08017] FX We thank the patients who participated in this study; M. BenBarak and P. Chandra for assistance with the peptide array; J. Frost for technical assistance with the vervet samples; R. Palmour and F. Ervin for housing the vervets at the Behavioral Science Foundation, St. Kitts, Eastern Caribbean, and numerous unnamed staff at our institutions for their effort in patient recruitment, clinical assessment, and sample preparation. This work was supported by the John Douglas French Alzheimer's Foundation (T. W.-C.), the Department of Veterans Affairs (T. W.-C., E. R. P., G. L., and J. A. Y.), and National Institute on Aging Grants AG20603 (to T. W.-C.), AG10491, AG030539 (to J. A. G.), P50 AG005136 (to E. R. P.), and AG08017 (to J. F. Q. and J. A. K.). NR 62 TC 88 Z9 89 U1 2 U2 11 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 JUL 21 PY 2009 VL 106 IS 29 BP 12145 EP 12150 DI 10.1073/pnas.0904866106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 473BI UT WOS:000268178400059 PM 19581601 ER PT J AU Cheng, HL Liu, PX Wang, ZGC Zou, LH Santiago, S Garbitt, V Gjoerup, OV Iglehart, JD Miron, A Richardson, AL Hahn, WC Zhao, JJ AF Cheng, Hailing Liu, Pixu Wang, Zhigang C. Zou, Lihua Santiago, Stephanie Garbitt, Victoria Gjoerup, Ole V. Iglehart, J. Dirk Miron, Alexander Richardson, Andrea L. Hahn, William C. Zhao, Jean J. TI SIK1 Couples LKB1 to p53-Dependent Anoikis and Suppresses Metastasis SO SCIENCE SIGNALING LA English DT Article ID FOCAL ADHESION KINASE; MAMMARY EPITHELIAL-CELLS; HUMAN BREAST-CANCER; PROTEIN-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; HEPATOCELLULAR-CARCINOMA; SURVIVAL SIGNALS; P53; APOPTOSIS; TUMOR AB Resistance to anoikis, the subtype of apoptosis triggered by lack of adhesion, contributes to malignant transformation and the development of metastasis. Although several lines of evidence suggest that p53 plays a critical role in anoikis, the pathway(s) that connect cell detachment to p53 remain undefined. Here, through the use of a kinome-wide loss-of-function screen, we identify the serine-threonine kinase SIK1 (salt-inducible kinase 1) as a regulator of p53-dependent anoikis. Inactivation of SIK1 compromised p53 function in anoikis and allowed cells to grow in an anchorage-independent manner. In vivo, SIK1 loss facilitated metastatic spread and survival of disseminated cells as micrometastases in lungs. The presence of functional SIK1 was required for the activity of the kinase LKB1 in promoting p53-dependent anoikis and suppressing anchorage-independent growth, Matrigel invasion, and metastatic potential. In human cancers, decreased expression of the gene encoding SIK1 closely correlated with development of distal metastases in breast cancers from three independent cohorts. Together, these findings indicate that SIK1 links LKB1 to p53-dependent anoikis and suppresses metastasis. C1 [Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cheng, Hailing; Liu, Pixu; Wang, Zhigang C.; Zou, Lihua; Santiago, Stephanie; Garbitt, Victoria; Iglehart, J. Dirk; Miron, Alexander; Richardson, Andrea L.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Cheng, Hailing; Liu, Pixu; Santiago, Stephanie; Garbitt, Victoria; Zhao, Jean J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Wang, Zhigang C.; Zou, Lihua; Iglehart, J. Dirk; Miron, Alexander; Richardson, Andrea L.; Zhao, Jean J.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Gjoerup, Ole V.] Univ Pittsburgh, Inst Canc, Mol Virol Program, Pittsburgh, PA 15213 USA. [Hahn, William C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Hahn, William C.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Hahn, William C.] MIT, Cambridge, MA 02142 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu; jean_zhao@dfci.harvard.edu FU NCI NIH HHS [R01 CA134502, BC051565, P50 CA089393, P50 CA089393-09, R01 CA134502-02]; PHS HHS [W81XWH-07-1-0408] NR 71 TC 59 Z9 62 U1 2 U2 11 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 JUL 21 PY 2009 VL 2 IS 80 AR ra35 DI 10.1126/scisignal.2000369 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 569MK UT WOS:000275601000004 PM 19622832 ER PT J AU Zhang, P Cantiello, HF AF Zhang, Peng Cantiello, Horacio F. TI Measurement of charge distribution in actin bundles by surface potential microscopy SO APPLIED PHYSICS LETTERS LA English DT Article DE atomic force microscopy; bioelectric potentials; biological techniques; feature extraction; gold; image segmentation; molecular biophysics; proteins; surface potential ID ELECTROSTATIC FORCE MICROSCOPY; F-ACTIN; FILAMENTS AB Bundles of filamentous actin (F-actin) deposited on a gold-plated surface were concurrently imaged using atomic force microscopy (AFM) and surface potential microscopy (SPM). The surface potential was mapped as a function of tip distance to surface using a constant bias potential. There was an uneven spatial distribution of charges detected by SPM, consistent with the segmented topological features shown by AFM of the actin bundles. SPM analysis showed localized changes in surface potential between the axial and transversal sections of the bundles, which are consistent with nonuniform charge distributions of adsorbed salt ions on F-actin. C1 [Zhang, Peng] Massachusetts Gen Hosp, Nephrol Div & Electrophysiol Core, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Zhang, P (reprint author), Massachusetts Gen Hosp, Nephrol Div & Electrophysiol Core, 149 13th St, Charlestown, MA 02129 USA. EM cantiello@helix.mgh.harvard.edu NR 21 TC 6 Z9 6 U1 0 U2 6 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD JUL 20 PY 2009 VL 95 IS 3 AR 033701 DI 10.1063/1.3167281 PG 3 WC Physics, Applied SC Physics GA 475ZA UT WOS:000268405300089 ER PT J AU Lang, JE Magbanua, MJM Scott, JH Makrigiorgos, GM Wang, G Federman, S Esserman, LJ Park, JW Haqq, CM AF Lang, Julie E. Magbanua, Mark Jesus M. Scott, Janet H. Makrigiorgos, G. Mike Wang, Gang Federman, Scot Esserman, Laura J. Park, John W. Haqq, Christopher M. TI A comparison of RNA amplification techniques at sub-nanogram input concentration SO BMC GENOMICS LA English DT Article ID GENE-EXPRESSION PROFILES; BREAST-CANCER; LINEAR AMPLIFICATION; NANOGRAM AMOUNTS; MESSENGER-RNA; MICROARRAY EXPERIMENTS; CDNA MICROARRAYS; PATTERNS; BIOPSIES; SAMPLES AB Background: Gene expression profiling of small numbers of cells requires high-fidelity amplification of sub-nanogram amounts of RNA. Several methods for RNA amplification are available; however, there has been little consideration of the accuracy of these methods when working with very low-input quantities of RNA as is often required with rare clinical samples. Starting with 250 picograms-3.3 nanograms of total RNA, we compared two linear amplification methods 1) modified T7 and 2) Arcturus RiboAmp HS and a logarithmic amplification, 3) Balanced PCR. Microarray data from each amplification method were validated against quantitative real-time PCR (QPCR) for 37 genes. Results: For high intensity spots, mean Pearson correlations were quite acceptable for both total RNA and low-input quantities amplified with each of the 3 methods. Microarray filtering and data processing has an important effect on the correlation coefficient results generated by each method. Arrays derived from total RNA had higher Pearson's correlations than did arrays derived from amplified RNA when considering the entire unprocessed dataset, however, when considering a gene set of high signal intensity, the amplified arrays had superior correlation coefficients than did the total RNA arrays. Conclusion: Gene expression arrays can be obtained with sub-nanogram input of total RNA. High intensity spots showed better correlation on array-array analysis than did unfiltered data, however, QPCR validated the accuracy of gene expression array profiling from low-input quantities of RNA with all 3 amplification techniques. RNA amplification and expression analysis at the sub-nanogram input level is both feasible and accurate if data processing is used to focus attention to high intensity genes for microarrays or if QPCR is used as a gold standard for validation. C1 [Lang, Julie E.; Esserman, Laura J.] Univ Calif San Francisco, Dept Surg, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Magbanua, Mark Jesus M.; Scott, Janet H.; Federman, Scot; Park, John W.; Haqq, Christopher M.] Univ Calif San Francisco, Dept Med Oncol, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Haqq, Christopher M.] Univ Calif San Francisco, Dept Urol, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Makrigiorgos, G. Mike; Wang, Gang] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lang, Julie E.] Univ Arizona, Arizona Canc Ctr, Dept Surg, Tucson, AZ 85724 USA. RP Lang, JE (reprint author), Univ Calif San Francisco, Dept Surg, Ctr Comprehens Canc, 1500 Divisadero St, San Francisco, CA 94143 USA. EM jlang@azcc.arizona.edu; mmmagbanua@cc.ucsf.edu; jscott@cc.ucsf.edu; mmakrigiorgos@lroc.harvard.edu; gwang@lroc.harvard.edu; sfederman@cc.ucsf.edu; laura.esserman@ucsfmedctr.org; jpark@cc.ucsf.edu; chaqq@cougarbiotechnology.com FU National Cancer Institute [P50 CA89520, R01 CA101042-01]; NCI; UC Discovery [S97-49, 99-10055]; DOD [BC020504] FX Research was supported by National Cancer Institute Grants P50 CA89520, R01 CA101042-01 and NCI Interdisciplinary Research Teams for Molecular Target Assessment (U54 CA90788); UC Discovery (S97-49, 99-10055); and a gift from Bank of the West. G. M. M was supported by DOD grant BC020504. We wish to thank Dr. Joe De Risi (UCSF) for providing protocols and training to our group. We acknowledge Daniel B. Khodabakhsh and Julia Crothers (UCSF) for their contributions. We wish to thank Pamela Derrish (UCSF) for her editorial assistance. Many thanks to Dr. George Watts (University of Arizona Genomics Core) for advice in preparation of this manuscript. NR 35 TC 14 Z9 15 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 20 PY 2009 VL 10 AR 326 DI 10.1186/1471-2164-10-326 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 490NN UT WOS:000269507800001 PM 19619282 ER PT J AU Harris, LN Broadwater, G Abu-Khalaf, M Cowan, D Thor, AD Budman, D Cirrincione, CT Berry, DA Winer, EP Hudis, CA Hayes, DF Friedman, P Ellis, M Dressler, L AF Harris, Lyndsay N. Broadwater, Gloria Abu-Khalaf, Maysa Cowan, David Thor, Ann D. Budman, Daniel Cirrincione, Constance T. Berry, Donald A. Winer, Eric P. Hudis, Clifford A. Hayes, Daniel F. Friedman, Paula Ellis, Matthew Dressler, Lynn TI Topoisomerase II alpha Amplification Does Not Predict Benefit From Dose-Intense Cyclophosphamide, Doxorubicin, and Fluorouracil Therapy in HER2-Amplified Early Breast Cancer: Results of CALGB 8541/150013 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TRIAL COMPARING DOXORUBICIN; IN-SITU HYBRIDIZATION; ADJUVANT CHEMOTHERAPY; PROTEIN OVEREXPRESSION; GENE AMPLIFICATION; ERBB-2; SENSITIVITY; ACTIVATION; HER2; METHOTREXATE AB Purpose We have demonstrated that patients with HER2-amplified tumors derive more benefit from higher doses of doxorubicin-containing chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil [CAF]). Because topoisomerase II alpha(Topo-II alpha) is a target for doxorubicin and is coamplified in 20% to 50% of HER2-amplified tumors, we postulated that Topo-II alpha copy number might account for the benefit from CAF dose escalation in HER2-positive tumors. To address this hypothesis, we examined Topo-II alpha and HER2 copy number, CAF dose, and clinical outcomes in Cancer and Leukemia Group B (CALGB) 8541. Patients and Methods Topo-II alpha and HER2 copy number were measured by fluorescent in situ hybridization (FISH) using a triple-probe system, which includes Topo-II alpha, HER2, and chromosome 17 (CEP17). Topo-II alpha and/or HER2 were classified as amplified (>= two copies/CEP17, deleted (<= 0.67 copies/CEP17) and normal copy number (> .67 to < 2.0 copies/CEP17). Results Topo-II alpha/HER2/CEP17 measurement was successful in 624 of 687 cases. HER2 was amplified in 117 cases (19%). Topo-II alpha was amplified in 41 cases (7%) and deleted in 69 cases (11%). Topo-II alpha amplification was highly correlated with HER2 amplification (39 of 41; P < .0001), HER2 by immunohistochemistry, and by dual-probe FISH. Topo-II alpha was deleted in both the HER2-amplified (30 of 69; 43%), normal (22 of 69; 32%) and HER2-deleted tumors (17 of 69; 25%). Although Topo-II alpha-amplified tumors were nearly always HER2 amplified, these tumors did not receive benefit from increasing the dose of CAF (P = .15). Conclusion The correlative companion study CALGB 8541-150013 does not support the hypothesis that Topo-II alpha amplification is the mechanism behind benefit from increased dose of anthracyclines in HER2-positive breast cancer. C1 Yale Canc Ctr, New Haven, CT USA. Univ N Carolina, Chapel Hill, NC USA. Duke Univ, Durham, NC 27706 USA. Univ Colorado, Denver, CO 80202 USA. N Shore Hosp Ctr, Long Isl City, NY 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. Univ Michigan, Ann Arbor, MI 48109 USA. Cent Off, Canc & Leukemia Grp B, Chicago, IL USA. Washington Univ, St Louis, MO USA. RP Harris, LN (reprint author), Yale Univ, 333 Cedar St,WWW 213, New Haven, CT 06850 USA. EM lyndsay.harris@yale.edu FU NCI NIH HHS [P30 CA016672] NR 34 TC 34 Z9 36 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2009 VL 27 IS 21 BP 3430 EP 3436 DI 10.1200/JCO.2008.18.4085 PG 7 WC Oncology SC Oncology GA 471II UT WOS:000268049100006 PM 19470942 ER PT J AU Stark, JR Perner, S Stampfer, MJ Sinnott, JA Finn, S Eisenstein, AS Ma, J Fiorentino, M Kurth, T Loda, M Giovannucci, EL Rubin, MA Mucci, LA AF Stark, Jennifer R. Perner, Sven Stampfer, Meir J. Sinnott, Jennifer A. Finn, Stephen Eisenstein, Anna S. Ma, Jing Fiorentino, Michelangelo Kurth, Tobias Loda, Massimo Giovannucci, Edward L. Rubin, Mark A. Mucci, Lorelei A. TI Gleason Score and Lethal Prostate Cancer: Does 3+4=4+3? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADICAL PROSTATECTOMY; PROGNOSTIC-SIGNIFICANCE; CARDIOVASCULAR-DISEASE; PHYSICIANS HEALTH; RADIATION-THERAPY; RANDOMIZED-TRIAL; GRADING SYSTEM; NEEDLE-BIOPSY; BETA-CAROTENE; PROGRESSION AB Purpose Gleason grading is an important predictor of prostate cancer (PCa) outcomes. Studies using surrogate PCa end points suggest outcomes for Gleason score (GS) 7 cancers vary according to the predominance of pattern 4. These studies have influenced clinical practice, but it is unclear if rates of PCa mortality differ for 3 + 4 and 4 + 3 tumors. Using PCa mortality as the primary end point, we compared outcomes in Gleason 3 + 4 and 4 + 3 cancers, and the predictive ability of GS from a standardized review versus original scoring. Patients and Methods Three study pathologists conducted a blinded standardized review of 693 prostatectomy and 119 biopsy specimens to assign primary and secondary Gleason patterns. Tumor specimens were from PCa patients diagnosed between 1984 and 2004 from the Physicians' Health Study and Health Professionals Follow-Up Study. Lethal PCa (n = 53) was defined as development of bony metastases or PCa death. Hazard ratios (HR) were estimated according to original GS and standardized GS. We compared the discrimination of standardized and original grading with C-statistics from models of 10-year survival. Results For prostatectomy specimens, 4 + 3 cancers were associated with a three-fold increase in lethal PCa compared with 3 + 4 cancers (95% CI, 1.1 to 8.6). The discrimination of models of standardized scores from prostatectomy (C-statistic, 0.86) and biopsy (C-statistic, 0.85) were improved compared to models of original scores (prostatectomy C-statistic, 0.82; biopsy C-statistic, 0.72). Conclusion Ignoring the predominance of Gleason pattern 4 in GS 7 cancers may conceal important prognostic information. A standardized review of GS can improve prediction of PCa survival. C1 [Stark, Jennifer R.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, New York, NY 10021 USA. RP Stark, JR (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM stark@hsph.harvard.edu RI Rider, Jennifer/A-5371-2011; Kurth, Tobias/A-9243-2012; OI Kurth, Tobias/0000-0001-7169-2620; Rubin, Mark/0000-0002-8321-9950; Rider, Jennifer/0000-0002-2637-6036; Finn, Stephen/0000-0002-8628-5814 FU National Cancer Institute [5R01CA058684-13, 5R01CA042182-20, CA34944, CA40360, CA097193]; Department of Defense [W81XWH-05-1-0562]; National Research Service Award Training Program in Cancer Epidemiology and a Dana-Farber/Harvard Cancer Center [T32 CA009001-32]; National Heart, Lung, and Blood Institute [HL-26490, HL-34595] FX Supported by Grants No. 5R01CA058684-13 and 5R01CA042182-20 from the National Cancer Institute; Grant No. W81XWH-05-1-0562 from the Department of Defense; and Grant No. T32 CA009001-32 from the National Research Service Award Training Program in Cancer Epidemiology and a Dana-Farber/Harvard Cancer Center SPORE Career Development Award (J. R. S.). The Physicians Health Study is supported by Grants No. CA34944, CA40360, and CA097193 from the National Cancer Institute and Grants No. HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute. NR 33 TC 158 Z9 162 U1 1 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2009 VL 27 IS 21 BP 3459 EP 3464 DI 10.1200/JCO.2008.20.4669 PG 6 WC Oncology SC Oncology GA 471II UT WOS:000268049100010 PM 19433685 ER PT J AU Apperley, JF Cortes, JE Kim, DW Roy, L Roboz, GJ Rosti, G Bullorsky, EO Abruzzese, E Hochhaus, A Heim, D de Souza, CA Larson, RA Lipton, JH Khoury, HJ Kim, HJ Sillaber, C Hughes, TP Erben, P Van Tornout, J Stone, RM AF Apperley, Jane F. Cortes, Jorge E. Kim, Dong-Wook Roy, Lydia Roboz, Gail J. Rosti, Gianantonio Bullorsky, Eduardo O. Abruzzese, Elisabetta Hochhaus, Andreas Heim, Dominik de Souza, Carmino A. Larson, Richard A. Lipton, Jeffrey H. Khoury, H. Jean Kim, Hyeoung-Joon Sillaber, Christian Hughes, Timothy P. Erben, Philipp Van Tornout, Jan Stone, Richard M. TI Dasatinib in the Treatment of Chronic Myeloid Leukemia in Accelerated Phase After Imatinib Failure: The START A Trial 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 CHRONIC MYELOGENOUS LEUKEMIA; STEM-CELL TRANSPLANTATION; CYTOGENETIC RESPONSES; BCR-ABL; BLAST CRISIS; FOLLOW-UP; RESISTANCE; THERAPY; LYN; INDEPENDENCE AB Purpose Patients with chronic myelogenous leukemia in accelerated phase (CML-AP) that is resistant or intolerant to imatinib have limited therapeutic options. Dasatinib, a potent inhibitor of BCR-ABL and SRC-family kinases, has efficacy in patients with CML-AP who have experienced treatment failure with imatinib. We now report follow-up data from the full patient cohort of 174 patients enrolled onto a phase II trial to provide a more complete assessment of the efficacy and safety of dasatinib in this population. Patients and Methods Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily. Results At a median follow-up of 14.1 months (treatment duration, 0.1 to 21.7 months), major and complete hematologic responses were attained by 64% and 45% of patients, respectively, and major and complete cytogenetic responses were achieved in 39% and 32% of patients, respectively. Responses were achieved irrespective of imatinib status (resistant or intolerant), prior stem-cell transplantation, or the presence of prior BCR-ABL mutation. The 12-month progression-free survival and overall survival rates were 66% and 82%, respectively. Dasatinib was generally well tolerated; the most frequent nonhematologic severe treatment-related adverse event was diarrhea (52%; grade 3 to 4, 8%). Cytopenias were common, including grade 3 to 4 neutropenia (76%) and thrombocytopenia (82%). Pleural effusion occurred in 27% of patients (grade 3 to 4, 5%). Conclusion Dasatinib is effective in patients with CML-AP after imatinib treatment failure. C1 [Apperley, Jane F.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Med, London W12 0NN, England. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Catholic Univ Korea, St Marys Hosp, Seoul, South Korea. Chonnam Natl Univ, Hwasun Gun, Jeollanam Do, South Korea. CHU Poitiers, Clin Res Ctr, Poitiers, France. Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, New York, NY 10021 USA. S Orsola Malpighi Univ Hosp, Bologna, Italy. Osped S Eugenio, Rome, Italy. British Hosp Buenos Aires, Buenos Aires, DF, Argentina. Univ Heidelberg, Med Fak Mannheim, D-6800 Mannheim, Germany. Univ Basel Hosp, CH-4031 Basel, Switzerland. Univ Estadual Campinas, Campinas, SP, Brazil. Univ Chicago, Chicago, IL 60637 USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Emory Univ, Sch Med, Atlanta, GA USA. Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria. Univ Adelaide, Adelaide, SA, Australia. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Apperley, JF (reprint author), Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Med, Du Cane Rd, London W12 0NN, England. EM j.apperley@imperial.ac.uk RI Sangue, Inct/I-1919-2013; OI Larson, Richard/0000-0001-9168-3203; Hochhaus, Andreas/0000-0003-0626-0834 FU NCI NIH HHS [P30 CA016672] NR 30 TC 115 Z9 119 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2009 VL 27 IS 21 BP 3472 EP 3479 DI 10.1200/JCO.2007.14.3339 PG 8 WC Oncology SC Oncology GA 471II UT WOS:000268049100012 PM 19487385 ER PT J AU Angelov, L Doolittle, ND Kraemer, DF Siegal, T Barnett, GH Peereboom, DM Stevens, G McGregor, J Jahnke, K Lacy, CA Hedrick, NA Shalom, E Ference, S Bell, S Sorenson, L Tyson, RM Haluska, M Neuwelt, EA AF Angelov, Lilyana Doolittle, Nancy D. Kraemer, Dale F. Siegal, Tali Barnett, Gene H. Peereboom, David M. Stevens, Glen McGregor, John Jahnke, Kristoph Lacy, Cynthia A. Hedrick, Nancy A. Shalom, Edna Ference, Sandra Bell, Susan Sorenson, Lisa Tyson, Rose Marie Haluska, Marianne Neuwelt, Edward A. TI Blood-Brain Barrier Disruption and Intra-Arterial Methotrexate-Based Therapy for Newly Diagnosed Primary CNS Lymphoma: A Multi-Institutional Experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 01-05, 2007 CL Chicago, IL SP Amer Soc Clin Oncol ID CENTRAL-NERVOUS-SYSTEM; HIGH-DOSE METHOTREXATE; ENHANCED CHEMOTHERAPY DELIVERY; TERM-FOLLOW-UP; PHASE-II; DEFERRED RADIOTHERAPY; EUROPEAN ORGANIZATION; COGNITIVE FUNCTIONS; MULTICENTER; SURVIVAL AB Purpose Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. Patients and Methods This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age >= 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age >= 60 years and KPS >= 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. Conclusion This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens. C1 Cleveland Clin, Brain Tumor & Neuro Oncol Ctr, Cleveland, OH USA. Cleveland Clin, Dept Neurosurg, Cleveland, OH USA. Cleveland Clin, Dept Hematol, Cleveland, OH USA. Cleveland Clin, Dept Med Oncol, Cleveland, OH USA. Ohio State Univ, Med Ctr, Dept Neurosurg, Columbus, OH 43210 USA. Oregon Hlth & Sci Univ, Dept Neurol, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Dept Publ Hlth, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Dept Prevent Med, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. Oregon State Univ, Dept Pharm Practice, Corvallis, OR 97331 USA. Portland VA Med Ctr, Portland, OR USA. Hadassah Hebrew Univ Hosp, Leslie & Michael Gaffin Ctr Neurooncol, Jerusalem, Israel. RP Neuwelt, EA (reprint author), 3181 SW Sam Jackson Pk Rd,Mailcode L603, Portland, OR 97239 USA. EM neuwelte@ohsu.edu RI McGregor, John/K-6870-2013 FU NCI NIH HHS [R01 CA137488, CA137488, R01 CA137488-15, R13 CA086959, R13 CA086959-10]; NINDS NIH HHS [NS34608, NS44687, R37 NS044687, R01 NS034608, R01 NS044687] NR 47 TC 82 Z9 84 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 JUL 20 PY 2009 VL 27 IS 21 BP 3503 EP 3509 DI 10.1200/JCO.2008.19.3789 PG 7 WC Oncology SC Oncology GA 471II UT WOS:000268049100016 PM 19451444 ER PT J AU Richardson, PG Xie, WL Mitsiades, C Chanan-Khan, AA Lonial, S Hassoun, H Avigan, DE Oaklander, AL Kuter, DJ Wen, PY Kesari, S Briemberg, HR Schlossman, RL Munshi, NC Heffner, LT Doss, D Esseltine, DL Weller, E Anderson, KC Amato, AA AF Richardson, Paul G. Xie, Wanling Mitsiades, Constantine Chanan-Khan, Asher A. Lonial, Sagar Hassoun, Hani Avigan, David E. Oaklander, Anne Louise Kuter, David J. Wen, Patrick Y. Kesari, Santosh Briemberg, Hannah R. Schlossman, Robert L. Munshi, Nikhil C. Heffner, L. Thompson Doss, Deborah Esseltine, Dixie-Lee Weller, Edie Anderson, Kenneth C. Amato, Anthony A. TI Single-Agent Bortezomib in Previously Untreated Multiple Myeloma: Efficacy, Characterization of Peripheral Neuropathy, and Molecular Correlations With Response and Neuropathy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; PLUS DEXAMETHASONE; PHASE-II; REFRACTORY MYELOMA; INDUCTION THERAPY; ONCOLOGY-GROUP; APEX TRIAL; FOLLOW-UP; THALIDOMIDE; MULTICENTER AB Purpose To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. Patients and Methods Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients ( grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. Conclusion Single-agent bortezomib is effective in previously untreated myeloma. Baseline myelomaassociated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients. C1 [Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Millennium Pharmaceut Inc, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Richardson, PG (reprint author), Dana Farber Canc Inst, 44 Binney St,Dana 1B02, Boston, MA 02115 USA. EM richardson@dfci.harvard.edu RI Kesari, Santosh/E-8461-2013 FU Public Health Service [NINDS R01NS42866, P30 EY 12196]; Millennium Pharmaceuticals; Johnson & Johnson Pharmaceuticals Research & Development, LLC FX Supported in part by the Public Health Service (Grant No. NINDS R01NS42866, P30 EY 12196) and by Millennium Pharmaceuticals and Johnson & Johnson Pharmaceuticals Research & Development, LLC. NR 55 TC 138 Z9 146 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 JUL 20 PY 2009 VL 27 IS 21 BP 3518 EP 3525 DI 10.1200/JCO.2008.18.3087 PG 8 WC Oncology SC Oncology GA 471II UT WOS:000268049100018 PM 19528374 ER PT J AU Park, Y Choi, W Yaqoob, Z Dasari, R Badizadegan, K Feld, MS AF Park, YongKeun Choi, Wonshik Yaqoob, Zahid Dasari, Ramachandra Badizadegan, Kamran Feld, Michael S. TI Speckle-field digital holographic microscopy SO OPTICS EXPRESS LA English DT Article ID DIFFRACTION PHASE MICROSCOPY; FLUORESCENCE MICROSCOPY; REFRACTIVE-INDEX; DYNAMICS; ILLUMINATION; CELLS AB The use of coherent light in conventional holographic phase microscopy (HPM) poses three major drawbacks: poor spatial resolution, weak depth sectioning, and fixed pattern noise due to unwanted diffraction. Here, we report a technique which can overcome these drawbacks, but maintains the advantage of phase microscopy - high contrast live cell imaging and 3D imaging. A speckle beam of a complex spatial pattern is used for illumination to reduce fixed pattern noise and to improve optical sectioning capability. By recording of the electric field of speckle, we demonstrate high contrast 3D live cell imaging without the need for axial scanning - neither objective lens nor sample stage. This technique has great potential in studying biological samples with improved sensitivity, resolution and optical sectioning capability. (C) 2009 Optical Society of America C1 [Park, YongKeun; Choi, Wonshik; Yaqoob, Zahid; Dasari, Ramachandra; Badizadegan, Kamran; Feld, Michael S.] MIT, George R Harrison Spect Lab, Cambridge, MA 02139 USA. [Park, YongKeun] Harvard MIT, Dept Hlth Sci & Technol, Cambridge, MA 02139 USA. [Choi, Wonshik] Korea Univ, Dept Phys, Seoul 136701, South Korea. [Badizadegan, Kamran] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Badizadegan, Kamran] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Park, Y (reprint author), MIT, George R Harrison Spect Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM wonshik@mit.edu RI Park, YongKeun/B-9017-2009 FU National Institutes of Health [P41-RR02594]; National Science Foundation [DBI-0754339]; Hamamatsu Corporation; Samsung Scholarship; Whitaker Health Science Fellowship FX This work was funded by the National Center for Research Resources of the National Institutes of Health (P41-RR02594), the National Science Foundation (DBI-0754339) and Hamamatsu Corporation. Y.-K. Park was supported by Samsung Scholarship and Whitaker Health Science Fellowship. NR 21 TC 61 Z9 62 U1 1 U2 12 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 JUL 20 PY 2009 VL 17 IS 15 BP 12285 EP 12292 DI 10.1364/OE.17.012285 PG 8 WC Optics SC Optics GA 475XE UT WOS:000268399500009 PM 19654630 ER PT J AU Dunfee, RL Thomas, ER Gabuzda, D AF Dunfee, Rebecca L. Thomas, Elaine R. Gabuzda, Dana TI Enhanced macrophage tropism of HIV in brain and lymphoid tissues is associated with sensitivity to the broadly neutralizing CD4 binding site antibody b12 SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTION; GP120; ENVELOPE; ENTRY; DEMENTIA; CONFORMATION; PATHOGENESIS; SPECIFICITY; CORECEPTORS AB Macrophages in the central nervous system (CNS) and other tissues are an important cellular reservoir for human immunodeficiency virus type 1 (HIV) infection, particularly in the later stages of disease. Macrophage-tropic HIV strains have an enhanced capacity to enter cells expressing low levels of CD4 through mechanisms that are not well understood. Here, we use a panel of primary HIV envelopes from brain and lymphoid tissues to examine the relationship between neutralization sensitivity to reagents targeting the CD4 binding site and virus entry into macrophages. Neutralization assays using pseudotyped viruses showed an association between the capacity of HIV to enter macrophages and increased sensitivity to the broadly neutralizing monoclonal antibody (mAb) b12, which recognizes a conserved epitope overlapping the CD4 binding site, but not sensitivity to soluble CD4 (sCD4) or b6, a non-neutralizing CD4 binding site mAb. Furthermore, loss of an N-linked glycosylation site at position 386 in the V4 region of Env enhanced macrophage tropism together with b12 sensitivity, but not neutralization by sCD4, b6, or a broadly neutralizing AIDS patient serum. These findings suggest that exposure of the b12 epitope, rather than exposure of the CD4 binding site per se, enhances HIV macrophage tropism, possibly by exposing a region on the outer domain of gp120 that is initially recognized by CD4. These findings suggest overlap between specific gp120 determinants in or near the b12 epitope and those conferring macrophage tropism. C1 [Dunfee, Rebecca L.; Thomas, Elaine R.; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Dunfee, Rebecca L.; Thomas, Elaine R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Gabuzda, Dana] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Gabuzda, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM dunfeer@niaid.nih.gov; EThomas@arrowt.co.uk; dana_gabuzda@dfci.harvard.edu FU NIH [MH83588]; Harvard University Center for AIDS Research and DFCI/Harvard Cancer Center FX We thank Dennis Burton (Scripps) for providing the b12 and b6 antibodies. This work was supported by NIH grant MH83588. Core facilities were supported by Harvard University Center for AIDS Research and DFCI/Harvard Cancer Center grants. NR 37 TC 27 Z9 28 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUL 20 PY 2009 VL 6 AR 69 DI 10.1186/1742-4690-6-69 PG 7 WC Virology SC Virology GA 487TX UT WOS:000269300500001 PM 19619305 ER PT J AU Pryaslova, JP Lyamin, OI Siegel, JM Mukhametov, LM AF Pryaslova, Julia P. Lyamin, Oleg I. Siegel, Jerome M. Mukhametov, Lev M. TI Behavioral sleep in the walrus SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Quiet sleep; REM sleep; Behavioral sleep; Sleep variability; Continuous swimming; Breathing pattern; Walrus; Pinnipeds ID SEAL PAGOPHILUS-GROENLANDICA; MAMMALIAN SLEEP; FUR-SEAL; PATTERNS; PUPS; WAKEFULNESS; ASYMMETRY; WAKE; EEG AB In this study we examined behavioral sleep in the walrus, the only living species of the family Odobenidae. The behavior of four 1.5-2-year-old captive walruses was videotaped continuously for 7-17 days and scored in 1-min epochs. When walruses had access to water and land, behavioral sleep, the combined amount of quiet and rapid eye movement (REM) sleep, occupied on average 17 +/- 4% of 24 h (n = 4) with the majority of sleep occurring on land. All walruses alternated periods of almost continuous swimming lasting for 40-84 h with periods of rest on land lasting for 2-19 h. When in water they were predominantly awake (88-99% of the time). On land walruses were asleep on average 40-74% of the time. The total sleep time varied between 0 and 60% of 24 h with the daily amount of REM sleep ranging from 0 to 5% of 24 h. In water, walruses slept while floating at the surface, lying on the bottom or standing and leaning against the pool wall. REM sleep in water occurred in all positions. On land the breathing pattern was regular during quiet sleep (most pauses were <30s) and arrhythmic in REM sleep (apneas lasted up to 160s). While in water the irregularity of breathing further increased (apneas were >4 min) and all REM sleep episodes occurred during a single apnea. Data indicate that the pattern of sleep and breathing in walruses is similar to the Otariidae seats while on land and the Phocidae seats while in water. Published by Elsevier B.V. C1 [Lyamin, Oleg I.; Siegel, Jerome M.] Vet Affairs Greater Los Angeles Healthcare Syst S, Neurobiol Res 151A3, North Hills, CA 91343 USA. [Pryaslova, Julia P.; Lyamin, Oleg I.; Mukhametov, Lev M.] Utrish Dolphinarium Ltd, Moscow 119071, Russia. [Lyamin, Oleg I.; Siegel, Jerome M.] Univ Calif Los Angeles, Dept Psychiat, Sch Med, Los Angeles, CA USA. RP Lyamin, OI (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst S, Neurobiol Res 151A3, 16111 Plummer St, North Hills, CA 91343 USA. EM olyamin@ucla.edu FU Utrish Dolphinarium Ltd. (Moscow, Russia); The Medical Research Service of the Department of Veterans Affairs (USA) FX This research was supported by Utrish Dolphinarium Ltd. (Moscow, Russia) and The Medical Research Service of the Department of Veterans Affairs (USA). The authors wish to thank the staff of the Utrish Dolphinarium and the Utrish Marine Station (Severtsov Institute of the Russian Academy of Sciences, Novorossiysk, Russia), for their help and assistance during the observations. We are also thankful to J. Lapierre for valuable comments on this manuscript. NR 40 TC 5 Z9 5 U1 3 U2 13 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 JUL 19 PY 2009 VL 201 IS 1 BP 80 EP 87 DI 10.1016/j.bbr.2009.01.033 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 447ZV UT WOS:000266231800012 PM 19428620 ER PT J AU Smolen, JS Kay, J Doyle, MK Landewe, R Matteson, EL Wollenhaupt, J Gaylis, N Murphy, FT Neal, JS Zhou, YY Visvanathan, S Hsia, EC Rahman, MU AF Smolen, Josef S. Kay, Jonathan Doyle, Mittie K. Landewe, Robert Matteson, Eric L. Wollenhaupt, Juergen Gaylis, Norman Murphy, Frederick T. Neal, Jeffrey S. Zhou, Yiying Visvanathan, Sudha Hsia, Elizabeth C. Rahman, Mahboob U. CA GO-AFTER Study Investigators TI Golimumab inpatients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial SO LANCET LA English DT Article ID DISEASE-ACTIVITY; MONOCLONAL-ANTIBODY; CLINICAL-TRIALS; CONCOMITANT METHOTREXATE; EFFICACY; ETANERCEPT; THERAPY; SAFETY; INFLIXIMAB; ADALIMUMAB AB Background Turnout necrosis factor a (TNF alpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNF alpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNF alpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNF alpha inhibitors. Methods 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNF alpha inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546. Findings Patients had discontinued previous TNF alpha inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14.0 (IQR 9.0-22.0) swollen and 26.0 (16.0-41.0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2.5 [95% Cl 1.5-4.2], p=0.0006), and 58 (38%) patients on 100 mg golimumab (2.8 [1.6-4.7], p=0.0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1-16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1-24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab. Interpretation Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNF alpha inhibitors. C1 [Smolen, Josef S.] Med Univ Vienna, A-1090 Vienna, Austria. [Smolen, Josef S.] Hietzing Hosp, Vienna, Austria. [Kay, Jonathan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kay, Jonathan] Havard Med Sch, Boston, MA USA. [Doyle, Mittie K.; Zhou, Yiying; Visvanathan, Sudha; Hsia, Elizabeth C.; Rahman, Mahboob U.] Centocor Researc & Dev, Malvern, PA USA. [Doyle, Mittie K.; Murphy, Frederick T.; Hsia, Elizabeth C.; Rahman, Mahboob U.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Landewe, Robert] Univ Hosp Maastricht, Maastricht, Netherlands. [Matteson, Eric L.] Mayo Clin, Rochester, MN USA. [Wollenhaupt, Juergen] Klin Eibek, Hamburg, Germany. [Gaylis, Norman] Arthrit & Rheumat Dis Specialties, Aventura, FL USA. [Murphy, Frederick T.] Altoona Ctr Clin Res, Duncansville, PA USA. [Neal, Jeffrey S.] Bluegrass Community Res, Lexington, KY USA. RP Smolen, JS (reprint author), Med Univ Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM josef.smolen@wienkav.at OI Kay, Jonathan/0000-0002-8970-4260 FU Centocor Research and Development and Schering-Plough Research Institute FX This study was sponsored by Centocor Research and Development and Schering-Plough Research Institute. We thank the patients, investigators, and study personnel who made the trial possible; and Scott Newcomer, medical writer for Centocor Ortho Biotech Services, a wholly owned subsidiary of Johnson & Johnson, for his assistance in the preparation of this report. NR 39 TC 248 Z9 264 U1 1 U2 14 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 JUL 18 PY 2009 VL 374 IS 9685 BP 210 EP 221 DI 10.1016/S0140-6736(09)60506-7 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 474DP UT WOS:000268263000029 PM 19560810 ER PT J AU Kaufman, DS Shipley, WU Feldman, AS AF Kaufman, Donald S. Shipley, William U. Feldman, Adam S. TI Bladder cancer SO LANCET LA English DT Review ID TRANSITIONAL-CELL-CARCINOMA; PHASE-II TRIAL; BACILLUS-CALMETTE-GUERIN; METASTATIC UROTHELIAL CANCER; COOPERATIVE-ONCOLOGY-GROUP; CISPLATIN-BASED CHEMOTHERAPY; 2ND TRANSURETHRAL RESECTION; GEMCITABINE PLUS CISPLATIN; RANDOMIZED CLINICAL-TRIALS; MOLECULAR TARGETED THERAPY AB Bladder cancer is a heterogeneous disease, with 70% of patients presenting with superficial tumours, which tend to recur but are generally not life threatening, and 30% presenting as muscle-invasive disease associated with a high risk of death from distant metastases. The main presenting symptom of all bladder cancers is painless haematuria, and the diagnosis is established by urinary cytology and transurethral tumour resection. Intravesical treatment is used for carcinoma in situ and other high grade non-muscle-invasive tumours. The standard of care for muscle-invasive disease is radical cystoprostatectomy, and several types of urinary diversions are offered to patients, with quality of life as an important consideration. Bladder preservation with transurethral tumour resection, radiation, and chemotherapy can in some cases be equally curative. Several chemotherapeutic agents have proven to tie useful as neoadjuvant or adjuvant treatment and in patients with metastatic disease. We discuss bladder preserving approaches, combination chemotherapy including new agents, targeted therapies, and advances in molecular biology. C1 [Kaufman, Donald S.] Massachusetts Gen Hosp, Claire & John Bertucci Ctr Genitourinary Canc, Dept Med, Boston, MA 02114 USA. [Shipley, William U.] Massachusetts Gen Hosp, Claire & John Bertucci Ctr Genitourinary Canc, Dept Radiat Oncol, Boston, MA 02114 USA. [Feldman, Adam S.] Massachusetts Gen Hosp, Claire & John Bertucci Ctr Genitourinary Canc, Dept Urol, Boston, MA 02114 USA. RP Kaufman, DS (reprint author), Massachusetts Gen Hosp, Claire & John Bertucci Ctr Genitourinary Canc, Dept Med, Yawkey Bldg,Fruit St, Boston, MA 02114 USA. EM dskaufman@partners.org NR 129 TC 405 Z9 430 U1 8 U2 61 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 JUL 18 PY 2009 VL 374 IS 9685 BP 239 EP 249 DI 10.1016/S0140-6736(09)60491-8 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 474DP UT WOS:000268263000033 PM 19520422 ER PT J AU Stanley, TL Joy, T Hadigan, CM Liebau, JG Makimura, H Chen, CY Thomas, BJ Weise, SB Robbins, GK Grinspoon, SK AF Stanley, Takara L. Joy, Tisha Hadigan, Colleen M. Liebau, James G. Makimura, Hideo Chen, Cindy Y. Thomas, Bijoy J. Weise, Steven B. Robbins, Gregory K. Grinspoon, Steven K. TI Effects of switching from lopinavir/ritonavir to atazanavir/ritonavir on muscle glucose uptake and visceral fat in HIV-infected patients SO AIDS LA English DT Article DE atazanavir; glucose; HIV; intra-abdominal fat; lipids; lipodystrophy; lopinavir ID TWICE-DAILY LOPINAVIR/RITONAVIR; ONCE-DAILY ATAZANAVIR/RITONAVIR; HORMONE-RELEASING FACTOR; PROTEASE INHIBITORS; INSULIN-RESISTANCE; GROWTH-HORMONE; ADIPOCYTE DIFFERENTIATION; HIV-1-INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; SKELETAL-MUSCLE AB Objective: To determine the effects of switching from lopinavir/ritonavir (LPV/r) to atazanavir/ritonavir (ATV/r) on muscle glucose uptake, glucose homeostasis, lipids, and body composition. Methods: Fifteen HIV-infected men and women on a regimen containing LPV/r and with evidence of hyperinsulinemia and/or dyslipidemia were randomized to continue LPV/r or to switch to ATV/r (ATV 300 mg and ritonavir 100 mg daily) for 6 months. The primary endpoint was change in thigh muscle glucose uptake as measured by positron emission tomography. Secondary endpoints included abdominal visceral adipose tissue, fasting lipids, and safety parameters. The difference over time between treatment groups (treatment effect of ATV/r relative to LPV/r) was determined by repeated measures ANCOVA. Results: After 6 months, anterior thigh muscle glucose uptake increased significantly (treatment effect +18.2 +/- 5.9 mu mol/kg per min, ATV/r vs. LPV/r, P=0.035), and visceral adipose tissue area decreased significantly in individuals who switched to ATV/r (treatment effect -31 +/- 11 cm(2), ATV/r vs. LPV/r, P=0.047). Switching to ATV/r significantly decreased triglyceride (treatment effect -182 +/- 64 mg/dl, ATV/r vs. LPV/r, P=0.02) and total cholesterol (treatment effect -23 +/- 8 mg/dl, ATV/r vs. LPV/r, P=0.01), whereas high-density lipoprotein and low-density lipoprotein did not change significantly. Fasting glucose also decreased significantly following switch to ATV/r (treatment effect -15 +/- 4 mg/dl, ATV/r vs. LPV/r, P=0.002). Conclusion: Switching from LPV/r to ATV/r significantly increases glucose uptake by muscle, decreases abdominal visceral adipose tissue, improves lipid parameters, and decreases fasting glucose over 6 months. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Stanley, Takara L.; Joy, Tisha; Liebau, James G.; Makimura, Hideo; Chen, Cindy Y.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Robbins, Gregory K.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Thomas, Bijoy J.; Weise, Steven B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Thomas, Bijoy J.; Weise, Steven B.] Harvard Univ, Sch Med, Boston, MA USA. [Hadigan, Colleen M.] NIH, Bethesda, MD 20892 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NIH [M01-RR01066, 1 ULI RR025758-01, T32 HID052961-03, K01 AI062435, K24 DK064545-06]; Harvard Clinical and Translational Science Center; National Center for Research Resources; Boehringer Ingelheim, Gilead; Schering-Plough; Bristol Myers Squibb and Theratechnologies FX Funding was provided by BMS in the form of an investigator initiated research grant and NIH M01-RR01066 and 1 ULI RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. NIH funding also provided by T32 HID052961-03 trainee support to TS., K01 AI062435 to G.R., and K24 DK064545-06 to S.G. G.R. has received grant support from Boehringer Ingelheim, Gilead, and Schering-Plough, and has been a consultant for Abbott Laboratories. S.G. has received research support from Bristol Myers Squibb and Theratechnologies and served as a consultant for Theratechnologies and Serono, Inc. NR 40 TC 31 Z9 32 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 17 PY 2009 VL 23 IS 11 BP 1349 EP 1357 DI 10.1097/QAD.0b013e32832ba904 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 470GJ UT WOS:000267962900007 PM 19474651 ER PT J AU Barth, MC Ahluwalia, N Anderson, TJT Hardy, GJ Sinha, S Alvarez-Cardona, JA Pruitt, IE Rhee, EP Colvin, RA Gerszten, RE AF Barth, Marita C. Ahluwalia, Neil Anderson, Thomas J. T. Hardy, Gregory J. Sinha, Sumita Alvarez-Cardona, Jose A. Pruitt, Ivy E. Rhee, Eugene P. Colvin, Richard A. Gerszten, Robert E. TI Kynurenic Acid Triggers Firm Arrest of Leukocytes to Vascular Endothelium under Flow Conditions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED-RECEPTOR; INFLAMMATORY-BOWEL-DISEASE; FUNCTIONAL EXPRESSION; CHEMOTACTIC FACTORS; PATHWAY METABOLISM; MOLECULAR-CLONING; DENDRITIC CELLS; MICE REVEALS; ADHESION; TRYPTOPHAN AB Recent studies have demonstrated that kynurenic acid (KYNA), a compound produced endogenously by the interferon-gamma-induced degradation of tryptophan by indoleamine 2,3-dioxygenase, activates the previously orphaned G protein-coupled receptor, GPR35. This receptor is expressed in immune tissues, although its potential function in immunomodulation remains to be explored. We determined that GPR35 was most highly expressed on human peripheral monocytes. In an in vitro vascular flow model, KYNA triggered the firm arrest of monocytes to both fibronectin and ICAM-1, via beta(1) integrin- and beta(2) integrin-mediated mechanisms, respectively. Incubation of monocytes with pertussis toxin prior to use in flow experiments significantly reduced the KYNA-induced monocyte adhesion, suggesting that adhesion is triggered by a G(i)-mediated process. Furthermore, KYNA-triggered adhesion of monocytic cells was reduced by short hairpin RNA-mediated silencing of GPR35. Although GPR35 is expressed at slightly lower levels on neutrophils, KYNA induced firm adhesion of these cells to an ICAM-1-expressing monolayer as well. KYNA also elicited neutrophil shedding of surface L-selectin, another indicator of leukocyte activation. Taken together, these data suggest that KYNA could be an important early mediator of leukocyte recruitment. C1 [Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. EM Gerszten.Robert@mgh.harvard.edu OI Anderson, Thomas/0000-0002-2762-6703 FU NHLBI NIH HHS [HL65584, R01 HL065584] NR 41 TC 58 Z9 60 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 17 PY 2009 VL 284 IS 29 BP 19189 EP 19195 DI 10.1074/jbc.M109.024042 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469OE UT WOS:000267908300008 PM 19473985 ER PT J AU Kao, SY AF Kao, Shyan-Yuan TI DNA damage induces nuclear translocation of parkin SO JOURNAL OF BIOMEDICAL SCIENCE LA English DT Article ID RECESSIVE JUVENILE PARKINSONISM; VIRUS TYPE-1 TAX; SUBSTANTIA-NIGRA; OXIDATIVE DAMAGE; ALPHA-SYNUCLEIN; HUMAN BRAIN; DISEASE; PROTEIN; GENE; REPAIR AB Parkinson's disease (PD) is the second most common form of human degenerative disorder. Mutation of parkin is one of the most prevalent causes of autosomal recessive PD. Parkin is an E3 ubiquitin ligase that acts on a variety of substrates, resulting in polyubiquitination and degradation by the proteasome or monoubiquitination and regulation of biological activity. However, the cellular functions of parkin that relate to its pathological involvement in PD are not well understood. Here I show that parkin translocates into nucleus upon DNA damage. Nuclear translocation of parkin appears to be required to promote DNA repair. These findings suggest that DNA damage induces nuclear translocation of parkin leading to the PCNA interaction and possibly other nuclear proteins involved in DNA repair. These results suggest that parkin promotes DNA repair and protects against genotoxicity, and implicate DNA damage as a potential pathogenic mechanism in parkinsonism. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Kao, SY (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM shyan-yuan_kao@meei.harvard.edu NR 29 TC 14 Z9 14 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1021-7770 J9 J BIOMED SCI JI J. Biomed. Sci. PD JUL 17 PY 2009 VL 16 AR 67 DI 10.1186/1423-0127-16-67 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 482MX UT WOS:000268894100001 PM 19615059 ER PT J AU Sundrud, MS Mazitschek, R Whitman, M AF Sundrud, M. S. Mazitschek, Ralph Whitman, Malcolm TI Halofuginone inhibits T(H)17 cell differentiation by activating the amino acid starvation response (vol 324, pg 1334, 2009) SO SCIENCE LA English DT Correction C1 [Mazitschek, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Mazitschek, Ralph] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02142 USA. [Mazitschek, Ralph] Broad Inst, Chem Biol Program, Cambridge, MA 02142 USA. EM mwhitman@hms.harvard.edu RI Mazitschek, Ralph/E-3741-2013 OI Mazitschek, Ralph/0000-0002-1105-689X NR 1 TC 0 Z9 0 U1 0 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 JUL 17 PY 2009 VL 325 IS 5938 BP 267 EP 267 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 471DZ UT WOS:000268036600017 ER PT J AU Alousi, AM Weisdorf, DJ Logan, BR Bolanos-Meade, J Carter, S DiFronzo, N Pasquini, M Goldstein, SC Ho, VT Hayes-Lattin, B Wingard, JR Horowitz, MM Levine, JE AF Alousi, Amin M. Weisdorf, Daniel J. Logan, Brent R. Bolanos-Meade, Javier Carter, Shelly DiFronzo, Nancy Pasquini, Marcelo Goldstein, Steven C. Ho, Vincent T. Hayes-Lattin, Brandon Wingard, John R. Horowitz, Mary M. Levine, John E. CA Blood & Marrow Transplant Clin Tri TI Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network SO BLOOD LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium CY DEC 06-09, 2008 CL San Francisco, CA SP Amer Soc Hematol (ASH), Sanofi Aventis U.S. ID INITIAL THERAPY; CHRONIC GVHD; METHOTREXATE; CYCLOSPORINE; PROPHYLAXIS; PREDNISONE; DIFTITOX; EFFICACY; STEROIDS; MODERATE AB Acute graft-versus-host disease (aGVHD) is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of patients completely respond. This randomized, 4-arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n = 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, MMF 44%, denileukin 62%, and pentostatin 57%. Efficacy and toxicity data suggest the use of MMF plus corticosteroids is the most promising regimen to compare against corticosteroids alone in a definitive phase 3 trial. This study is registered at http://www. clinicaltrials.gov as NCT00224874. (Blood. 2009; 114: 511-517) C1 [Alousi, Amin M.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Weisdorf, Daniel J.] Univ Minnesota, Dept Bone Marrow Transplant, Minneapolis, MN USA. [Logan, Brent R.] Med Coll Wisconsin, Dept Populat Hlth, Milwaukee, WI 53226 USA. [Bolanos-Meade, Javier] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Carter, Shelly] EMMES Corp, Rockville, MD USA. [DiFronzo, Nancy] NHLBI, Transfus Med & Cellular Therapeut Branch, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Pasquini, Marcelo] Med Coll Wisconsin, Dept Med, Div Neoplast Dis & Related Disorders, CIBMTR, Milwaukee, WI 53226 USA. [Goldstein, Steven C.] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Ho, Vincent T.] Dana Farber Canc Inst, Dept Med Oncol Hematol Malignancies, Boston, MA 02115 USA. [Hayes-Lattin, Brandon] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97201 USA. [Wingard, John R.] Univ Florida, Dept Med, Shands Canc Ctr, Gainesville, FL USA. [Levine, John E.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Horowitz, Mary M.] Froedtert & Med Coll Wisconsin, Dept Med, Div Neoplast Dis & Related Disorders, Milwaukee, WI USA. [Horowitz, Mary M.] Froedtert & Med Coll Wisconsin, CIBMTR, Milwaukee, WI USA. RP Alousi, AM (reprint author), 1515 Holcombe Blvd,Unit 423, Houston, TX 77030 USA. EM aalousi@mdanderson.org OI Levine, John/0000-0002-9133-0800 FU NCI NIH HHS [U24 CA076518]; NHLBI NIH HHS [U10 HL069249, U10 HL069286, U10 HL069294, U10 HL069301, U10 HL069330, U10 HL069348] NR 24 TC 110 Z9 114 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 16 PY 2009 VL 114 IS 3 BP 511 EP 517 DI 10.1182/blood-2009-03-212290 PG 7 WC Hematology SC Hematology GA 471ML UT WOS:000268061800008 PM 19443659 ER PT J AU Azab, AK Azab, F Blotta, S Pitsillides, CM Thompson, B Runnels, JM Roccaro, AM Ngo, HT Melhem, MR Sacco, A Jia, XY Anderson, KC Lin, CP Rollins, BJ Ghobrial, IM AF Azab, Abdel Kareem Azab, Feda Blotta, Simona Pitsillides, Costas M. Thompson, Brian Runnels, Judith M. Roccaro, Aldo M. Ngo, Hai T. Melhem, Molly R. Sacco, Antonio Jia, Xiaoying Anderson, Kenneth C. Lin, Charles P. Rollins, Barrett J. Ghobrial, Irene M. TI RhoA and Rac1 GTPases play major and differential roles in stromal cell-derived factor-1-induced cell adhesion and chemotaxis in multiple myeloma SO BLOOD LA English DT Article ID BONE-MARROW; ACTIN CYTOSKELETON; IN-VIVO; MIGRATION; FACTOR-1-ALPHA; INHIBITION; LOCOMOTION; BIOLOGY; KINASE; VLA-4 AB The interaction of multiple myeloma (MM) cells with the bone marrow (BM) milieu plays a crucial role in MM pathogenesis. Stromal cell-derived factor-1 (SDF1) regulates homing of MM cells to the BM. In this study, we examined the role of RhoA and Rac1 GTPases in SDF1-induced adhesion and chemotaxis of MM. We found that both RhoA and Rac1 play key roles in SDF1-induced adhesion of MM cells to BM stromal cells, whereas RhoA was involved in chemotaxis and motility. Furthermore, both ROCK and Rac1 inhibitors reduced SDF1-induced polymerization of actin and activation of LIMK, SRC, FAK, and cofilin. Moreover, RhoA and Rac1 reduced homing of MM cells to BM niches. In conclusion, we characterized the role of RhoA and Rac1 GTPases in SDF1-induced adhesion, chemotaxis, and homing of MM cells to the BM, providing the framework for targeting RhoA and Rac1 GTPases as novel MM therapy. (Blood. 2009; 114: 619-629) C1 [Azab, Abdel Kareem; Azab, Feda; Blotta, Simona; Runnels, Judith M.; Roccaro, Aldo M.; Ngo, Hai T.; Melhem, Molly R.; Sacco, Antonio; Jia, Xiaoying; Anderson, Kenneth C.; Rollins, Barrett J.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Pitsillides, Costas M.; Thompson, Brian; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Mayer 548A, Boston, MA 02115 USA. EM Irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128 FU NIH [R01CA125690, EB000664]; Leukemia & Lymphoma Society FX This study is supported in part by R01CA125690, NIH EB000664 (Bethesda, MD), and the Leukemia & Lymphoma Society (White Plains, NY) to I. M. G. NR 34 TC 63 Z9 66 U1 0 U2 10 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 JUL 16 PY 2009 VL 114 IS 3 BP 619 EP 629 DI 10.1182/blood-2009-01-199281 PG 11 WC Hematology SC Hematology GA 471ML UT WOS:000268061800022 PM 19443661 ER PT J AU Gutierrez, A Sanda, T Grebliunaite, R Carracedo, A Salmena, L Ahn, YB Dahlberg, S Neuberg, D Moreau, LA Winter, SS Larson, R Zhang, JH Protopopov, A Chin, L Pandolfi, PP Silverman, LB Hunger, SP Sallan, SE Look, AT AF Gutierrez, Alejandro Sanda, Takaomi Grebliunaite, Ruta Carracedo, Arkaitz Salmena, Leonardo Ahn, Yebin Dahlberg, Suzanne Neuberg, Donna Moreau, Lisa A. Winter, Stuart S. Larson, Richard Zhang, Jianhua Protopopov, Alexei Chin, Lynda Pandolfi, Pier Paolo Silverman, Lewis B. Hunger, Stephen P. Sallan, Stephen E. Look, A. Thomas TI High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia SO BLOOD LA English DT Article ID HUMAN CANCERS; MUTATIONS; GENE; PATHWAY; RESISTANCE; ONCOGENE; THERAPY; NOTCH1; TUMORS AB To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL. (Blood. 2009; 114: 647-650) C1 [Gutierrez, Alejandro; Sanda, Takaomi; Grebliunaite, Ruta; Ahn, Yebin; Moreau, Lisa A.; Silverman, Lewis B.; Sallan, Stephen E.; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Gutierrez, Alejandro; Silverman, Lewis B.; Sallan, Stephen E.; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Carracedo, Arkaitz; Salmena, Leonardo; Pandolfi, Pier Paolo] Beth Israel Deaconess Canc Ctr, Canc Genet Program, Boston, MA USA. [Dahlberg, Suzanne; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Winter, Stuart S.] Univ New Mexico, Hlth Sci Ctr, Dept Pediat, Albuquerque, NM 87131 USA. [Winter, Stuart S.] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. [Zhang, Jianhua; Protopopov, Alexei; Chin, Lynda] Belfer Inst Innovat Canc Sci, Ctr Appl Canc Sci, Boston, MA USA. [Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hunger, Stephen P.] Univ Colorado, Sch Med, Aurora, CO USA. [Hunger, Stephen P.] Childrens Hosp, Ctr Canc & Blood Disorders, Aurora, CO USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM Thomas_look@dfci.harvard.edu RI Carracedo, Arkaitz/F-7029-2011; OI Carracedo, Arkaitz/0000-0001-5957-1260; Gutierrez, Alejandro/0000-0002-0249-9007; Larson, Richard/0000-0001-9168-3203 FU National Institutes of Health [5P01CA68484, 1K08CA133103]; Community Foundation of the National Capital Region; Children's Oncology Group [CA98543, CA114766]; William Lawrence Foundation; American Society of Hematology-Amos Medical Faculty Development program; University of Colorado; Center for Applied Cancer Science FX This work was supported by the National Institutes of Health (grant 5P01CA68484; S. E. S., A. T. L.) and by an award from the Wine Advocate Fund for Philanthropy of the Community Foundation of the National Capital Region. Children's Oncology Group cell banking and sample distribution were supported by the Children's Oncology Group 9900 cell biology study and grants CA98543 and CA114766. A. G. is supported by the William Lawrence Foundation, the American Society of Hematology-Amos Medical Faculty Development program, and by the National Institutes of Health (grant 1K08CA133103). S. P. H. is the Ergen Family Chair in Pediatric Cancer at the University of Colorado. The array CGH analyses were performed and supported in part by the Center for Applied Cancer Science of the Robert A. and Renee NR 23 TC 203 Z9 208 U1 5 U2 15 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 JUL 16 PY 2009 VL 114 IS 3 BP 647 EP 650 DI 10.1182/blood-2009-02-206722 PG 4 WC Hematology SC Hematology GA 471ML UT WOS:000268061800025 PM 19458356 ER PT J AU Patterson, TF Mackool, BT Gilman, MD Piris, A AF Patterson, Thomas F. Mackool, Bonnie T. Gilman, Matthew D. Piris, Adriano TI A Man with Skin and Pulmonary Lesions after Bone Marrow Transplantation Disseminated fusarium infection involving the lungs and skin SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Annual Conference on Infectious Diseases of Adults CY APR 16, 2008 CL Boston, MA ID INVASIVE FUNGAL-INFECTIONS; CARE CANCER CENTER; HEMATOLOGIC MALIGNANCIES; NEUTROPENIC PATIENTS; RISK-FACTORS; ASPERGILLOSIS; EPIDEMIOLOGY; ZYGOMYCOSIS; EXPERIENCE; MANAGEMENT C1 [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, San Antonio, TX 78229 USA. [Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Mackool, Bonnie T.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Gilman, Matthew D.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Piris, Adriano] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Patterson, TF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, San Antonio, TX 78229 USA. NR 26 TC 7 Z9 7 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 JUL 16 PY 2009 VL 361 IS 3 BP 287 EP 296 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 470LL UT WOS:000267976100012 PM 19605834 ER PT J AU Zahid, M Good, CB Singla, I Sonel, AF AF Zahid, Maliha Good, Chester B. Singla, Ish Sonel, Ali F. TI Clinical Significance of Borderline Elevated Troponin I Levels Across Different Assays in Patients With Suspected Acute Coronary Syndrome SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIAC TROPONIN; MYOCARDIAL-INFARCTION; MORTALITY; RISK; TERM AB We aimed to elucidate the clinical significance of borderline troponin I (TnI) increases and see if such increases are of similar significance across different assays. Markedly increased TnI is a strong predictor of adverse cardiac events. It is not clear if borderline increases with different commercially available TnI assays provide similar prognostic information. From January 2001 to February 2004, 3 different TnI assays (Beckman Access TnI, Beckman Access AccuTnI, and Vitros ECI Troponin) were used to evaluate the peak TO value in 1,152 consecutive patients admitted with suspected acute coronary syndrome/non-ST-elevation myocardial infarction (MI). Recommended cutoffs were used to differentiate borderline from marked increases reported as consistent with MI. Clinical data and 30-day death/new MIs were determined by chart abstraction. Demographics and cardiac risk factors were similar for the 3 groups. Frequency of borderline TnI ranged widely among assays (18.7% to 42.1%) but was significantly less with the Vitros ECI Troponin assay (p < 0.0001). Prognostic significance of borderline increased TnI values also varied greatly by assay, with borderline Beckman Access AccuTnI increases being predictive of adverse 30-day outcomes (odds ratio 4.0, 95% confidence interval 1.46 to 10.97, p = 0.007), but not with the other 2 assays. Borderline increases were significantly associated with chronic renal insufficiency (CRI; serum creatine > 1.5); the relation to adverse 30-day outcomes and borderline increases persisted after correcting for CRI in a multivariate logistic regression model. In conclusion, although borderline increased TnI levels are common and significantly associated with CRI, they do not all portend the same clinical prognosis. This study highlights the need for standardization of TnI levels across different assays. (C) 2009 Published by Elsevier Inc. (Am J Cardiol 2009;104:164-168) C1 [Zahid, Maliha; Good, Chester B.; Singla, Ish; Sonel, Ali F.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Good, Chester B.; Sonel, Ali F.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Good, Chester B.; Sonel, Ali F.] Ctr Healthy Equ & Res Promot, Pittsburgh, PA USA. RP Zahid, M (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM maz7@pitt.edu NR 11 TC 10 Z9 10 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 JUL 15 PY 2009 VL 104 IS 2 BP 164 EP 168 DI 10.1016/j.amjcard.2009.03.012 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 477TB UT WOS:000268540500003 PM 19576340 ER PT J AU Melloni, C Alexander, KP Ou, FS LaPointe, NMA Roe, MT Newby, LK Baloch, K Ho, PM Rumsfeld, JS Peterson, ED AF Melloni, Chiara Alexander, Karen P. Ou, Fang-Shu LaPointe, Nancy M. Allen Roe, Matthew T. Newby, L. Kristin Baloch, Khaula Ho, P. Michael Rumsfeld, John S. Peterson, Eric D. TI Predictors of Early Discontinuation of Evidence-Based Medicine After Acute Coronary Syndrome SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; MEDICATION ADHERENCE; PATIENT COMMUNICATION; SECONDARY PREVENTION; ADVERSE OUTCOMES; ARTERY-DISEASE; THERAPY; MORTALITY; NONADHERENCE; ASSOCIATION AB Use of evidence-based medicine (EBM) improves outcomes after acute coronary syndromes (ACS), yet patients often discontinue prescribed therapies after discharge. Although such discontinuation is well documented, patients' reasons for medication discontinuation have not been reported. MAINTAIN is a longitudinal follow-up registry of CRUSADE/ACTION, which enrolled patients during an ACS hospitalization from January 2006 to September 2007. All discharge medications were obtained from hospital charts. Patients were interviewed by telephone 3 months after discharge to determine if EBM classes prescribed at discharge were continued (aspirin, clopidogrel, beta blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and lipid-lowering medications). If discontinuation occurred, patients were asked if it was with provider knowledge/input or not (self-discontinuation). A multivariable logistic regression model was performed to identify factors associated with self-discontinuation of prescribed EBM. Of the 1,077 patients interviewed, 1,006 (93.4%) were discharged on aspirin, 816 (75.8%) on clopidogrel, 982 (91.2%) on beta blockers, 745 (69.2%) on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 968 (89.9%) on lipid-lowering medications. At 3-month follow-up, 304 patients (28.2%) had discontinued >= 1 of these prescribed EBM classes. Although many reported provider involvement, most discontinuation (61.5%) was self-determined. Factors independently associated with self-discontinuation were no pharmacy coinsurance, increasing number of medications, not using reminder tools (e.g., pillbox), lower education, and dialysis. In conclusion, 1/3 of patients with ACS discontinue >= 1 of their prescribed EBMs within 3 months of hospital discharge, and most of this discontinuation is without provider involvement. Patient education, better prescription drug coverage, and reminder strategies may improve use of EBMs at 3 months after discharge from ACS admission. (C) 2009 Published by Elsevier Inc. (Am J Cardiol 2009;104:175-181) C1 [Melloni, Chiara; Alexander, Karen P.; Ou, Fang-Shu; Roe, Matthew T.; Newby, L. Kristin; Baloch, Khaula; Peterson, Eric D.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Melloni, Chiara; Alexander, Karen P.; Ou, Fang-Shu; Roe, Matthew T.; Newby, L. Kristin; Baloch, Khaula; Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [LaPointe, Nancy M. Allen] Duke Univ, Med Ctr, Div Clin Pharmacol, Durham, NC 27710 USA. [Ho, P. Michael; Rumsfeld, John S.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Ho, P. Michael; Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. RP Melloni, C (reprint author), Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. EM mello004@mc.duke.edu FU Bristol-Myers Squibb/Sanoti-Aventis Pharmaceuticals; Merck Schering-Plough Pharmaceutical FX MAINTAIN is funded by Bristol-Myers Squibb/Sanoti-Aventis Pharmaceuticals partnership and by Merck Schering-Plough Pharmaceutical. NR 28 TC 51 Z9 56 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2009 VL 104 IS 2 BP 175 EP 181 DI 10.1016/j.amjcard.2009.03.013 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 477TB UT WOS:000268540500005 PM 19576342 ER PT J AU Dhaliwal, AS Habib, G Deswal, A Verduzco, M Souchek, J Ramasubbu, K Aguilar, D Ma, TS Jneid, HM Bolos, M Bozkurt, B AF Dhaliwal, Amandeep S. Habib, Gabriel Deswal, Anita Verduzco, Melinda Souchek, Julianne Ramasubbu, Kumudha Aguilar, David Ma, Tony S. Jneid, Hani M. Bolos, Mariana Bozkurt, Biykem TI Impact of Alpha 1-Adrenergic Antagonist Use for Benign Prostatic Hypertrophy on Outcomes in Patients With Heart Failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; DOUBLE-BLIND; ALPHA(1)-ADRENERGIC RECEPTORS; PLASMA NOREPINEPHRINE; HYPERTENSIVE PATIENTS; ALPHA-ADRENOCEPTOR; PRAZOSIN THERAPY; CARVEDILOL; DOXAZOSIN; TRIAL AB Previous clinical trials have shown that alpha(1)-adrenergic antagonists are not effective in subjects with heart failure (HF) and might increase HF rates when used for hypertension. However, alpha(1)-adrenergic antagonists may be prescribed to subjects with HF who have symptomatic benign prostatic hyperplasia. We sought to determine any association between alpha(1)-adrenergic antagonist use, commonly prescribed for benign prostatic hyperplasia, and the clinical outcomes of subjects with HF receiving contemporary therapy. An existing database of 388 subjects with decompensated HF admissions from 2002 to 2004 at the Veterans Affairs Hospital was analyzed according to the use of alpha(1)-adrenergic antagonists at discharge. Covariate-adjusted Cox proportional hazard models were used to examine any association with future admissions for decompensated HF and total mortality. Alpha-1-adrenergic antagonist therapy was prescribed in 25% of our HF population, predominantly for benign prostatic hyperplasia, and was not associated with significant increases in the combined risk of all-cause mortality and rehospitalization for HF (hazard ratio 1.24, 95% confidence interval 0.93 to 1.65, p = 0.14), HF hospitalization (hazard ratio 1.20, 95% confidence interval 0.85 to 1.70, p 0.31), or all-cause mortality (hazard ratio 1.10, 95% confidence interval 0.78 to 1.56, p 0.57). In patients not receiving beta-blocker therapy, alpha(1)-adrenergic antagonist therapy was significantly associated with increased HF hospitalizations (hazard ratio 1.94, 95% confidence interval 1.14 to 3.32, p = 0.015). In conclusion, in patients with chronic HF, the use of alpha(1)-adrenergic antagonists was significantly associated with more HF hospitalizations when prescribed without concomitant beta blockade. Thus, background beta-blocker therapy appears to be protective against the potential harmful effects of alpha(1)-adrenergic antagonist therapy in patients with HF. Published by Elsevier Inc. (Am J Cardiol 2009;104:270-275) C1 [Dhaliwal, Amandeep S.; Habib, Gabriel; Deswal, Anita; Verduzco, Melinda; Souchek, Julianne; Ramasubbu, Kumudha; Ma, Tony S.; Jneid, Hani M.; Bozkurt, Biykem] Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Cardiol Sect, Houston, TX USA. [Deswal, Anita; Ramasubbu, Kumudha; Aguilar, David; Bolos, Mariana; Bozkurt, Biykem] Baylor Coll Med, Winters Ctr Heart Failure Res, Houston, TX 77030 USA. RP Bozkurt, B (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Cardiol Sect, Houston, TX USA. EM bbozkurt@bcm.tmc.edu FU Veterans Affairs Medical Research Service; National Institutes of Health, Bethesda, Maryland [NIH-K12] FX Dr. Bozkurt is a recipient of a Merit Entry Level grant support from the Veterans Affairs Medical Research Service. Dr. Aguilar is a recipient of the Mentored Clinical Scientist Development Program (NIH-K12 Award) award from the National Institutes of Health, Bethesda, Maryland. NR 29 TC 7 Z9 10 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 JUL 15 PY 2009 VL 104 IS 2 BP 270 EP 275 DI 10.1016/j.amjcard.2009.03.030 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 477TB UT WOS:000268540500022 PM 19576359 ER PT J AU Jensen, JK Atar, D Kristensen, SR Mickley, H Januzzi, JL AF Jensen, Jesper K. Atar, Dan Kristensen, Soren R. Mickley, Hans Januzzi, James L., Jr. TI Usefulness of Natriuretic Peptide Testing for Long-Term Risk Assessment Following Acute Ischemic Stroke SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HEART-FAILURE; PROGNOSTIC VALUE; PLASMA-LEVELS; NT-PROBNP; MORTALITY; TRIAL; DISEASE; DIAGNOSIS; SUBTYPES; TIME AB Acute-phase levels of B-type natriuretic peptide (BNP) and the N-terminal fragment of the BNP prohormone (NT-pro-BNP) have been associated with mortality when measured in patients with an acute ischemic stroke; however, data regarding the longer-term value of NT-pro-BNP for long-term prognostication after ischemic stroke are limited. Two hundred sixteen patients (mean age 67 +/- 13 years) with acute ischemic stroke were seen 6 months after index admission at which time a structured evaluation including measurement of plasma NT-pro-BNP was performed. Patients were followed for 45 months, with all-cause mortality as the clinical end point. Median NT-pro-BNP concentration for the entire group was 147 pg/ml (10th to 90th percentiles 37 to 869). At follow-up 45 patients (21%) had died. NT-pro-BNP concentrations were significantly higher in decedents (308 pg/ml, 10th to 90th percentiles 74 to 2,279) than in the 171 survivors (132 pg/ml, 10th to 90th percentiles 35 to 570, p < 0.001). Patients with NT-pro-BNP <= 147 pg/ml had a significantly improved survival rate on univariate analysis (p < 0.001). In multivariate analysis after adjustment for age, stroke severity, heart and renal failures, levels of NT-pro-BNP were an independent predictor of mortality > 6 months after stroke (adjusted hazard ratio 1.5, 95% confidence interval 1.1 to 1.9, p = 0.005). In conclusion, NT-pro-BNP concentrations measured during the stable phase after acute ischemic stroke are strongly predictive of long-term mortality. (C) 2009 Elsevier Inc. (Am J Cardiol 2009;104:287-291) C1 [Jensen, Jesper K.; Mickley, Hans] Odense Univ Hosp, Dept Cardiol, DK-5000 Odense, Denmark. [Atar, Dan] Aarhus Univ Hosp, Aalborg Hosp, Cardiovasc Res Ctr, Dept Clin Biochem, Aalborg, Denmark. [Kristensen, Soren R.] Univ Oslo, Aker Univ Hosp, Div Cardiol, Oslo, Norway. [Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Jensen, JK (reprint author), Odense Univ Hosp, Dept Cardiol, DK-5000 Odense, Denmark. EM jesperkjensen@dadlnet.dk RI Kristensen, Soren/D-4440-2013 OI Kristensen, Soren/0000-0002-2649-506X FU Klinisk Institut at Odense University Hospital, Odense, Denmark; Novo Nordisk Foundation, Copenhagen, Denmark; Danish Heart Foundation FX This study was supported by a grant front the Klinisk Institut at Odense University Hospital, Odense, Denmark, and the Novo Nordisk Foundation, Copenhagen, Denmark. Dr. Jensen was supported by a grant from the Danish Heart Foundation. NR 28 TC 17 Z9 19 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2009 VL 104 IS 2 BP 287 EP 291 DI 10.1016/j.amjcard.2009.03.029 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 477TB UT WOS:000268540500025 PM 19576362 ER PT J AU Hernandez, JO Norstrom, J Wysock, G AF Hernandez, Jovino Ocasio Norstrom, Jeni Wysock, Glenn TI Acyclovir-induced renal failure in an obese patient SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE Acyclovir; Antivirals; Doxycycline; Kidney failure; Moxifloxacin; Obesity; Toxicity ID INTRAVENOUS ACYCLOVIR; NEPHROTOXICITY AB Purpose. A case of acyclovir-induced acute renal failure in an obese patient is described. Summary. A 60-year-old white man arrived at the emergency department complaining of confusion and disorientation. He was 5 ft 7 in tall and weighed 108.9 kg. His medical and surgical histories included chronic obstructive pulmonary disease (COPD), sleep apnea not requiring biphasic positive airway pressure, obesity, oxygen supplementation, and appendectomy. He also had a history of cyst drainage on the back of his neck, with recent drainage emitting a foul odor, and suffered recurrent herpes cold sores on his chin. A lumbar puncture revealed abnormal cerebral spinal fluid. A diagnosis of herpes encephalitis was considered, and the patient was empirically treated with i.v. acyclovir 1 g over 60 minutes every eight hours, with the dosage based on actual body weight. He was also given moxifloxacin 400 mg i.v. daily for possible COPD exacerbation and doxycycline 100 mg i.v. twice daily for possible leptospirosis meningitis. On hospital day 3, his serum creatinine (SCr) and blood urea nitrogen (BUN) concentrations rose to 2.8 g/dL and 32 mg/dL, respectively. Acyclovir was subsequently discontinued, as were all i.v. antibiotics. On day 7, hydration therapy was initiated, as was therapy to alkalinize the urine, and his neurologic status began to improve. At discharge, the patient's SCr and BUN levels were 3.1 g/dL and 38 mg/dL, respectively. His discharge diagnoses included encephalitis with possible viral origin and acyclovir-induced nephrotoxicity. Conclusion. An obese man receiving excessive doses of i.v. acyclovir developed acute but reversible renal failure. C1 [Hernandez, Jovino Ocasio] Winter Haven Hosp, Serv Pharm, Winter Haven, FL 33881 USA. [Norstrom, Jeni] VA Boston Healthcare Syst, Boston, MA USA. [Norstrom, Jeni] Univ Florida, Sch Pharm, Gainesville, FL USA. RP Hernandez, JO (reprint author), Winter Haven Hosp, Serv Pharm, 200 Ave F NE, Winter Haven, FL 33881 USA. EM jovino.hernandez@mfms.com NR 22 TC 8 Z9 8 U1 2 U2 2 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUL 15 PY 2009 VL 66 IS 14 BP 1288 EP 1291 DI 10.2146/ajhp080307 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 467UW UT WOS:000267769600015 PM 19574603 ER PT J AU Hung, WW Wisnivesky, JP Siu, AL Ross, JS AF Hung, William W. Wisnivesky, Juan P. Siu, Albert L. Ross, Joseph S. TI Cognitive Decline among Patients with Chronic Obstructive Pulmonary Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chronic obstructive pulmonary disease; cognitive impairment; longitudinal survey ID IMPAIRMENT; DEFICITS; COPD AB Rationale: Prior research has suggested an association between chronic obstructive pulmonary disease (COPD) and the development of cognitive decline; however, these studies have been cross-sectional or small case series. Objectives: To determine whether COPD increases the risk of cognitive decline among older adults surveyed in a large, population-based longitudinal cohort. Methods: We included data from the 1996 to 2002 waves of the Health and Retirement Study, a biennial nationally representative survey. We studied respondents who completed cognitive testing in 1996 and at least one subsequent survey, and excluded those with unknown history of COPD. Clinical history of COPD was based on self-report; severity was categorized based on use of oxygen or disease-related activity limitations. Our primary outcome was cognitive performance, measured using a validated 35-point scale. We examined the effect of COPD on cognition using multivariable mixed linear models accounting for repeated measurements, adjusted for sociodemographic and clinical characteristics. Measurements and Main Results: A total of 4,150 adults were included in our study. Among them, 12% reported a history of COPD (29% severe, 71% nonsevere disease). On repeated measurement, mean cognition scores of older adults with both severe and nonsevere COPD were significantly lower when compared with adults without COPD (2.6 points [P < 0.001] and 0.9 points [P < 0,001], respectively). After multivariable adjustment, mean scores of adults with severe COPD remained lower (0.9 point [P < 0.001]), whereas mean score of adults with nonsevere COPD was no longer different (P = 0.39) when compared with adults without COPD. Conclusions. Severe COPD was associated with lower cognitive performance on standardized measurement over time. C1 [Hung, William W.; Siu, Albert L.; Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY 10029 USA. [Wisnivesky, Juan P.] Mt Sinai Sch Med, Dept Med, Div Gen Internal Med, New York, NY 10029 USA. [Wisnivesky, Juan P.] Mt Sinai Sch Med, Dept Med, Div Pulm Crit Care & Sleep Med, New York, NY 10029 USA. [Hung, William W.; Siu, Albert L.; Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Hung, William W.; Siu, Albert L.; Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Hlth Serv Res & Dev, Serv Res Enhancement Award Program, Bronx, NY USA. RP Hung, WW (reprint author), Mt Sinai Sch Med, Dept Geriatr & Adult Dev, 1 Gustave L Levy Pl,Box 1070, New York, NY 10029 USA. EM william.hung@mssm.edu NR 23 TC 57 Z9 61 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2009 VL 180 IS 2 BP 134 EP 137 DI 10.1164/rccm.200902-0276OC PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 472EP UT WOS:000268112500007 PM 19423714 ER PT J AU Wong, K Lyddon, R Dracheva, S AF Wong, Kevin Lyddon, Rebecca Dracheva, Stella TI TaqMan-based, real-time quantitative polymerase chain reaction method for RNA editing analysis SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE RNA editing; GluR5; Multiplex qPCR; Taqman ID SEROTONIN 2C RECEPTOR; PCR DATA-ANALYSIS; MESSENGER-RNA; ADENOSINE; TRANSMISSION; DEAMINASES; MECHANISM; CORTEX; GLUR2; BRAIN AB Abnormal adenosine to inosine (A-to-1) messenger RNA (mRNA) editing has been linked to several disease states afflicting the central nervous system. Here we report an assay to determine RNA editing frequencies at specific sites that is based on quantitative polymerase chain reaction (qPCR) with TaqMan probes. The assay was tested by measuring the frequency of the A-to-1 mRNA editing at the Q/R site of the human kainate receptor Subunit GluR5 and was compared with two established methods of assessing RNA editing: sequencing of individual clones and restriction analysis. The qPCR assay displayed high sensitivity and reproducibility, demonstrated exceptional discrimination between edited and Unedited transcript variants, and proved to have several advantages over the other editing methods. Due to the fact that TaqMan-based qPCR technology can be easily adapted to different editing targets, the increased capabilities afforded by this new technique should facilitate various RNA editing studies that aim to elucidate the role of this process in normal physiology and in disease. Published by Elsevier Inc. Published by Elsevier Inc. C1 [Wong, Kevin; Dracheva, Stella] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [Lyddon, Rebecca; Dracheva, Stella] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP Dracheva, S (reprint author), Bronx VA Med Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM stella.dracheva@mssm.edu FU VA Merit award; American Foundation for Suicide Prevention; VISN3 Mental Illness Research and Education Clinical Center (MIRECC) FX Postmortem brain tissue was donated by the Stanley Medical Research Institute's array Collection Courtesy of Michael B. Knable, E. Fuller Torrey, Maree J Webster, and Robert H. Yolken. This Study was supported by a VA Merit award (S.D.), a grant from the American Foundation for Suicide Prevention (S.D.), and the VISN3 Mental Illness Research and Education Clinical Center (MIRECC). NR 28 TC 6 Z9 6 U1 2 U2 3 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 JUL 15 PY 2009 VL 390 IS 2 BP 173 EP 180 DI 10.1016/j.ab.2009.04.011 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 457QB UT WOS:000266946000011 PM 19371717 ER PT J AU Daniel, KD Kim, GY Vassiliou, CC Galindo, M Guimaraes, AR Weissleder, R Charest, A Langer, R Cima, MJ AF Daniel, Karen D. Kim, Grace Y. Vassiliou, Christophoros C. Galindo, Marilyn Guimaraes, Alexander R. Weissleder, Ralph Charest, Al Langer, Robert Cima, Michael J. TI Implantable diagnostic device for cancer monitoring SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Magnetic nanoparticle; Cancer biomarker; In vivo sensor; Human chorionic gonadotrophin ID HUMAN CHORIONIC-GONADOTROPIN; FREE BETA-SUBUNIT; PARATHYROID-HORMONE; SERUM; NANOPARTICLES; RECURRENCE; BIOMARKERS; ACCURACY; ASCITES; MARKERS AB Biopsies provide required information to diagnose cancer but, because of their invasiveness, they are difficult to use for managing cancer therapy. The ability to repeatedly sample the local environment for tumor biomarker, chemotherapeutic agent, and tumor metabolite concentrations could improve early detection of metastasis and personalized therapy. Here we describe an implantable diagnostic device that senses the local in vivo environment. This device, which could be left behind during biopsy, uses a semi-permeable membrane to contain nanoparticle magnetic relaxation switches. A cell line secreting a model cancer biomarker produced ectopic tumors in mice. The transverse relaxation time (T(2)) of devices in tumor-bearing mice was 20 +/- 10% lower than devices in control mice after 1 day by magnetic resonance imaging (p < 0.01). Short term applications for this device are numerous, including verification of successful tumor resection. This may represent the first continuous monitoring device for soluble cancer biomarkers; in vivo. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kim, Grace Y.; Cima, Michael J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Langer, Robert; Cima, Michael J.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Langer, Robert] MIT, Div Biol Engn, Cambridge, MA 02139 USA. [Charest, Al] Tufts Med Ctr, Dept Neurosurg, Boston, MA USA. [Charest, Al] MIT, Dept Biol, Cambridge, MA 02139 USA. [Charest, Al] MIT, Ctr Canc Res, Cambridge, MA 02139 USA. [Guimaraes, Alexander R.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Guimaraes, Alexander R.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Vassiliou, Christophoros C.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Kim, Grace Y.; Langer, Robert] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. [Daniel, Karen D.; Galindo, Marilyn; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Cima, MJ (reprint author), MIT, Dept Mat Sci & Engn, 77 Massachusetts Ave,Room 12-011, Cambridge, MA 02139 USA. EM mjcima@mit.edu FU NCI Centers of Cancer Nanotechnology Excellence [5 U54 CA119349-12]; NSF Division of Materials Research Award [0746264] FX This work was supported by NCI Centers of Cancer Nanotechnology Excellence No. 5 U54 CA119349-12 grant and NSF Division of Materials Research Award No. 0746264. We would like to acknowledge Stephen Woolfenden for assistance with in vivo studies and Lee Josephson at CMIR for assistance with MRSw. NR 28 TC 27 Z9 28 U1 0 U2 26 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD JUL 15 PY 2009 VL 24 IS 11 BP 3252 EP 3257 DI 10.1016/j.bios.2009.04.010 PG 6 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA 465IY UT WOS:000267577900012 PM 19442510 ER PT J AU Fujiwara, N Murata, Y Arai, K Egi, Y Lu, J Wu, O Singhal, AB Lo, EH AF Fujiwara, Norio Murata, Yoshihiro Arai, Ken Egi, Yasuhiro Lu, Jie Wu, Ona Singhal, Aneesh B. Lo, Eng H. TI Combination therapy with normobaric oxygen (NBO) plus thrombolysis in experimental ischemic stroke SO BMC NEUROSCIENCE LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; TISSUE-PLASMINOGEN ACTIVATOR; HYPERBARIC OXYGENATION; TIME WINDOW; RAT MODEL; HYPEROXIA; BRAIN; NEUROPROTECTION; REPERFUSION; FUTURE AB Background: The widespread use of tissue plasminogen activator (tPA), the only FDA-approved acute stroke treatment, remains limited by its narrow therapeutic time window and related risks of brain hemorrhage. Normobaric oxygen therapy (NBO) may be a useful physiological strategy that slows down the process of cerebral infarction, thus potentially allowing for delayed or more effective thrombolysis. In this study we investigated the effects of NBO started simultaneously with intravenous tPA, in spontaneously hypertensive rats subjected to embolic middle cerebral artery (MCA) stroke. After homologous clot injection, animals were randomized into different treatment groups: saline injected at 1 hour; tPA at 1 hour; saline at 1 hour plus NBO; tPA at 1 hour plus NBO. NBO was maintained for 3 hours. Infarct volume, brain swelling and hemorrhagic transformation were quantified at 24 hours. Outcome assessments were blinded to therapy. Results: Upon clot injection, cerebral perfusion in the MCA territory dropped below 20% of pre-ischemic baselines. Both tPA-treated groups showed effective thrombolysis (perfusion restored to nearly 100%) and smaller infarct volumes (379 +/- 57 mm(3) saline controls; 309 +/- 58 mm(3) NBO; 201 +/- 78 mm(3) tPA; 138 +/- 30 mm(3) tPA plus NBO), showing that tPA-induced reperfusion salvages ischemic tissue and that NBO does not significantly alter this neuroprotective effect. NBO had no significant effect on hemorrhagic conversion, brain swelling, or mortality. Conclusion: NBO can be safely co-administered with tPA. The efficacy of tPA thrombolysis is not affected and there is no induction of brain hemorrhage or edema. These experimental results require clinical confirmation. C1 [Singhal, Aneesh B.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Neuroprotect Res Lab, Boston, MA 02115 USA. [Fujiwara, Norio; Murata, Yoshihiro; Arai, Ken; Egi, Yasuhiro; Lu, Jie; Wu, Ona; Lo, Eng H.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Neuroprotect Res Lab, Boston, MA 02115 USA. RP Singhal, AB (reprint author), Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Neuroprotect Res Lab, Boston, MA 02115 USA. EM nfujiwara@partners.org; asinghal2@gmail.com; karai@partners.org; yasu.egi@gmail.com; lucy_lj1124@yahoo.com; onawu@partners.org; asinghal@partners.org; Lo@helix.mgh.harvard.edu FU NIH [R01-NS51412, P50-NS51343, P50-NS10828, R01-NS48422, R01-NS56458, R37-NS37074] FX The authors gratefully thank Dr. Xiaoying Wang and our SPOTRIAS co-investigators for helpful discussions. Supported in part by NIH grants R01-NS51412, P50-NS51343, P50-NS10828, R01-NS48422, R01-NS56458, and R37-NS37074. NR 31 TC 26 Z9 28 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD JUL 15 PY 2009 VL 10 AR 79 DI 10.1186/1471-2202-10-79 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 480AH UT WOS:000268703300003 PM 19604385 ER PT J AU Saphner, T Triest-Robertson, S Li, HL Holzman, P AF Saphner, Tom Triest-Robertson, Shirley Li, Hailun Holzman, Paul TI The Association of Nonalcoholic Steatohepatitis and Tamoxifen in Patients With Breast Cancer SO CANCER LA English DT Article DE body mass index; cirrhosis; diabetes; fatty liver disease; tamoxifen-induced hepatic steatosis; tamoxifen; nonalcoholic steatohepatitis; NASH; fatty liver disease ID NON-ALCOHOLIC STEATOHEPATITIS; ADJUVANT TAMOXIFEN; HEPATIC STEATOSIS; FATTY LIVER; THERAPY; BEZAFIBRATE; CIRRHOSIS; WOMEN; NASH AB BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a form of liver damage that can progress to cirrhosis. NASH is associated with obesity and diabetes. The condition also may be associated with some medications, including tamoxifen. Early case reports and small series have documented NASH in patients who received tamoxifen. METHODS: The records of patients registered in the St. Vincent Hospital Cancer Registry of Green Bay Wisconsin from January 1, 1992 to December 31, 2000 were reviewed. RESULTS: In total, 1105 patients with breast cancer were evaluated for NASH, and 24 cases of NASH were documented (2.2%). Seven patients had NASH before their diagnosis of breast cancer, and 17 patients developed NASH after their diagnosis of breast cancer. In multivariate analysis, the factors associated with NASH were tamoxifen use (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.06-63.72), body mass index (BMI) (OR, 1.13; 95% CI, 1.06-1.20), and age (OR, 95% CI, 0.91-0.99). NASH improved after tamoxifen was stopped. After discontinuation of tamoxifen, transaminase levels returned to normal in 14 of 16 patients. CONCLUSIONS: NASH was present in 24 of 1105 patients with breast cancer (2.2%). Seven patients had NASH before they were diagnosed with breast cancer, and 17 patients developed NASH after their diagnosis. NASH was associated with the use of tamoxifen and improved when tamoxifen was stopped. Cancer 2009;115:3189-95. (C) 2009 American Cancer Society. C1 [Saphner, Tom] St Marys Hosp, Dept Oncol, Green Bay, WI USA. [Triest-Robertson, Shirley] St Vincents Hosp, Dept Oncol, Green Bay, WI USA. [Li, Hailun] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Holzman, Paul] St Marys Hosp, Dept Pathol, Green Bay, WI USA. RP Saphner, T (reprint author), Green Bay Oncol, POB 13453, Green Bay, WI 54307 USA. EM tsaphner@gboncology.com NR 36 TC 25 Z9 29 U1 1 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 JUL 15 PY 2009 VL 115 IS 14 BP 3189 EP 3195 DI 10.1002/cncr.24374 PG 7 WC Oncology SC Oncology GA 468JM UT WOS:000267813700006 PM 19484789 ER PT J AU Donelan, K Hobrecker, K Schapira, L Mailhot, JR Goulart, BH Chabner, BA AF Donelan, Karen Hobrecker, Karin Schapira, Lidia Mailhot, Johanna R. Goulart, Bernardo H. Chabner, Bruce A. TI Medical Interpreter Knowledge of Cancer and Cancer Clinical Trials SO CANCER LA English DT Article DE cancer; clinical trials; disparities; limited English proficiency ID CARE; COMMUNICATION; SERVICES AB BACKGROUND: Cancer patients with limited English proficiency may need specialized assistance to communicate with health professionals about cancer and clinical trials. METHODS: Medical interpreters working in several Boston-area hospitals were invited to participate in training sessions about cancer and cancer clinical trials. We did a pre and post survey-based assessment of knowledge of basic concepts in cancer and clinical trials, and post assessment of satisfaction, among 97 interpreters in cancer training and education sessions and 79 participants in clinical trial training and education sessions. RESULTS: Participants had a range of prior experience with interpretation in the context of cancer and clinical trials. Training increased mean accuracy from 49% to 72% in knowledge items about cancer, and from 72% to 78% in knowledge about clinical trials. Interpreters reported several areas of concern with respect to standards of practice. CONCLUSIONS: Pretest surveys of medical interpreters revealed several areas of important knowledge gaps about cancer and clinical trials. Posttest assessment showed that training can be useful to improving short-term accuracy, but that more work is needed to develop curricula and testing measures to address these knowledge gaps. Cancer 2009;115:3283-92. (C) 2009 American Cancer Society. C1 [Donelan, Karen] Massachusetts Gen Hosp, Inst Technol Assessment, Patient Care Serv, Boston, MA 02114 USA. [Donelan, Karen; Mailhot, Johanna R.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Schapira, Lidia; Chabner, Bruce A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Goulart, Bernardo H.] Univ Washington, Div Hematol, Med Ctr, Seattle, WA 98195 USA. RP Donelan, K (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Patient Care Serv, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM kdonelan@partners.org FU National Cancer Institute award to Massachusetts General Hospital [5 R21 CA101712-02] FX Funding for interpreter participation in training sessions was provided by the National Cancer Institute award to Massachusetts General Hospital, 5 R21 CA101712-02 (Bruce A Chabner, principal Investigator). NR 24 TC 5 Z9 5 U1 2 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2009 VL 115 IS 14 BP 3283 EP 3292 DI 10.1002/cncr.24377 PG 10 WC Oncology SC Oncology GA 468JM UT WOS:000267813700016 PM 19484791 ER PT J AU Mack, JW Block, SD Nilsson, M Wright, A Trice, E Friedlander, R Paulk, E Prigerson, HG AF Mack, Jennifer W. Block, Susan D. Nilsson, Matthew Wright, Alexi Trice, Elizabeth Friedlander, Robert Paulk, Elizabeth Prigerson, Holly G. TI Measuring Therapeutic Alliance Between Oncologists and Patients With Advanced Cancer The Human Connection Scale SO CANCER LA English DT Article DE end-of-life care; health-related quality of life; patient-physician relationship; peaceful acceptance; terminal illness; trust ID QUALITY-OF-LIFE; PALLIATIVE CARE; COMMUNICATION-SKILLS; TERMINAL ILLNESS; WORKING ALLIANCE; DYING PATIENTS; END; PERSPECTIVES; PROGNOSIS; DISEASE AB BACKGROUND: Patients consider their human connection with a physician an important aspect of end-of-life (EOL) care. In this study, the authors sought to develop and validate a measure of therapeutic alliance between patients with advanced cancer and their physicians and to evaluate the effects of therapeutic alliance on EOL experiences and care. METHODS: The Human Connection (THC) scale was developed to measure the extent to which patients felt a sense of mutual understanding, caring, and trust with their physicians. The scale was administered to 217 patients with advanced cancer along with measures of attributes that have been related hypothetically to therapeutic alliance, including emotional acceptance of terminal illness. EOL outcomes in 90 patients who died during the study also were examined. RESULTS: The 16-item THC questionnaire was consistent internally (Cronbach alpha = .90) and valid based on its expected positive association with emotional acceptance of terminal illness (r = .31; P < .0001). THC scores were related inversely to symptom burden (r = -.19; P = .006), functional status (Karnofsky performance status; r = .22; P = .001), and mental illness (THC score: 50.69 for patients with any Diagnostic and Statistical Manual [DSM] diagnosis vs 55.22 for patients with no DSM diagnosis; P = .03). THC scores were not associated significantly with EOL discussions (P = .68). Among the patients who died, EOL intensive care unit (ICU) care was associated inversely with therapeutic alliance (THC score: 46.5 for patients who received ICU care vs 55.5 for patients without ICU care; P = .002), so that patients with higher THC scores were less likely to spend time in the ICU during the last week of life. CONCLUSIONS: The THC scale is a valid and reliable measure of therapeutic alliance between patients with advanced cancer and their physicians. In addition, there was no evidence to suggest that EOL discussions harm patients' therapeutic alliance. A strong therapeutic alliance was associated with emotional acceptance of a terminal illness and with decreased ICU care at the EOL among patients with advanced cancer. Cancer 2009;115:3302-11. (C) 2009 American Cancer Society. C1 [Mack, Jennifer W.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mack, Jennifer W.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Mack, Jennifer W.] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Block, Susan D.; Nilsson, Matthew; Wright, Alexi; Trice, Elizabeth; Prigerson, Holly G.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. [Wright, Alexi; Trice, Elizabeth] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Friedlander, Robert] New Hampshire Oncol Hematol PA, Hooksett, NH USA. [Paulk, Elizabeth] Univ Texas SW Med Ctr Dallas, Palliat Care Serv, Dallas, TX 75390 USA. RP Mack, JW (reprint author), Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM jennifer_mack@dfci.harvard.edu FU National Institute of Mental Health [MH63892]; National Cancer Institute [CA106370]; Center for Psycho-Oncology and Palliative Care Research, Dana-Farber Cancer Institute; American Cancer Society Mentored Research Scholar Grant FX Dr. Mack was Supported by an American Cancer Society Mentored Research Scholar Grant. NR 48 TC 45 Z9 45 U1 3 U2 16 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2009 VL 115 IS 14 BP 3302 EP 3311 DI 10.1002/cncr.24360 PG 10 WC Oncology SC Oncology GA 468JM UT WOS:000267813700018 PM 19484795 ER PT J AU Ho-Tin-Noe, B Goerge, T Wagner, DD AF Ho-Tin-Noe, Benoit Goerge, Tobias Wagner, Denisa D. TI Platelets: Guardians of Tumor Vasculature SO CANCER RESEARCH LA English DT Review ID ENDOTHELIAL INTERACTION; P-SELECTIN; ANGIOGENESIS; HEMORRHAGE; CANCER; MICROVASCULATURE; THROMBOCYTOPENIA; ANGIOPOIETIN-1; PRESERVATION; INTEGRITY AB Solid tumors generate a prothrombotic environment capable of platelet activation. Recent findings indicate that the activated platelets are crucial regulators of tumor vascular homeostasis in that they prevent tumor hemorrhage. Surprisingly, this effect is independent of platelets' capacity to form thrombi and instead relies on the secretion of their granule content. Thus, targeting platelet secretory activities may represent a new approach to specifically destabilize tumor vasculature. [Cancer Res 2009;69(14):5623-6] C1 [Ho-Tin-Noe, Benoit; Goerge, Tobias; Wagner, Denisa D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Ho-Tin-Noe, Benoit; Goerge, Tobias; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ho-Tin-Noe, Benoit] Hop Xavier Bichat, INSERM, U698, Paris, France. [Goerge, Tobias] Univ Munster, Dept Dermatol, D-4400 Munster, Germany. RP Wagner, DD (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM wagner@idi.harvard.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [P01 HL066105, R37 HL041002] FX Grant support: National Heart, Lung, and Blood Institute of the National Institutes of Health grants P01 HL066105 and R37 HL041002 (to D.D. Wagner). NR 31 TC 35 Z9 35 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 JUL 15 PY 2009 VL 69 IS 14 BP 5623 EP 5626 DI 10.1158/0008-5472.CAN-09-1370 PG 4 WC Oncology SC Oncology GA 475LJ UT WOS:000268360300002 PM 19584268 ER PT J AU Rebbeck, TR Mitra, N Domchek, SM Wan, F Chuai, S Friebel, TM Panossian, S Spurdle, A Chenevix-Trench, G Singer, CF Pfeiler, G Neuhausen, SL Lynch, HT Garber, JE Weitzel, JN Isaacs, C Couch, F Narod, SA Rubinstein, WS Tomlinson, GE Ganz, PA Olopade, OI Tung, N Blum, JL Greenberg, R Nathanson, KL Daly, MB AF Rebbeck, Timothy R. Mitra, Nandita Domchek, Susan M. Wan, Fei Chuai, Shannon Friebel, Tara M. Panossian, Saarene Spurdle, Amanda Chenevix-Trench, Georgia Singer, Christian F. Pfeiler, Georg Neuhausen, Susan L. Lynch, Henry T. Garber, Judy E. Weitzel, Jeffrey N. Isaacs, Claudine Couch, Fergus Narod, Steven A. Rubinstein, Wendy S. Tomlinson, Gail E. Ganz, Patricia A. Olopade, Olufunmilayo I. Tung, Nadine Blum, Joanne L. Greenberg, Roger Nathanson, Katherine L. Daly, Mary B. CA kConFab TI Modification of Ovarian Cancer Risk by BRCA1/2-interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers SO CANCER RESEARCH LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; MODIFIES BREAST-CANCER; DNA-DAMAGE RESPONSE; UNKNOWN CLINICAL-SIGNIFICANCE; NBS1 GENE; HAPLOTYPE FREQUENCIES; SEQUENCE VARIANTS; 657DEL5 MUTATION; FANCONI-ANEMIA; REPAIR AB Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (P(corr)) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (P(corr) = 0.007). At NBS1, we observed a P(corr) = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (P(corr) = 0.044) and BARD1 (P(corr) = 0.012) were associated with ovarian cancer risk. At BNP1, two common haplotypes were significantly associated with ovarian cancer risk (P(corr) = 0.011). At MRE11, we observed a significant haplotype association (P(corr) = 0.012). and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (P(corr) = 0.026). Variants in genes that interact biologically with BRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801-10] C1 [Rebbeck, Timothy R.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.; Mitra, Nandita; Wan, Fei; Chuai, Shannon; Friebel, Tara M.; Panossian, Saarene] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Domchek, Susan M.; Greenberg, Roger; Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Daly, Mary B.] Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. [Spurdle, Amanda; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Singer, Christian F.; Pfeiler, Georg] Med Univ Vienna, Dept Obstet & Gynaecol, Vienna, Austria. [Neuhausen, Susan L.] Univ Calif Irvine, Dept Med, Div Epidemiol, Irvine, CA 92717 USA. [Lynch, Henry T.] Creighton Univ, Dept Med, Omaha, NE 68178 USA. [Lynch, Henry T.] Creighton Univ, Dept Prevent Med & Publ Hlth, Omaha, NE 68178 USA. [Garber, Judy E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Weitzel, Jeffrey N.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Isaacs, Claudine] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Couch, Fergus] Mayo Clin, Coll Med, Rochester, MN USA. [Narod, Steven A.] Womens Coll Hosp, Toronto, ON M5S 1B2, Canada. [Rubinstein, Wendy S.] NorthShore Univ HealthSyst, Evanston, IL USA. [Tomlinson, Gail E.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Tomlinson, Gail E.] Univ Texas SW Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. [Blum, Joanne L.] Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. [Tomlinson, Gail E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Olopade, Olufunmilayo I.] Univ Chicago, Chicago, IL 60637 USA. RP Rebbeck, TR (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, Abramson Canc Ctr, 217 Blockley Hall, Philadelphia, PA 19104 USA. EM rebbeck@mail.med.upenn.edu RI Spurdle, Amanda/A-4978-2011; OI Spurdle, Amanda/0000-0003-1337-7897; Nathanson, Katherine/0000-0002-6740-0901 FU NIH [5UO1 CA86389, R01-CA083855, R01-CA74115, P30-CA51008-19, R01-CA102776, M01 RR00043]; National Breast Cancer Foundation; National Health and Medical Research Council; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; Cancer Foundation of Western Australia FX Revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Death and Human Services. NIH grants 5UO1 CA86389 (H.T. Lynch), R01-CA083855 and R01-CA74115 (S.L. Neuhausen), P30-CA51008-19 (C. Isaacs), and R01-CA102776 and R01-CA083855 (T.R. Rebbeck) and NIH General Clinical Research Center grant M01 RR00043 awarded to the City of Hope National Medical Center (J.N. Weitzel). The Kathleen Cunningham Consortium for Research into Familial Breast Cancer is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. NR 46 TC 21 Z9 21 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2009 VL 69 IS 14 BP 5801 EP 5810 DI 10.1158/0008-5472.CAN-09-0625 PG 10 WC Oncology SC Oncology GA 475LJ UT WOS:000268360300026 PM 19584272 ER PT J AU McMillin, DW Ooi, M Delmore, J Negri, J Hayden, P Mitsiades, N Jakubikova, J Maira, SM Garcia-Echeverria, C Schlossman, R Munshi, NC Richardson, PG Anderson, KC Mitsiades, CS AF McMillin, Douglas W. Ooi, Melissa Delmore, Jake Negri, Joseph Hayden, Patrick Mitsiades, Nicolas Jakubikova, Jana Maira, Sauveur-Michel Garcia-Echeverria, Carlos Schlossman, Robert Munshi, Nikhil C. Richardson, Paul G. Anderson, Kenneth C. Mitsiades, Constantine S. TI Antimyeloma Activity of the Orally Bioavailable Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 SO CANCER RESEARCH LA English DT Article ID MULTIPLE-MYELOMA CELLS; SET ENRICHMENT ANALYSIS; GENE-EXPRESSION; THERAPEUTIC APPLICATIONS; IDENTIFICATION; SIGNATURE; GROWTH; CANCER; ACTIVATION; IDENTIFY AB The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway mediates proliferation, survival, and drug resistance in multiple myeloma (MM) cells. Here, we tested the anti-MM activity of NVP-BEZ235 (BEZ235), which inhibits PI3K/Akt/mTOR signaling at the levels of PI3K and mTOR. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric survival assays showed that MM cell lines exhibited dose- and time-dependent decreased viability after exposure to BEZ235 (IC(50), 25-800 nmol/L or 48 hours). MM cells highly sensitive (IC(50), <25 nmol/L) to BEZ235 (e.g., MM.1S, MM.1R, Dox40, and KMS-12-PE) included both lines sensitive and resistant to conventional (dexamethasone, cytotoxic chemotherapeutics) agents. Pharmacologically relevant BEZ235 concentrations (25-400 nmol/L,) induced rapid commitment to and induction of MM.1S and OPM-2 cell death. Furthermore, normal donor peripheral blood mononuclear cells were less sensitive (IC(50), >800 nmol/L) than the majority of MM cell lines tested, suggesting a favorable therapeutic index. In addition, BEZ235 was able to target MM cells in the presence of exogenous interleukin-6, insulin-like growth factor-1, stromal cells, or osteoclasts, which are known to protect against various anti-MM agents. Molecular profiling revealed that BEZ235 treatment decreased the amplitude of transcriptional signatures previously associated with myc, ribosome, and proteasome function, as well as high-risk MM and undifferentiated human embryonic stem cells. In vivo xenograft studies revealed significant reduction in tumor burden (P = 0.011) and survival (P = 0.028) in BEZ235-treated human MM tumor-bearing mice. Combinations of BEZ235 with conventional (e.g., dexamethasone and doxorubicin) or novel (e.g., bortezomib) anti-MM agents showed lack of antagonism. These results indicate that BEZ235 merits clinical testing, alone and in combination with other agents, in MM. [Cancer Res 2009;69(14):5835-42] C1 [McMillin, Douglas W.; Ooi, Melissa; Delmore, Jake; Negri, Joseph; Hayden, Patrick; Mitsiades, Nicolas; Jakubikova, Jana; Schlossman, Robert; 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. [McMillin, Douglas W.; Ooi, Melissa; Delmore, Jake; Negri, Joseph; Hayden, Patrick; Mitsiades, Nicolas; Jakubikova, Jana; Anderson, Kenneth C.; Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Maira, Sauveur-Michel; Garcia-Echeverria, Carlos] Novartis Inst Biomed Res, Basel, Switzerland. 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" Program at the Dana-Farber Cancer Institute; Chambers Medical Foundation; Cobb Family Fellowship; NIH [R01CA050947, PO-1-78378] FX "Dunkin Donuts Rising Stars" Program at the Dana-Farber Cancer Institute (C.S. Mitsiades), Chambers Medical Foundation (P.G. Richardson and C.S. Mitsiades), Cobb Family Fellowship (D.W. McMillin), and NIH grants R01CA050947 (K.C. Anderson and C.S. Mitsiades) and PO-1-78378 (K.C. Anderson). NR 31 TC 90 Z9 94 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 JUL 15 PY 2009 VL 69 IS 14 BP 5835 EP 5842 DI 10.1158/0008-5472.CAN-08-4285 PG 8 WC Oncology SC Oncology GA 475LJ UT WOS:000268360300030 PM 19584292 ER PT J AU Sicard, P Jacquet, S Kobayashi, KS Flavell, RA Marber, MS AF Sicard, Pierre Jacquet, Sebastien Kobayashi, Koichi S. Flavell, Richard A. Marber, Michael S. TI Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1 SO CARDIOVASCULAR RESEARCH LA English DT Article DE Postconditioning; TAK1; RIP2; MDP; Ischaemia-reperfusion ID ISCHEMIA-REPERFUSION INJURY; PERMEABILITY TRANSITION PORE; MYOCARDIAL-INFARCTION; TRANSGENIC MICE; TNF-ALPHA; ACTIVATION; HEART; MECHANISMS; PROTECTION; ENDOTOXIN AB Despite their ability to cause septic shock and myocardial dysfunction, components of Gram-negative bacterial cell walls, like lipopolysaccharide, have been shown in numerous studies to induce myocardial protection during ischaemia-reperfusion injury. Muramyl dipeptide (MDP) is another such component recognized by an intracellular receptor, nucleotide-binding oligomerization domain 2. Receptor activation leads to intracellular signals through receptor interacting protein-2 (RIP2) and tumour growth factor-beta-activated kinase-1 (TAK1). However, little is known about the RIP2/TAK1 pathway in the heart. The aim of this study was to determine whether the RIP2/TAK1 pathway has a cardioprotective role in a mouse model of myocardial infarction. We isolated and subjected wild-type (WT) and RIP2(-/-) mouse hearts to 30 min of global ischaemia and 120 min of reperfusion with or without perfusion of MDP (10 mu g/mL) before or after the ischaemic period and determined the infarct size. We examined activation of the TAK1/nuclear factor kappa B (NF kappa B) signalling pathway. The effect of TAK1 inhibition on MDP-induced cardioprotection was also evaluated. Exposure to MDP during reperfusion significantly reduced infarct size in WT hearts (from 51.7 +/- 5.6% in control to 38.1 +/- 6.7%, P < 0.05), but not in RIP2(-/-) hearts or in WT hearts with coincident pharmacological inhibition of TAK1. MDP treatment significantly increased the levels of p-TAK1 and p-JNK (Jun N-terminal kinase) and led to NF kappa B activation via phosphorylation and degradation of IkappaB in the WT, but not in the RIP2(-/-), myocardium. These results indicate that MDP at reperfusion induced cardioprotection through an RIP2/TAK1-dependent mechanism. C1 [Sicard, Pierre; Jacquet, Sebastien; Marber, Michael S.] Kings Coll London, British Heart Fdn Ctr Res Excellence, Div Cardiovasc, Rayne Inst,St Thomas Hosp, London SE1 7EH, England. [Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. [Flavell, Richard A.] Yale Univ, Dept Immunobiol, Howard Hughes Med Inst, Sch Med, New Haven, CT 06520 USA. RP Jacquet, S (reprint author), Kings Coll London, British Heart Fdn Ctr Res Excellence, Div Cardiovasc, Rayne Inst,St Thomas Hosp, Lambeth Palace Rd, London SE1 7EH, England. EM sebastien.jacquet@kcl.ac.uk RI Sicard, Pierre/B-1637-2010; OI Sicard, Pierre/0000-0001-8100-9792; Sicard, Pierre/0000-0001-5837-3916 FU British Heart Foundation [07/073/23432]; Department of Health; NIDDK NIH HHS [R01 DK074738, R01 DK074738-05] NR 30 TC 6 Z9 9 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUL 15 PY 2009 VL 83 IS 2 BP 277 EP 284 DI 10.1093/cvr/cvp055 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 463OF UT WOS:000267440800013 PM 19213760 ER PT J AU Wu, CJ Ritz, J AF Wu, Catherine J. Ritz, Jerome TI Revealing Tumor Immunity after Hematopoietic Stem Cell Transplantation SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID CHRONIC MYELOGENOUS LEUKEMIA; GRAFT; RECIPIENTS; INDUCTION; HLA AB Allogeneic hematopoietic stem cell transplantation is currently the most effective method for inducing tumor immunity. However, the diversity of target antigens recognized by donor T cells has not been established. New studies show that tumor-reactive T cells are directed against diverse tumor-specific targets as well as minor histocompatibility antigens. C1 [Wu, Catherine J.; Ritz, Jerome] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr,Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Ritz, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr,Harvard Stem Cell Inst, M530,44 Binney St, Boston, MA 02115 USA. EM jerome_ritz@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 NR 12 TC 7 Z9 7 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2009 VL 15 IS 14 BP 4515 EP 4517 DI 10.1158/1078-0432.CCR-09-0873 PG 3 WC Oncology SC Oncology GA 482SG UT WOS:000268908400001 PM 19584145 ER PT J AU Yip, S Miao, JY Cahill, DP Iafrate, AJ Aldape, K Nutt, CL Louis, DN AF Yip, Stephen Miao, Jiangyong Cahill, Daniel P. Iafrate, A. John Aldape, Ken Nutt, Catherine L. Louis, David N. TI MSH6 Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance SO CLINICAL CANCER RESEARCH LA English DT Article ID MISMATCH-REPAIR SYSTEM; COLORECTAL-CANCER; MALIGNANT GLIOMAS; DNA-REPAIR; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; MICROSATELLITE INSTABILITY; ALKYLATING-AGENTS; MGMT; O-6-BENZYLGUANINE; RECURRENT AB Purpose: Over the past few years, the alkylating agent temozolomide has become the standard-of-care therapy for patients with glioblastoma, the most common brain tumor. Recently, large-scale cancer genome sequencing efforts have identified a hypermutation phenotype and inactivating MSH6 mismatch repair gene mutations in recurrent, post-temozolomide glioblastomas, particularly those growing more rapidly during temozolomide treatment. This study aimed to clarify the timing and role of MSH6 mutations in mediating glioblastoma temozolomide resistance. Experimental Design: MSH6 sequence and microsatellite instability (MSI) status were determined in matched prechemotherapy and postchemotherapy glioblastomas identified by The Cancer Genome Atlas (TCGA) as having posttreatment MSH6 mutations. Temozolomide-resistant lines were derived in vitro through selective growth under temozolomide, and the MSH6 gene was sequenced in resistant clones. The role of MSH6 inactivation in mediating resistance was explored using lentiviral short hairpin RNA knockdown and MSH6 reconstitution. Results: MSH6 mutations were confirmed in posttreatment TCGA glioblastomas but absent in matched pretreatment tumors. The posttreatment hypermutation phenotype displayed a signature bias toward CpC transitions and was not associated with MSI. In vitro modeling through exposure of an MSH6 wild-type glioblastoma line to temozolomide resulted in resistant clones; one clone showed an MSH6 mutation,Thr(1219)lle, that had been independently noted in two treated TCGA glioblastomas. Knockdown of MSH6 in the glioblastoma line U251 increased resistance to temozolomide cytotoxicity and reconstitution restored cytotoxicity in MSH6-null glioma cells. Conclusions: MSH6 mutations are selected in glioblastomas during temozolomide therapy both in vitro and in vivo and are causally associated with temozolomide resistance. C1 [Yip, Stephen; Miao, Jiangyong; Cahill, Daniel P.; Iafrate, A. John; Nutt, Catherine L.; Louis, David N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pathol Serv, Boston, MA 02114 USA. [Cahill, Daniel P.; Louis, David N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg Serv, Boston, MA 02114 USA. [Iafrate, A. John; Louis, David N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Yip, Stephen; Miao, Jiangyong; Iafrate, A. John; Nutt, Catherine L.; Louis, David N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Aldape, Ken] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Louis, DN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pathol Serv, WRN225, Boston, MA 02114 USA. EM louis@helix.mgh.harvard.edu RI Nutt, Catherine/K-8794-2012; OI Cahill, Daniel/0000-0003-2552-6546 FU NIH [CA57683]; Royal College of Physicians and Surgeons of Canada; Burroughs-Wellcome Career Award FX NIH CA57683 (C.L. Nutt and D.N. Louis) and Clinician Investigator Fellowship from The Royal College of Physicians and Surgeons of Canada (S. Yip), and a Burroughs-Wellcome Career Award in the Medical Sciences (D.P. Cahill). 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 37 TC 117 Z9 123 U1 5 U2 11 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 JUL 15 PY 2009 VL 15 IS 14 BP 4622 EP 4629 DI 10.1158/1078-0432.CCR-08-3012 PG 8 WC Oncology SC Oncology GA 482SG UT WOS:000268908400015 PM 19584161 ER PT J AU Baba, Y Nosho, K Shima, K Freed, E Irahara, N Philips, J Meyerhardt, JA Hornick, JL Shivdasani, RA Fuchs, CS Ogino, S AF Baba, Yoshifumi Nosho, Katsuhiko Shima, Kaori Freed, Ellen Irahara, Natsumi Philips, Juliet Meyerhardt, Jeffrey A. Hornick, Jason L. Shivdasani, Ramesh A. Fuchs, Charles S. Ogino, Shuji TI Relationship of CDX2 Loss with Molecular Features and Prognosis in Colorectal Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; HOMEOBOX GENE-EXPRESSION; POPULATION-BASED SAMPLE; MICROSATELLITE INSTABILITY; COLON-CANCER; FAMILY-HISTORY; IMMUNOHISTOCHEMICAL SURVEY; LINE-1 HYPOMETHYLATION; BRAF MUTATION; MUTANT MICE AB Purpose: The homeodomain transcription factor CDX2 is a relatively specific immunchistochemical marker for gastrointestinal carcinoma. However, no study has comprehensively examined the relationship between CDX2 expression in colon cancer and clinical, pathologic, prognostic, and molecular features, including microsatellite instability and CpG island methylator phenotype (CIMP). Experimental Design: Utilizing 621 colorectal cancers with clinical outcome and molecular data, CDX2 loss was detected in 183 (29%) tumors by immunohistochemistry. Results: In multivariate logistic regression analysis, CDX2 loss was associated with female gender [odds ratio (OR), 3.32; P < 0.0001], CIMP-high (OR, 4.42; P = 0.0003), high tumor grade (OR, 2.69; P = 0.0085), stage IV disease (OR, 2.03; P = 0.019), and inversely with LINE-1 hypomethylation (for a 30% decline; OR, 0.33; P = 0.0031), p53 expression (OR, 0.55; P = 0.011), and beta-catenin activation (OR, 0.60; P = 0.037), but not with body mass index, tumor location, microsatellite instability, BRAF, KRAS, PIK3CA, p21, or cyclooxygenase-2. CDX2 loss was not independently associated with patient survival. However, the prognostic effect of CDX2 loss seemed to differ according to family history of colorectal cancer (P-interaction = 0.0094). CDX2 loss was associated with high overall mortality (multivariate hazard ratio, 2.40; 95% Cl, 1.28-4.51) among patients with a family history of colorectal cancer; no such association was present (multivariate hazard ratio, 0.97; 95% Cl, 0.66-1.41) among patients without a family history of colorectal cancer. Conclusions: CDX2 loss in colorectal cancer is independently associated with female gender, CIMP-high, high-level LINE-1 methylation, high tumor grade, and advanced stage. CDX2 loss may be associated with poor prognosis among patients with a family history of colorectal cancer. C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Pathol, Dana Farber Canc Inst,Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Baba, Yoshifumi; Nosho, Katsuhiko; Shima, Kaori; Freed, Ellen; Irahara, Natsumi; Philips, Juliet; Meyerhardt, Jeffrey A.; Shivdasani, Ramesh A.; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Pathol, Dana Farber Canc Inst,Ctr Mol Oncol Pathol, 44 Binney St,Room JF 215C, Boston, MA 02115 USA. EM shuji.ogino@dfci.harvard.edu FU U.S. NIH [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826, K07 CA97992]; Entertainment Industry Foundation National Colorectal Cancer Research Alliance; Japan Society for Promotion of Science FX U.S. NIH grants P01 CA87969 (S. Hankinson), P01 CA55075 (W. Willett), P50 CA127003 (C.S. Fuchs), K07 CA122826 (S. Ogino), and K07 CA97992 (J.A. Meyerhardt); and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. K. Nosho was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Cancer Institute or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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 51 TC 60 Z9 67 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2009 VL 15 IS 14 BP 4665 EP 4673 DI 10.1158/1078-0432.CCR-09-0401 PG 9 WC Oncology SC Oncology GA 482SG UT WOS:000268908400019 PM 19584150 ER PT J AU Bradbury, PA Zhai, RH Ma, C Xu, W Hopkins, J Kulke, MJ Asomaning, K Wang, ZX Su, L Heist, RS Lynch, TJ Wain, JC Christiani, D Liu, G AF Bradbury, Penelope A. Zhai, Rihong Ma, Clement Xu, Wei Hopkins, Jessica Kulke, Matthew J. Asomaning, Kofi Wang, Zhaoxi Su, Li Heist, Rebecca S. Lynch, Thomas J. Wain, John C. Christiani, David Liu, Geoffrey TI Vascular Endothelial Growth Factor Polymorphisms and Esophageal Cancer Prognosis SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; FACTOR GENE POLYMORPHISMS; TUMOR ANGIOGENESIS; FACTOR EXPRESSION; CONTINUOUS TRAITS; GASTRIC-CANCER; BREAST-CANCER; VEGF GENE; ASSOCIATION; ADENOCARCINOMA AB Purpose: Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability. The VEGF gene is polymorphic. We investigated the prognostic significance of three VEGF single nucleotide polymorphisms (SNP) in esophageal cancer. Experimental Design: Three hundred sixty-one patients were genotyped for three VEGF SNPs (-460T/C, 405G/C, and 936C/T) using DNA extracted from prospectively collected blood samples. The association of each individual SNP, and haplotypes of the three SNPs, on overall survival (OS) was investigated. Results: The variant allele of 936C/T was associated with improved OS compared with the wildtype genotype (log-rank P < 0.001). This association remained significant for OS after adjustments for age, gender, performance status, and disease stage [VEGF 936C/T: adjusted hazard ratio (AHR), 0.70; 95% confidence interval (95% CI), 0.49-0.99; P = 0.04; VEGF 936T/T: AHR, 0.11; 95% Cl, 0.02-0.82; P = 0.03]. No independent associations were found for VEGF -460T/C and VEGF 405G/C. The CGC haplotype of the three VEGF SNPs (-460T/C, 405G/C, and 936C/T) combined was associated with reduced OS compared with all other patients (CGC/CGC: AHR, 1.51; 95% Cl, 1.00-2.30; P = 0.05). Conclusions: VEGF 936C/T, and a haplotype of 460T/C, 405G/C, and 936C/T combined, has potential prognostic significance in esophageal cancer. C1 [Bradbury, Penelope A.; Ma, Clement; Xu, Wei; Hopkins, Jessica; Liu, Geoffrey] Univ Toronto, Ontario Canc Inst, Princess Margaret Hosp, Dept Med, Toronto, ON M5G 2M9, Canada. [Liu, Geoffrey] Univ Toronto, Ontario Canc Inst, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. [Zhai, Rihong; Asomaning, Kofi; Wang, Zhaoxi; Su, Li; Heist, Rebecca S.; Christiani, David; Liu, Geoffrey] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Cambridge, MA 02138 USA. [Kulke, Matthew J.] Dana Farber Canc Inst, Dept Adult Oncol Med Oncol, Boston, MA USA. [Heist, Rebecca S.; Lynch, Thomas J.; Liu, Geoffrey] Harvard Univ, Sch Med, Dept Med, MGH Canc Ctr, Boston, MA USA. [Wain, John C.] Harvard Univ, Sch Med, Thorac Surg Unit, Boston, MA USA. [Christiani, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit, Boston, MA USA. [Hopkins, Jessica] McMaster Univ, Community Hlth Family Med, Hamilton, ON, Canada. RP Liu, G (reprint author), Univ Toronto, Ontario Canc Inst, Princess Margaret Hosp, Dept Med, 610 Univ Ave,Suite 7-124, Toronto, ON M5G 2M9, Canada. EM Geoffrey.Liu@uhn.on.ca RI Liu, Geoffrey/N-4421-2016 FU NIH [R01 CA109193, RO3 CA110822, R01 CA074386, R01 CA092824]; Doris Duke Charitable Foundation; Kevin Jackson Memorial Fund; Alan B. Brown Chair in Molecular Genomics; Flight Attendant Medical Research Institute [062409_YCSA]; Ontario Cancer Research Network Fellowship FX NIH grants R01 CA109193, RO3 CA110822, R01 CA074386, and R01 CA092824; Doris Duke Charitable Foundation; Kevin Jackson Memorial Fund; Alan B. Brown Chair in Molecular Genomics; Flight Attendant Medical Research Institute grant 062409_YCSA, and Ontario Cancer Research Network Fellowship. 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 29 TC 36 Z9 38 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2009 VL 15 IS 14 BP 4680 EP 4685 DI 10.1158/1078-0432.CCR-09-0192 PG 6 WC Oncology SC Oncology GA 482SG UT WOS:000268908400021 PM 19584152 ER PT J AU Mosquera, JM Mehra, R Regan, MM Perner, S Genega, EM Bueti, G Shah, RB Gaston, S Tomlins, SA Wei, JT Kearney, MC Johnson, LA Tang, JM Chinnaiyan, AM Rubin, MA Sanda, MG AF Mosquera, Juan-Miguel Mehra, Rohit Regan, Meredith M. Perner, Sven Genega, Elizabeth M. Bueti, Gerri Shah, Rajal B. Gaston, Sandra Tomlins, Scott A. Wei, John T. Kearney, Michael C. Johnson, Laura A. Tang, Jeffrey M. Chinnaiyan, Arul M. Rubin, Mark A. Sanda, Martin G. TI Prevalence of TMPRSS2-ERG Fusion Prostate Cancer among Men Undergoing Prostate Biopsy in the United States SO CLINICAL CANCER RESEARCH LA English DT Article ID GENE FUSION; HETEROGENEITY; TRANSCRIPTS; EXPRESSION; URINE AB Purpose: Fusion of the TMPRSS2 prostate-specific gene with the ERG transcription factor is a putatively oncogenic gene rearrangement that is commonly found in prostate cancer tissue from men undergoing prostatectomy. However, the prevalence of the fusion was less common in samples of transurethral resection of the prostate from a Swedish cohort of patients with incidental prostate cancer followed by watchful waiting, raising the question as to whether the high prevalence in prostatectomy specimens reflects selection bias. We sought to determine the prevalence of TMPRSS2-ERG gene fusion among prostate-specific antigen - screened men undergoing prostate biopsy in the United States. Experimental Design: We studied 140 prostate biopsies from the same number of patients for TMPRSS2-ERG fusion status with a fluorescent in situ hybridization assay. One hundred and thirty-four samples (100 cancer and 34 benign) were assessable. Results: ERG gene rearrangement was detected in 46% of prostate biopsies that were found to have prostate cancer and in 0% of benign prostate biopsies (P < 0.0001). Evaluation of morphologic features showed that cribriform growth, blue-tinged mucin, macronucleoli, and collagenous micronodules were significantly more frequent in TMPRSS2-ERG fusion - positive prostate cancer biopsies than gene fusion - negative prostate cancer biopsies (P <= 0.04). No significant association with Gleason score was detected. In addition, non-Caucasian patients were less likely to have positive fusion status (P = 0.02). Conclusions: This is the first prospective North American multicenter study to characterize TMPRSS2-ERG prostate cancer prevalence in a cohort of patients undergoing needle biopsy irrespective of whether or not they subsequently undergo prostatectomy. Our results show that this gene rearrangement is common among North American men who have prostate cancer on biopsy, is absent in benign prostate biopsy, and is associated with specific morphologic features. These findings indicate a need for prospective studies to evaluate the relationship of TMPRSS2-ERG rearrangement with clinical course of screening-detected prostate cancer in North American men, and a need for the development of noninvasive screening tests to detect TMPRSS2-ERG rearrangement. C1 [Sanda, Martin G.] Beth Israel Deaconess Med Ctr, Div Urol, Boston, MA 02115 USA. [Mosquera, Juan-Miguel; Perner, Sven; Johnson, Laura A.; Tang, Jeffrey M.; Rubin, Mark A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Mosquera, Juan-Miguel; Regan, Meredith M.; Perner, Sven; Genega, Elizabeth M.; Gaston, Sandra; Kearney, Michael C.; Rubin, Mark A.; Sanda, Martin G.] Harvard Univ, Sch Med, Boston, MA USA. [Shah, Rajal B.; Wei, John T.; Chinnaiyan, Arul M.] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Shah, Rajal B.; Chinnaiyan, Arul M.] Univ Michigan, Sch Med, Michigan Urol Ctr, Ann Arbor, MI 48109 USA. [Genega, Elizabeth M.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Gaston, Sandra] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02115 USA. [Perner, Sven] Univ Ulm, Dept Pathol, Ulm, Germany. [Rubin, Mark A.] MIT, Broad Inst, Cambridge, MA 02139 USA. [Rubin, Mark A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Regan, Meredith M.; Rubin, Mark A.] Dana Farber Harvard Comprehens Canc Ctr, Boston, MA USA. RP Sanda, MG (reprint author), Beth Israel Deaconess Med Ctr, Div Urol, 330 Brookline Ave,Rabb 440, Boston, MA 02115 USA. EM msanda@bidmc.harvard.edu RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015; Wei, John/E-8967-2012; OI Rubin, Mark/0000-0002-8321-9950 FU NIH [P50 CA090381, R01AG21404, U01 CA113913, P50 CA69568]; German Research Foundation Deutsche Forschungsgemeinschaft DFG [PE1179/1-2]; Department of Defense [PC061474]; ERDN [U01 CA111275] FX NIH Prostate Specialized Programs of Research Excellence (SPORE) at the Dana-Farber/Harvard Cancer Center NCI P50 CA090381 (M.A. Rubin), R01AG21404 (M.A. Rubin), German Research Foundation Deutsche Forschungsgemeinschaft DFG no. PE1179/1-2 (S. Perner), Department of Defense Prostate Cancer Training Award PC061474, NIH grant U01 CA113913 for the Beth Israel Deaconess Early Detection Research Network (ERDN; Harvard/Michigan Prostate Cancer Clinical Center; M. Sanda), ERDN U01 CA111275 and SPORE P50 CA69568 (A.M. Chinnaiyan); A.M. Chinnaiyan is a Howard Hughes Medical Institute Investigator.; 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 20 TC 121 Z9 126 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2009 VL 15 IS 14 BP 4706 EP 4711 DI 10.1158/1078-0432.CCR-08-2927 PG 6 WC Oncology SC Oncology GA 482SG UT WOS:000268908400025 PM 19584163 ER PT J AU Butt, AA Wang, XQ Budoff, M Leaf, D Kuller, LH Justice, AC AF Butt, Adeel A. Wang Xiaoqiang Budoff, Matthew Leaf, David Kuller, Lewis H. Justice, Amy C. TI Hepatitis C Virus Infection and the Risk of Coronary Disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID FATTY LIVER-DISEASE; ARTERY-DISEASE; HEPATOCELLULAR-CARCINOMA; HEMODIALYSIS-PATIENTS; ATHEROSCLEROSIS; VETERANS; HIV; INFLAMMATION; ASSOCIATION; COCAINE AB Background. The association between hepatitis C virus (HCV) infection and coronary artery disease (CAD) is controversial. We conducted this study to determine and quantify this association. Methods. We used an established, national, observational cohort of all HCV-infected veterans receiving care at all Veterans Affairs facilities, the Electronically Retrieved Cohort of HCV Infected Veterans, to identify HCV-infected subjects and HCV-uninfected control subjects. We used the Cox proportional-hazards model to determine the risk of CAD among HCV-infected subjects and control subjects. Results. We identified 82,083 HCV-infected and 89,582 HCV-uninfected subjects. HCV-infected subjects were less likely to have hypertension, hyperlipidemia, and diabetes but were more likely to abuse alcohol and drugs and to have renal failure and anemia. HCV-infected subjects had lower mean (+/- standard deviation) total plasma cholesterol (175 +/- 40.8 mg/dL vs. 198 +/- 41.0 mg/dL), low-density lipoprotein cholesterol (102 +/- 36.8 mg/dL vs. 119 +/- 38.2 mg/dL), and triglyceride (144 +/- 119 mg/dL vs. 179 +/- 151 mg/dL) levels, compared with HCV-uninfected subjects (P < .001 for all comparisons). In multivariable analysis, HCV infection was associated with a higher risk of CAD (hazard ratio, 1.25; 95% confidence interval, 1.20-1.30). Traditional risk factors (age, hypertension, chronic obstructive pulmonary disease, diabetes, and hyperlipidemia) were associated with a higher risk of CAD in both groups, whereas minority race and female sex were associated with a lower risk of CAD. Conclusions. HCV-infected persons are younger and have lower lipid levels and a lower prevalence of hypertension. Despite a favorable risk profile, HCV infection is associated with a higher risk of CAD after adjustment for traditional risk factors. C1 [Butt, Adeel A.] Univ Pittsburgh, Med Ctr, Sch Med, Pittsburgh, PA 15213 USA. [Justice, Amy C.] Yale Univ, Sch Med & Publ Hlth, New Haven, CT USA. [Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Butt, Adeel A.; Wang Xiaoqiang] Univ Pittsburgh, Grad Sch Publ Hlth, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15213 USA. [Butt, Adeel A.; Wang Xiaoqiang] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15213 USA. [Leaf, David] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Leaf, David] Univ Calif Los Angeles, VA Greater Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Budoff, Matthew] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Los Angeles, CA USA. RP Butt, AA (reprint author), Univ Pittsburgh, Med Ctr, Sch Med, 3601 5th Ave,Ste 3A, Pittsburgh, PA 15213 USA. EM butta@dom.pitt.edu FU National Institutes of Health, National Institute on Drug Abuse [K23 DA016175-01A1] FX National Institutes of Health, National Institute on Drug Abuse (K23 DA016175-01A1 to A. A. B.). NR 44 TC 114 Z9 120 U1 1 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 JUL 15 PY 2009 VL 49 IS 2 BP 225 EP 232 DI 10.1086/599371 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 460XU UT WOS:000267226900011 PM 19508169 ER PT J AU Beppu, H Malhotra, R Beppu, Y Lepore, JJ Parmacek, MS Bloch, KD AF Beppu, Hideyuki Malhotra, Rajeev Beppu, Yuko Lepore, John J. Parmacek, Michael S. Bloch, Kenneth D. TI BMP type II receptor regulates positioning of outflow tract and remodeling of atrioventricular cushion during cardiogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Cardiogenesis; Bone morphogenetic protein; Cre-loxP; Endocardial cushion; Valvulogenesis; Cardiac outflow tract ID MORPHOGENETIC PROTEIN-RECEPTOR; SMOOTH-MUSCLE-CELLS; NEURAL CREST CELLS; ENDOCARDIAL CUSHION; CARDIAC MORPHOGENESIS; MOUSE EMBRYOGENESIS; HEART; MICE; GASTRULATION; DELETION AB Signaling of bone morphogenetic protein (BMP) via type I and type II receptors is involved in multiple processes contributing to cardiogenesis. To investigate the role of the BMP type II receptor (BMPRII) in heart development, the BMPRII gene was deleted throughout the embryo during gastrulation using a Mox2-Cre transgene. BMPR(flox/-);Mox2-Cre mice exhibited cardiac defects including double-outlet right ventricle, ventricular septal defect (VSD), atrioventricular (AV) cushion defects, and thickened valve leaflets. To characterize the tissue-specific functions of BMPRII in cardiogenesis, a series of Cre transgenes (alpha MHC-, Tie2-, Wnt1-, and SM22 alpha-Cre) was employed. Interestingly, myocardial development was normal when the BMPRII gene was deleted in myocardial cells using Mox2-Cre, alpha MHC-Cre, or SM22 alpha-Cre transgenes, suggesting that signaling by other BMP type II receptors may compensate for the absence of BMPRII in the myocardial cells. AV cushion defects including atrial septal defect, membranous VSD, and thickened valve leaflets were found in BMPR(flox/-);Tie2-Cre mice. Abnormal positioning of the aorta was observed in BMPRII(flox/-);Wnt1-Cre and BMPRII(flox/-);SM22 alpha-Cre mice. Taken together, these results demonstrate that endocardial BMPRII expression is required for septal formation and valvulogenesis. Moreover, mesenchymal BMPRII expression in the outflow tract cushion is required for proper positioning of the aorta. (C) 2009 Elsevier Inc. All rights reserved. C1 [Beppu, Hideyuki; Beppu, Yuko; Bloch, Kenneth D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Beppu, Hideyuki; Malhotra, Rajeev; Beppu, Yuko; Bloch, Kenneth D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiol Res Ctr, Charlestown, MA 02129 USA. [Lepore, John J.; Parmacek, Michael S.] Univ Penn, Sch Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA. RP Beppu, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, 55 Fruit St, Boston, MA 02114 USA. EM beppu-ind@umin.ac.jp OI Parmacek, Michael/0000-0003-1449-4665; Malhotra, Rajeev/0000-0003-0120-4630 FU American Heart Association Scientist Development [0535079N]; NIH [5R01 HL074352] FX The authors thank Drs. Calum MacRae and Donald B. Bloch for valuable discussions and experimental advice, and Dr. E. Dale Abel for alpha MHC-Cre transgenic mice. This work was supported by American Heart Association Scientist Development Grant 0535079N (HB) and a NIH grant 5R01 HL074352 (KDB). NR 39 TC 34 Z9 36 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2009 VL 331 IS 2 BP 167 EP 175 DI 10.1016/j.ydbio.2009.04.032 PG 9 WC Developmental Biology SC Developmental Biology GA 467XW UT WOS:000267777900006 PM 19409885 ER PT J AU Mayack, SR Shadrach, J Schepers, K Passegue, E Wagers, AJ AF Mayack, Shane R. Shadrach, Jennifer Schepers, Koen Passegue, Emmanuelle Wagers, Amy J. TI Blood stem cells: Regulation by the niche SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the Society-for-Developmental-Biology CY JUL 23-27, 2009 CL San Francisco, CA SP Soc Dev Biol C1 [Mayack, Shane R.; Shadrach, Jennifer; Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Schepers, Koen; Passegue, Emmanuelle] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2009 VL 331 IS 2 MA 32 BP 395 EP 395 DI 10.1016/j.ydbio.2009.05.041 PG 1 WC Developmental Biology SC Developmental Biology GA 467XW UT WOS:000267777900055 ER PT J AU Wood, AW Brown, YA AF Wood, Antony W. Brown, Yvonne A. TI Intraembryonic functions of IGF2 signaling in zebrafish SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the Society-for-Developmental-Biology CY JUL 23-27, 2009 CL San Francisco, CA SP Soc Dev Biol C1 [Wood, Antony W.; Brown, Yvonne A.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2009 VL 331 IS 2 MA 312 BP 477 EP 477 DI 10.1016/j.ydbio.2009.05.340 PG 1 WC Developmental Biology SC Developmental Biology GA 467XW UT WOS:000267777900333 ER PT J AU Blackiston, DJ Levin, M AF Blackiston, Douglas J. Levin, Michael TI Control of embryonic stem cell proliferation and migration can be controlled in vivo by pharmacological modulation of endogenous ion channels SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the Society-for-Developmental-Biology CY JUL 23-27, 2009 CL San Francisco, CA SP Soc Dev Biol C1 [Blackiston, Douglas J.; Levin, Michael] Forsyth Inst, Ctr Regenerat & Dev Biol, Boston, MA USA. [Levin, Michael] Tufts Univ, Dept Biol, Medford, MA 02155 USA. NR 0 TC 0 Z9 0 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2009 VL 331 IS 2 MA 419 BP 506 EP 506 DI 10.1016/j.ydbio.2009.05.561 PG 1 WC Developmental Biology SC Developmental Biology GA 467XW UT WOS:000267777900437 ER PT J AU Green, JB Tabler, JM Ossipova, OM Yamanaka, H Panousopoulou, E AF Green, Jeremy B. Tabler, Jacqueline M. Ossipova, Olga M. Yamanaka, Hiroaki Panousopoulou, Eleni TI Control of cell and tissue polarity in neurectoderm by the PAR-1 (MARK) proteins in Xenopus SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the Society-for-Developmental-Biology CY JUL 23-27, 2009 CL San Francisco, CA SP Soc Dev Biol C1 [Green, Jeremy B.; Tabler, Jacqueline M.; Yamanaka, Hiroaki; Panousopoulou, Eleni] Kings Coll London, Dept Craniofacial Dev, London WC2R 2LS, England. [Ossipova, Olga M.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2009 VL 331 IS 2 MA 420 BP 507 EP 507 DI 10.1016/j.ydbio.2009.05.447 PG 1 WC Developmental Biology SC Developmental Biology GA 467XW UT WOS:000267777900438 ER PT J AU Huett, A Leong, JM Podolsky, DK Xavier, RJ AF Huett, Alan Leong, John M. Podolsky, Daniel K. Xavier, Ramnik J. TI The cytoskeletal scaffold Shank3 is recruited to pathogen-induced actin rearrangements SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Bacterial infection; Attaching and effacing; Actin; Cytoskeleton; Synapse ID ESCHERICHIA-COLI TIR; POSTSYNAPTIC DENSITY PROTEINS; NCK SH2/SH3 ADAPTERS; PEDESTAL FORMATION; HOST-CELLS; ENTEROCYTE EFFACEMENT; TYROSINE KINASES; DENDRITIC SPINES; SUBSTRATE IRSP53; RECEPTOR AB The common gastrointestinal pathogens enteropathogenic Escherichia coli (EPEC) and Salmonella typhimurium both reorganize the gut epithelial cell actin cytoskeleton to mediate pathogenesis, utilizing mimicry of the host signaling apparatus. The PDZ domain-containing protein Shank3, is a large cytoskeletal scaffold protein with known functions in neuronal morphology and synaptic signaling, and is also capable of acting as a scaffolding adaptor during Ret tyrosine kinase signaling in epithelial cells. Using immunofluorescent and functional RNA-interference approaches we show that Shank3 is present in both EPEC- and S. typhimurium-induced actin rearrangements and is required for optimal EPEC pedestal formation. We propose that Shank3 is one of a number of host synaptic proteins likely to play key roles in bacteria-host interactions. (C) 2009 Elsevier Inc. All rights reserved. C1 [Huett, Alan; Podolsky, Daniel K.; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Gastrointestinal Unit, Ctr Study Inflammatory Bowel Dis,Sch Med, Boston, MA 02115 USA. [Huett, Alan; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Leong, John M.] Univ Massachusetts, Med Ctr, Dept Mol Genet & Microbiol, Worcester, MA 01655 USA. RP Xavier, RJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Gastrointestinal Unit, Ctr Study Inflammatory Bowel Dis,Sch Med, Boston, MA 02115 USA. EM xavier@molbio.mgh.harvard.edu FU National Institutes of Health [AI062773, AI46454, DK060049, DK043351] FX We would like to thank Tony Pawson (Mount Sinai Hospital, Toronto Canada) for his kind gift of Nck 1 and 2 double knockout and isogenic wild-type MEFs. Salmonella typhimurium Sl1344 DsRed2 was a gift from Dr HC Reinecker (Massachusetts General Hospital, Boston), and EPEC E2348/69 was obtained from Dr S Snapper (Massachusetts General Hospital). This work was supported by grants from the National Institutes of Health to RJX (NIH AI062773), JML (AI46454) and DKP (DK060049 and DK043351). NR 51 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUL 15 PY 2009 VL 315 IS 12 BP 2001 EP 2011 DI 10.1016/j.yexcr.2009.04.003 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 457TL UT WOS:000266956200001 PM 19371741 ER PT J AU Johnson, AD Kavousi, M Smith, AV Chen, MH Dehghan, A Aspelund, T Lin, JP van Duijn, CM Harris, TB Cupples, LA Uitterlinden, AG Launer, L Hofman, A Rivadeneira, F Stricker, B Yang, Q O'Donnell, CJ Gudnason, V Witteman, JC AF Johnson, Andrew D. Kavousi, Maryam Smith, Albert V. Chen, Ming-Huei Dehghan, Abbas Aspelund, Thor Lin, Jing-Ping van Duijn, Cornelia M. Harris, Tamara B. Cupples, L. Adrienne Uitterlinden, Andre G. Launer, Lenore Hofman, Albert Rivadeneira, Fernando Stricker, Bruno Yang, Qiong O'Donnell, Christopher J. Gudnason, Vilmundur Witteman, Jacqueline C. TI Genome-wide association meta-analysis for total serum bilirubin levels SO HUMAN MOLECULAR GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; ORGANIC CATION TRANSPORTER; UGT1A1-ASTERISK-28 ALLELE; OATP-C; GENE; POLYMORPHISMS; EXPRESSION; INHERITANCE; ROTTERDAM; DESIGN AB Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10(-324)) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 x 10(-13)), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain similar to 18.0 and similar to 1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 x 10(-13)), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated. C1 [Johnson, Andrew D.; Chen, Ming-Huei; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Kavousi, Maryam; Dehghan, Abbas; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando; Stricker, Bruno; Witteman, Jacqueline C.] Erasmus MC Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.; Rivadeneira, Fernando; Stricker, Bruno] Erasmus MC Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Reykjavik, Iceland. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Lin, Jing-Ping] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Harris, Tamara B.; Launer, Lenore] Natl Inst Agings Age, Gene Environm Susceptibil Study, Reykjavik, Iceland. [Cupples, L. Adrienne; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Stricker, Bruno] Inspectorate Hlth Care, The Hague, Netherlands. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM codonnell@nih.gov RI Aspelund, Thor/C-5983-2008; Aspelund, Thor/F-4826-2011; Johnson, Andrew/G-6520-2013; Yang, Qiong/G-5438-2014; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; OI Dehghan, Abbas/0000-0001-6403-016X; Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Cupples, L. Adrienne/0000-0003-0273-7965 FU NHLBI NIH HHS [N01-HC-25195, N02-HL-6-4278]; NIA NIH HHS [N01-AG-12100] NR 39 TC 113 Z9 115 U1 2 U2 9 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 JUL 15 PY 2009 VL 18 IS 14 BP 2700 EP 2710 DI 10.1093/hmg/ddp202 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 463OJ UT WOS:000267441200017 PM 19414484 ER PT J AU Wark, PA Wu, K van 't Veer, P Fuchs, CF Giovannucci, EL AF Wark, Petra A. Wu, Kana van 't Veer, Pieter Fuchs, Charles F. Giovannucci, Edward L. TI Family history of colorectal cancer: A determinant of advanced adenoma stage or adenoma multiplicity? SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE family history; cohort study; colorectal neoplasm; colorectal adenomas; colorectal cancer ID COLON-CANCER; 1ST-DEGREE RELATIVES; RISK-FACTORS; POLYPS; DYSPLASIA; CARCINOMA; CLASSIFICATION; SURVEILLANCE; METAANALYSIS; INDIVIDUALS AB A family history of colorectal cancer may increase colorectal cancer risk by influencing adenoma growth or enhancing the formation of new lesions. Data of men from the prospective Health Professionals Follow-Up Study who underwent an endoscopy between 1986 and 2004 were used to evaluate whether a family history of colorectal cancer is associated with adenoma multiplicity or advanced adenoma stage (>= 1 cm, histology with villous component or carcinoma in situ). 21.4% of the 3,881 adenoma patients and 13.9% of the 24,959 adenoma-free men had a first-degree relative with colorectal cancer. Thousand four hundred and ninety-six men were classified as having advanced and 1,507 as having nonadvanced adenomas. Six hundred and twenty-two men had multiple and 1,985 had single adenomas in the distal colon and rectum. A family history of colorectal cancer was similarly associated with advanced and nonadvanced adenomas [multivariable odds ratio (OR) (95% confidence interval): advanced vs. nonadvanced, 0.98 (0.82-1.17), advanced vs. adenoma-free: 1.67 (1.47-1.91), nonadvanced vs. adenoma-free: 1.70 (1.49-1.94)], although potential differences according to adenoma location were seen. A family history of colorectal cancer was more strongly associated with multiple distally located adenomas [odds ratio (95% confidence interval): multiple vs. single, 1.35 (1.09-1.68), multiple vs. no distally located adenomas: 2.02 (1.67-2.44), single vs. no distally located adenomas: 1.49 (1.32-1.68)]. The number of adenomas was also positively associated with a family history of colorectal cancer. Our findings suggest that at the population level, heritable factors may be more important in earlier stages of adenoma formation than at stages of adenoma advancement for at least distally located adenomas. (C) 2009 UICC C1 [Wark, Petra A.] London Sch Hyg & Trop Med, Canc Res UK Epidemiol & Genet Grp, Dept Epidemiol & Populat Hlth, London WC1, England. [Wark, Petra A.; van 't Veer, Pieter] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Wu, Kana; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Fuchs, Charles F.] Harvard Ctr Canc Prevent, Boston, MA USA. [Fuchs, Charles F.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Giovannucci, EL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM edward.giovannucci@channing.harvard.edu OI Wark, Petra/0000-0003-1020-4640 FU NCI [CA 55075]; Dutch Cancer Society; Netherlands Organisation for Health Research and Development; Cancer Research UK FX The HPFS is supported by NCI Research Grant CA 55075. Dr. Petra Wark's visit to the Harvard School of Public Health was made possible with support from the Dutch Cancer Society, and she was further supported by the Netherlands Organisation for Health Research and Development and Cancer Research UK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 41 TC 18 Z9 18 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2009 VL 125 IS 2 BP 413 EP 420 DI 10.1002/ijc.24288 PG 8 WC Oncology SC Oncology GA 460ZJ UT WOS:000267231600021 PM 19358277 ER PT J AU Whitson, JM Noonan, EJ Pookot, D Place, RF Dahiya, R AF Whitson, Jared M. Noonan, Emily J. Pookot, Deepa Place, Robert F. Dahiya, Rajvir TI Double stranded-RNA-mediated activation of P21 gene induced apoptosis and cell cycle arrest in renal cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE renal cell carcinoma; RNAa; saRNA; p21WAF1/CIP1; apoptosis; survivin/Birc5 ID BLADDER-CANCER CELLS; SURVIVIN EXPRESSION; DEPENDENT KINASE; MAMMALIAN-CELLS; IN-VIVO; P21(WAF1/CIP1); INTERFERENCE; INHIBITION; SIRNAS; DRUGS AB Small double stranded RNAs (dsRNA) are a new class of molecules which regulate gene expression. Accumulating data suggest that some dsRNA can function as tumor suppressors. Here, we report further evidence on the potential of dsRNA mediated p21 induction. Using the human renal cell carcinoma cell line A498, we found that dsRNA targeting the p21 promoter significantly induced the expression of p21 mRNA and protein levels. As a result, dsP21 transfected cells had a significant decrease in cell viability with a concomitant G1 arrest. We also observed a significant increase in apoptosis. These findings were associated with a significant decrease in survivin mRNA and protein levels. This is the first report that demonstrates dsRNA mediated gene activation in renal cell carcinoma and suggests that forced over-expression of p21 may lead to an increase in apoptosis through a survivin dependent mechanism. (C) 2009 UICC C1 [Whitson, Jared M.; Dahiya, Rajvir] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. [Noonan, Emily J.; Pookot, Deepa; Place, Robert F.; Dahiya, Rajvir] San Francisco VA Med Ctr, San Francisco, CA USA. RP Dahiya, R (reprint author), Vet Affairs Med Ctr, Urol Res Ctr 112F, 4150 Clement St, San Francisco, CA 94121 USA. EM rdahiya@urology.ucsf.edu FU NIH [RO1CA111470, RO1CA101844, RO1CA130860, T32DK007790] FX Grant sponsor: NIH; Grant numbers: RO1CA111470, RO1CA101844, RO1CA130860. T32DK007790. NR 33 TC 19 Z9 26 U1 0 U2 5 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 JUL 15 PY 2009 VL 125 IS 2 BP 446 EP 452 DI 10.1002/ijc.24370 PG 7 WC Oncology SC Oncology GA 460ZJ UT WOS:000267231600026 PM 19384944 ER PT J AU Smith, BD Arthur, DW Buchholz, TA Haffty, BG Hahn, CA Hardenbergh, PH Julian, TB Marks, LB Todor, DA Vicini, FA Whelan, TJ White, J Wo, JY Harris, JR AF Smith, Benjamin D. Arthur, Douglas W. Buchholz, Thomas A. Haffty, Bruce G. Hahn, Carol A. Hardenbergh, Patricia H. Julian, Thomas B. Marks, Lawrence B. Todor, Dorin A. Vicini, Frank A. Whelan, Timothy J. White, Julia Wo, Jennifer Y. Harris, Jay R. TI ACCELERATED PARTIAL BREAST IRRADIATION CONSENSUS STATEMENT FROM THE AMERICAN SOCIETY FOR RADIATION ONCOLOGY (ASTRO) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Accelerated partial-breast irradiation; Breast cancer; Consensus statement ID DOSE-RATE BRACHYTHERAPY; PHASE-II TRIAL; MULTICATHETER INTERSTITIAL BRACHYTHERAPY; INTENSITY-MODULATED RADIOTHERAPY; MAMMOSITE BALLOON BRACHYTHERAPY; INITIAL DOSIMETRIC EXPERIENCE; EXTERNAL-BEAM RADIOTHERAPY; AUSTRIAN MULTICENTER TRIAL; SURGICAL ADJUVANT BREAST; CARCINOMA-IN-SITU AB Purpose: To present guidance for patients and physicians regarding the use of accelerated partial-breast irradiation (APBI), based on current published evidence complemented by expert opinion. Methods and Materials: A systematic search of the National Library of Medicine's PubMed database yielded 645 candidate original research articles potentially applicable to APBI. Of these, 4 randomized trials and 38 prospective single-arm studies were identified. A Task Force composed of all authors synthesized the published evidence and, through a series of meetings, reached consensus regarding the recommendations contained herein. Results: The Task Force proposed three patient groups: (1) a "suitable: group, for whom APBI outside of a clinical trial is not generally considered warranted. Patients who choose treatment with APBI should be informed that whole-breast irradiation (WBI) is an established treatment with a much longer track record that has documented long-term effectiveness and safety. Conclusion: Accelerated partial-breast irradiation is a new technology that may ultimately demonstrate long-term effectiveness and safety comparable to that of WBI for selected patients with early breast cancer. This consensus statement is intended to provide guidance regarding the use of APBI outside of a clinical trial and to serve as a framework to promote additional clinical investigations into the optimal role of APBI in the treatment of breast cancer. (C) 2009 American Society for Radiation Oncology C1 [Smith, Benjamin D.] Wilford Hall USAF Med Ctr, Lackland AFB, TX 78236 USA. [Smith, Benjamin D.; Buchholz, Thomas A.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Arthur, Douglas W.; Todor, Dorin A.] Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. [Haffty, Bruce G.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Radiat Oncol, New Brunswick, NJ USA. [Hahn, Carol A.] Duke Univ, Sch Med, Dept Radiat Oncol, Durham, NC USA. [Hardenbergh, Patricia H.] Shaw Reg Canc Ctr, Veil, CO USA. [Julian, Thomas B.] Allegheny Gen Hosp, Dept Human Oncol, Pittsburgh, PA 15212 USA. [Marks, Lawrence B.] Univ N Carolina, Sch Med, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. [Vicini, Frank A.] William Beaumont Hosp, Dept Radiat Oncol, Royal Oak, MI 48072 USA. [Whelan, Timothy J.] Juravinski Canc Ctr, Dept Radiat Oncol, Hamilton, ON, Canada. [White, Julia] Med Coll Wisconsin, Dept Radiat Oncol, Milwaukee, WI 53226 USA. [Wo, Jennifer Y.] Harvard Radiat Oncol Residency Program, Boston, MA USA. [Harris, Jay R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Harris, Jay R.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Smith, BD (reprint author), 2200 Bergquist Dr,Suite 1, Lackland AFB, TX 78236 USA. EM benjamin.smith@lackland.af.mil RI Whelan, Timothy/D-3185-2017; OI Smith, Benjamin/0000-0001-7866-1093 NR 99 TC 419 Z9 439 U1 3 U2 26 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2009 VL 74 IS 4 BP 987 EP 1001 DI 10.1016/j.ijrobp.2009.02.031 PG 15 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 464KY UT WOS:000267505000003 PM 19545784 ER PT J AU Yoon, SS Stangenberg, L Lee, YJ Rothrock, C Dreyfuss, JM Baek, KH Waterman, PR Nielsen, GP Weissleder, R Mahmood, U Park, PJ Jacks, T Dodd, RD Fisher, CJ Ryeom, S Kirsch, DG AF Yoon, Sam S. Stangenberg, Lars Lee, Yoon-Jin Rothrock, Courtney Dreyfuss, Jonathan M. Baek, Kwan-Hyuck Waterman, Peter R. Nielsen, G. Petur Weissleder, Ralph Mahmood, Umar Park, Peter J. Jacks, Tyler Dodd, Rebecca D. Fisher, Carolyn J. Ryeom, Sandra Kirsch, David G. TI EFFICACY OF SUNITINIB AND RADIOTHERAPY IN GENETICALLY ENGINEERED MOUSE MODEL OF SOFT-TISSUE SARCOMA SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Sarcoma; radiotherapy; angiogenesis; sunitinib ID IONIZING-RADIATION; GENE-EXPRESSION; RECTAL-CANCER; GROWTH-FACTOR; TUMOR; SU11248; ANGIOGENESIS; IRRADIATION; AGENTS AB Purpose: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Methods and Materials: Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. Results: The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm(3) after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. Conclusion: SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS. (C) 2009 Elsevier Inc. C1 [Yoon, Sam S.; Lee, Yoon-Jin; Rothrock, Courtney] Massachusetts Gen Hosp, Div Surg Oncol, Dept Surg, Boston, MA 02114 USA. [Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stangenberg, Lars; Waterman, Peter R.; Weissleder, Ralph; Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Waterman, Peter R.; Weissleder, Ralph; Mahmood, Umar] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Dreyfuss, Jonathan M.; Baek, Kwan-Hyuck; Waterman, Peter R.; Weissleder, Ralph; Mahmood, Umar; Park, Peter J.; Ryeom, Sandra] Harvard Univ, Sch Med, Boston, MA USA. [Dreyfuss, Jonathan M.; Park, Peter J.] Brigham & Womens Hosp, Harvard Partners Ctr Genet & Genom, Boston, MA 02115 USA. [Baek, Kwan-Hyuck; Ryeom, Sandra] Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA. [Baek, Kwan-Hyuck; Ryeom, Sandra] Boston Childrens Hosp, Dept Surg, Boston, MA USA. [Jacks, Tyler] MIT, Ctr Canc Res, Dept Biol, Boston, MA USA. [Jacks, Tyler] MIT, Howard Hughes Med Inst, Boston, MA USA. [Dodd, Rebecca D.; Fisher, Carolyn J.; Kirsch, David G.] Duke Univ, Sch Med, Dept Radiat Oncol, Durham, NC USA. [Dodd, Rebecca D.; Fisher, Carolyn J.; Kirsch, David G.] Duke Univ, Sch Med, Dept Pharmacol, Durham, NC USA. [Dodd, Rebecca D.; Fisher, Carolyn J.; Kirsch, David G.] Duke Univ, Sch Med, Dept Canc Biol, Durham, NC USA. RP Yoon, SS (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Dept Surg, Yawkey 7B-7926,55 Fruit St, Boston, MA 02114 USA. EM syoon@partners.org FU NCI NIH HHS [P30 CA014051, K08 CA114176, K12 CA 87723-03, K12 CA087723, KO8 CA 114176, L30 CA109410, L30 CA109410-01, P30-CA14051, P50 CA086355, P50 CA086355-07, P50 CA86355, R21 CA117128, R21 CA117128-02, U24 CA092782, U24 CA092782-08, U24 CA92782, U54 CA119349, U54 CA119349-040003] NR 23 TC 28 Z9 29 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2009 VL 74 IS 4 BP 1207 EP 1216 DI 10.1016/j.ijrobp.2009.02.052 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 464KY UT WOS:000267505000034 PM 19545786 ER PT J AU Bei, M AF Bei, Marianna TI Molecular Genetics of Ameloblast Cell Lineage SO JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION LA English DT Article ID JUNCTIONAL EPIDERMOLYSIS-BULLOSA; LINKED AMELOGENESIS IMPERFECTA; ALPHA-3 CHAIN GENE; HOMOZYGOUS NONSENSE MUTATION; TOOTH DEVELOPMENT; TISSUE INTERACTIONS; LAMININ-5 SUBUNITS; MATURATION STAGE; ENAMEL FORMATION; MICE DISPLAY AB Late tooth morphogenesis is characterized by a series of events that determine crown morphogenesis and the histodifferentiation of epithelial cells into enamel-secreting ameloblasts and of mesenchymal cells into dentin-secreting odontoblasts. Functional ameloblasts are tall, columnar, polarized cells that synthesize and secrete a number of enamel-specific proteins. After depositing the full thickness of enamel matrix, ameloblasts shrink in size and regulate enamel maturation. Amelogenesis imperfecta (AI) is a heterogeneous group of inherited defects in enamel formation. Clinically, AI presents as a spectrum of enamel malformations that are categorized as hypoplastic, hypocalcified, or hypomaturation types, based upon the thickness and hardness of the enamel. The different types of AI are inherited, either as X-linked, autosomal-dominant, or autosomal-recessive traits. Recently, several gene mutations have been identified to cause the subtypes of AI. How these genes, however, coordinate their function to control amelogenesis is not understood. In this review, we discuss the role of genes that play definitive role on the determination of ameloblast cell fate and life cycle based on studies in transgenic animals. J. Exp. Zool. (Mol. Dev. Evol.) 312B:437-444, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Bei, Marianna] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Bei, Marianna] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Bei, M (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St,Rm 3-214, Charlestown, MA 02129 USA. EM mbei@partners.org FU NIH [RO3 DE 018415]; Shiseido Inc; Harvard Medical School FX Grant sponsor: NIH; Grant number: RO3 DE 018415; Grant sponsor: Shiseido Inc.; Grant sponsor: Harvard Medical School. NR 62 TC 26 Z9 26 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-5007 J9 J EXP ZOOL PART B JI J. Exp. Zool. Part B PD JUL 15 PY 2009 VL 312B IS 5 BP 437 EP 444 DI 10.1002/jez.b.21261 PG 8 WC Evolutionary Biology; Developmental Biology; Zoology SC Evolutionary Biology; Developmental Biology; Zoology GA 462JF UT WOS:000267347300006 PM 19090561 ER PT J AU Fiorina, P Jurewicz, M Augello, A Vergani, A Dada, S La Rosa, S Selig, M Godwin, J Law, K Placidi, C Smith, RN Capella, C Rodig, S Adra, CN Atkinson, M Sayegh, MH Abdi, R AF Fiorina, Paolo Jurewicz, Mollie Augello, Andrea Vergani, Andrea Dada, Shirine La Rosa, Stefano Selig, Martin Godwin, Jonathan Law, Kenneth Placidi, Claudia Smith, R. Neal Capella, Carlo Rodig, Scott Adra, Chaker N. Atkinson, Mark Sayegh, Mohamed H. Abdi, Reza TI Immunomodulatory Function of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Type 1 Diabetes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; VERSUS-HOST-DISEASE; NOD MICE; IN-VITRO; LYMPHOCYTE-PROLIFERATION; GRAFT-SURVIVAL; THERAPY; VIVO; ARTHRITIS; INFUSION AB Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders. The Journal of Immunology, 2009, 183: 993-1004. C1 [Abdi, Reza] Harvard Univ, Sch Med, Brigham & Womens Hosp, Transplantat Res Ctr,Div Nephrol, Boston, MA 02115 USA. [Fiorina, Paolo; Jurewicz, Mollie; Vergani, Andrea; Dada, Shirine; Godwin, Jonathan; Adra, Chaker N.; Sayegh, Mohamed H.; Abdi, Reza] Harvard Univ, Sch Med, Childrens Hosp, Transplantat Res Ctr, Boston, MA 02115 USA. [Fiorina, Paolo; Vergani, Andrea] Ist Sci San Raffaele, Dept Med, I-20132 Milan, Italy. [Augello, Andrea; La Rosa, Stefano; Placidi, Claudia; Capella, Carlo] Univ Insubria, Dept Pathol, Osped Circolo, Varese, Italy. [Augello, Andrea; La Rosa, Stefano; Placidi, Claudia; Capella, Carlo] Univ Insubria, Dept Human Morphol, Varese, Italy. [Law, Kenneth; Rodig, Scott] Brigham & Womens Hosp, Dept Pathol, Div Hematopathol, Boston, MA 02115 USA. [Selig, Martin; Smith, R. Neal] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Adra, Chaker N.] King Faisal Specialist Hosp & Res Ctr, Stem Cell Therapy Program, Riyadh 11211, Saudi Arabia. [Atkinson, Mark] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA. RP Abdi, R (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Transplantat Res Ctr,Div Nephrol, 221 Longwood Ave, Boston, MA 02115 USA. EM paolo.fiorina@childrens.harvard.edu; rabdi@rics.bwh.harvard.edu RI Augello, Andrea/C-7321-2013 OI Augello, Andrea/0000-0001-5959-7989 FU National Institutes of Health [P01 AI-41521]; Juvenile Diabetes Research Foundation (JDRF) [4-2007-1065]; Scott and Heidi Schuster Foundation; American Society of Transplantation-JDRF Faculty Grant; JDRF-Career Development Award FX This work is supported in part by National Institutes of Health P01 AI-41521, Juvenile Diabetes Research Foundation (JDRF) Grant 4-2007-1065, JDRF R&D Grant 4-2007-1065, and by the Scott and Heidi Schuster Foundation (M.H.S.). P.F. is the recipient of an American Society of Transplantation-JDRF Faculty Grant and a JDRF-Career Development Award. R.A. is the recipient of a JDRF Regular Grant. NR 48 TC 188 Z9 197 U1 3 U2 22 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2009 VL 183 IS 2 BP 993 EP 1004 DI 10.4049/jimmunol.0900803 PG 12 WC Immunology SC Immunology GA 468JD UT WOS:000267812600025 PM 19561093 ER PT J AU Kasorn, A Alcaide, P Jia, YH Subramanian, KK Sarraj, B Li, YT Loison, F Hattori, H Silberstein, LE Luscinskas, WF Luo, HR AF Kasorn, Anongnard Alcaide, Pilar Jia, Yonghui Subramanian, Kulandayan K. Sarraj, Bara Li, Yitang Loison, Fabien Hattori, Hidenori Silberstein, Leslie E. Luscinskas, William F. Luo, Hongbo R. TI Focal Adhesion Kinase Regulates Pathogen-Killing Capability and Life Span of Neutrophils via Mediating Both Adhesion-Dependent and -Independent Cellular Signals SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TYROSINE PHOSPHORYLATION; RESPIRATORY BURST; LEUKOCYTE RECRUITMENT; BIOLOGICAL SURFACES; NADPH OXIDASE; P-SELECTIN; ACTIVATION; PROTEIN; MIGRATION; PHAGOCYTOSIS AB Various neutrophil functions such as phagocytosis, superoxide production, and survival are regulated by integrin signaling. Despite the essential role of focal adhesion kinase (FAK) in mediating this signaling pathway, its exact function in neutrophils is ill defined. In this study, we investigated the role of FAK in neutrophils using a myeloid-specific conditional FAK knockout mouse. As reported in many other cell types, FAK is required for regulation of focal adhesion dynamics when neutrophils adhere to fibronectin or ICAM-1. Adhesion on VCAM-1-coated surfaces and chemotaxis after adhesion were not altered in FAK null neutrophils. In addition, we observed significant reduction in NADPH oxidase-mediated superoxide production and complement-mediated phagocytosis in FAK null neutrophils. As a result, these neutrophils displayed decreased pathogen killing capability both in vitro and in vivo in a mouse peritonitis model. In adherent cells, the defects associated with FAK deficiency are likely due to suppression of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) signaling and chemoattractant-elicited calcium signaling. Disruption of FAK also reduced chemoattractant-elicited superoxide production in suspended neutrophils in the absence of cell adhesion. This may be solely caused by suppression of PtdIns(3,4,5)P3 signaling in these cells, because the fMLP-elicited calcium signal was not altered. Consistent with decreased PtdIns(3,4,5)P3/Akt signaling in FAK null neutrophils, we also observed accelerated spontaneous death in these cells. Taken together, our results revealed previously unrecognized roles of FAK in neutrophil function and provided a potential therapeutic target for treatment of a variety of infectious and inflammatory diseases. The Journal of Immunology, 2009, 183: 1032-1043. C1 [Kasorn, Anongnard] Srinakharinwirot Univ, Fac Med, Dept Community Med, Bangkok, Thailand. [Jia, Yonghui; Subramanian, Kulandayan K.; Li, Yitang; Loison, Fabien; Hattori, Hidenori; Silberstein, Leslie E.; Luo, Hongbo R.] Harvard Univ, Sch Med, Dept Pathol, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Jia, Yonghui; Subramanian, Kulandayan K.; Li, Yitang; Loison, Fabien; Hattori, Hidenori; Silberstein, Leslie E.; Luo, Hongbo R.] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Alcaide, Pilar; Luscinskas, William F.] Brigham & Womens Hosp, Ctr Excellence Vasc Biol, Dept Pathol, Boston, MA 02115 USA. [Sarraj, Bara] Northwestern Univ, Div Organ Transplant, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. RP Luo, HR (reprint author), Karp Family Res Bldg,Room 10214, Boston, MA 02115 USA. EM Hongbo.Luo@childrens.harvard.edu RI Loison, Fabien/G-3385-2014 OI Loison, Fabien/0000-0002-6678-1730 FU National Institutes of Health Training [HL066987] FX B.S. is supported by National Institutes of Health Training Grant HL066987, and H.L. is supported by National Institutes of Health Grants HL085100, A1076471, and GM076084 and a Research Scholar Grant from American Cancer Society. NR 69 TC 21 Z9 23 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2009 VL 183 IS 2 BP 1032 EP 1043 DI 10.4049/jimmunol.0802984 PG 12 WC Immunology SC Immunology GA 468JD UT WOS:000267812600029 PM 19561112 ER PT J AU Lazaro, E Godfrey, SB Stamegna, P Ogbechie, T Kerrigan, C Zhang, M Walker, BD Le Gall, S AF Lazaro, Estibaliz Godfrey, Sasha Blue Stamegna, Pamela Ogbechie, Tobi Kerrigan, Christopher Zhang, Mei Walker, Bruce D. Le Gall, Sylvie TI Differential HIV Epitope Processing in Monocytes and CD4 T Cells Affects Cytotoxic T Lymphocyte Recognition SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 15th Conference on Retroviruses and Opportunistic Infections CY FEB 03-06, 2008 CL Boston, MA ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; CLASS-I MOLECULES; VIRAL LOAD; ENDOPLASMIC-RETICULUM; ANTIGEN PRESENTATION; TRIMS PRECURSORS; DENDRITIC CELLS; MHC; PEPTIDE AB The ability of cytotoxic T lymphocytes (CTLs) to clear virus-infected cells is dependent on the presentation of viral peptides processed intracellularly and displayed by major histocompatibility complex class I. Most CTL functional assays use exogenously added peptides, a practice that does not account for the kinetics and quantity of antigenic peptides produced by infectable cells. Here, we examined the relative ability of 2 major human immunodeficiency virus-infectable cell subsets-CD4 T lymphocytes and monocytes-to produce antigenic peptides, using cytosol as a source of peptidases and mass spectrometry to define the degradation products. We show clear subset-specific differences in the kinetics of peptide production and the ability of the peptides produced to sensitize cells for lysis by CTLs, with primary CD4 T lymphocytes having significantly lower proteolytic activity than monocytes. These differences in epitope processing by cell subsets may affect the efficiency of CTL-mediated clearance of infected subsets and contribute to the establishment of chronic infection. C1 [Le Gall, Sylvie] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst MGH MIT & Harvard,AIDS Res Ctr, Boston, MA 02129 USA. [Lazaro, Estibaliz; Godfrey, Sasha Blue; Stamegna, Pamela; Ogbechie, Tobi; Kerrigan, Christopher; Zhang, Mei; Walker, Bruce D.; Le Gall, Sylvie] Harvard Univ, Sch Med, Boston, MA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Le Gall, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst MGH MIT & Harvard,AIDS Res Ctr, CNY149 13th St, Boston, MA 02129 USA. EM sylvie_legall@hms.harvard.edu OI Godfrey, Sasha Blue/0000-0001-9992-5975 FU Howard Hughes Medical Institute; NIAID NIH HHS [AI60502, P30 AI060354, R01 AI028568, AI28568, R01 AI084753, R01 AI084753-01, R21 AI060502, R37 AI028568] NR 44 TC 18 Z9 19 U1 1 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 JUL 15 PY 2009 VL 200 IS 2 BP 236 EP 243 DI 10.1086/599837 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 458RD UT WOS:000267040300011 PM 19505257 ER PT J AU Ma, QL Yang, FS Rosario, ER Ubeda, OJ Beech, W Gant, DJ Chen, PP Hudspeth, B Chen, CR Zhao, YL Vinters, HV Frautschy, SA Cole, GM AF Ma, Qiu-Lan Yang, Fusheng Rosario, Emily R. Ubeda, Oliver J. Beech, Walter Gant, Dana J. Chen, Ping Ping Hudspeth, Beverly Chen, Cory Zhao, Yongle Vinters, Harry V. Frautschy, Sally A. Cole, Greg M. TI beta-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3-BETA; POLYUNSATURATED FATTY-ACIDS; DEPENDENT DIABETES-MELLITUS; APOLIPOPROTEIN-E GENOTYPE; GROWTH-FACTOR EXPRESSION; TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE AD; DOCOSAHEXAENOIC ACID; OXIDATIVE STRESS; NEURODEGENERATIVE DISEASES AB Both insulin resistance (type II diabetes) and beta-amyloid (A beta) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of A beta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. Increased phospho-IRS-1 is found in AD brain and insulin-resistant tissues from diabetics. Here, we report A beta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. This was accompanied by improvement in Y-maze performance. Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. These data indicate JNK mediates A beta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. C1 [Ma, Qiu-Lan; Yang, Fusheng; Rosario, Emily R.; Ubeda, Oliver J.; Beech, Walter; Gant, Dana J.; Chen, Ping Ping; Hudspeth, Beverly; Chen, Cory; Zhao, Yongle; Frautschy, Sally A.; Cole, Greg M.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Vinters, Harry V.; Frautschy, Sally A.; Cole, Greg M.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Vinters, Harry V.] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Ma, Qiu-Lan; Yang, Fusheng; Rosario, Emily R.; Ubeda, Oliver J.; Beech, Walter; Gant, Dana J.; Chen, Ping Ping; Hudspeth, Beverly; Chen, Cory; Zhao, Yongle; Frautschy, Sally A.; Cole, Greg M.] Greater Los Angeles Vet Affairs Healthcare Syst, Geriatr Res & Clin Ctr, Vet Affairs Med Ctr, North Hills, CA 91343 USA. RP Cole, GM (reprint author), Greater Los Angeles Healthcare Syst Res 151, Vet Affairs, Bldg 7,Room A101,16111 Plummer St, North Hills, CA 91343 USA. EM gmcole@ucla.edu FU National Institutes of Health (NIH) [R01 AT003008]; National Institute on Aging-NIH [R01 AG16570, AG13471, U01 AG028583, R01 AG021975]; Alzheimer's Association [NIRG-07-59659]; Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine FX This work was supported by National Institutes of Health (NIH) Grant R01 AT003008 (G. M. C.); National Institute on Aging-NIH Grants R01 AG16570 (G. M. C., H. V. V.), AG13471 (G. M. C.), U01 AG028583 (S. A. F.), and R01 AG021975 (S. A. F.); and Alzheimer's Association Grant NIRG-07-59659 (Q.-L. M.). H. V. V. was supported in part by the Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine. NR 99 TC 227 Z9 240 U1 3 U2 31 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 15 PY 2009 VL 29 IS 28 BP 9078 EP 9089 DI 10.1523/JNEUROSCI.1071-09.2009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 470YI UT WOS:000268018000022 PM 19605645 ER PT J AU Mizumori, M Ham, M Guth, PH Engel, E Kaunitz, JD Akiba, Y AF Mizumori, Misa Ham, Maggie Guth, Paul H. Engel, Eli Kaunitz, Jonathan D. Akiba, Yasutada TI Intestinal alkaline phosphatase regulates protective surface microclimate pH in rat duodenum SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID MUCUS-BICARBONATE BARRIER; CYSTIC-FIBROSIS; BRUSH-BORDER; ATP RELEASE; ADENOSINE-TRIPHOSPHATASE; CARBONIC-ANHYDRASES; MOUSE DUODENUM; KNOCKOUT MICE; P2X RECEPTORS; ACID AB Regulation of localized extracellular pH (pH(o)) maintains normal organ function. An alkaline microclimate overlying the duodenal enterocyte brush border protects the mucosa from luminal acid. We hypothesized that intestinal alkaline phosphatase (IAP) regulates pH(o) due to pH-sensitive ATP hydrolysis as part of an ecto-purinergic pH regulatory system, comprised of cell-surface P2Y receptors and ATP-stimulated duodenal bicarbonate secretion (DBS). To test this hypothesis, we measured DBS in a perfused rat duodenal loop, examining the effect of the competitive alkaline phosphatase inhibitor glycerol phosphate (GP), the ecto-nucleoside triphosphate diphosphohydrolase inhibitor ARL67156, and exogenous nucleotides or P2 receptor agonists on DBS. Furthermore, we measured perfusate ATP concentration with a luciferin-luciferase bioassay. IAP inhibition increased DBS and luminal ATP output. Increased luminal ATP output was partially CFTR dependent, but was not due to cellular injury. Immunofluorescence localized the P2Y(1) receptor to the brush border membrane of duodenal villi. The P2Y(1) agonist 2-methylthio-ADP increased DBS, whereas the P2Y(1) antagonist MRS2179 reduced ATP- or GP-induced DBS. Acid perfusion augmented DBS and ATP release, further enhanced by the IAP inhibitor l-cysteine, and reduced by the exogenous ATPase apyrase. Furthermore, MRS2179 or the highly selective P2Y(1) antagonist MRS2500 co-perfused with acid induced epithelial injury, suggesting that IAP/ATP/P2Y signalling protects the mucosa from acid injury. Increased DBS augments IAP activity presumably by raising pH(o), increasing the rate of ATP degradation, decreasing ATP-mediated DBS, forming a negative feedback loop. The duodenal epithelial brush border IAP-P2Y-HCO3- surface microclimate pH regulatory system effectively protects the mucosa from acid injury. C1 [Mizumori, Misa; Ham, Maggie; Kaunitz, Jonathan D.; Akiba, Yasutada] Univ Calif Los Angeles, Dept Med, Sch Med, Los Angeles, CA 90073 USA. [Engel, Eli] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90073 USA. [Guth, Paul H.; Kaunitz, Jonathan D.; Akiba, Yasutada] Greater Los Angles Vet Affairs Healthcare Syst, Los Angeles, CA 90073 USA. [Kaunitz, Jonathan D.; Akiba, Yasutada] Brentwood Biomed Res Inst, Los Angeles, CA 90073 USA. RP Kaunitz, JD (reprint author), W Los Angeles VA Med Ctr, Bldg 114,Suite 217,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jake@ucla.edu FU Department of Veterans Affairs Merit Review Award; NIH-NIDDK [R01 DK54221, P30 DK0413] FX We thank Jenifer Kugler for her assistance with manuscript preparation. This work was supported by a Department of Veterans Affairs Merit Review Award, NIH-NIDDK R01 DK54221 (J.D.K.), and the animal core of NIH-NIDDK P30 DK0413 (J. E. Rozengurt). NR 51 TC 48 Z9 48 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUL 15 PY 2009 VL 587 IS 14 BP 3651 EP 3663 DI 10.1113/jphysiol.2009.172270 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 471FF UT WOS:000268040500029 PM 19451200 ER PT J AU Wolpin, BM Stampfer, MJ AF Wolpin, Brian M. Stampfer, Meir J. TI Defining Determinants of Pancreatic Cancer Risk: Are We Making Progress? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID MALE SMOKERS; MEAT; CONSUMPTION; GLUCOSE; COHORT; FAT C1 [Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Wolpin, Brian M.; Stampfer, Meir J.] Harvard Univ, Sch Med, Boston, MA USA. [Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Wolpin, BM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM bwolpin@partners.org FU NCI NIH HHS [R01 CA124908] NR 12 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 15 PY 2009 VL 101 IS 14 BP 972 EP 973 DI 10.1093/jnci/djp182 PG 2 WC Oncology SC Oncology GA 472FE UT WOS:000268114300004 PM 19561317 ER PT J AU Brainard, DM Seung, E Frahm, N Cariappa, A Bailey, CC Hart, WK Shin, HS Brooks, SF Knight, HL Eichbaum, Q Yang, YG Sykes, M Walker, BD Freeman, GJ Pillai, S Westmoreland, SV Brander, C Luster, AD Tager, AM AF Brainard, Diana M. Seung, Edward Frahm, Nicole Cariappa, Annaiah Bailey, Charles C. Hart, William K. Shin, Hae-Sook Brooks, Sarah F. Knight, Heather L. Eichbaum, Quentin Yang, Yong-Guang Sykes, Megan Walker, Bruce D. Freeman, Gordon J. Pillai, Shiv Westmoreland, Susan V. Brander, Christian Luster, Andrew D. Tager, Andrew M. TI Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice SO JOURNAL OF VIROLOGY LA English DT Article ID SCID-HU MOUSE; HUMAN B-CELLS; HIV-1 INFECTION; T-CELLS; BONE-MARROW; HEMATOPOIETIC STEM; IN-VIVO; DISEASE PROGRESSION; TYPE-1 INFECTION; PROGENITOR CELLS AB The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34(+) fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4(+) T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4(+) and CD8(+) T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4(+) and CD8(+) T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4(+) cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies. C1 [Brainard, Diana M.; Seung, Edward; Hart, William K.; Shin, Hae-Sook; Brooks, Sarah F.; Luster, Andrew D.; Tager, Andrew M.] Harvard Univ, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp,Sch Med, Charlestown, MA 02129 USA. [Brainard, Diana M.; Frahm, Nicole; Knight, Heather L.; Eichbaum, Quentin; Walker, Bruce D.; Brander, Christian] Harvard Univ, Sch Med, Div Aids, Charlestown, MA 02129 USA. [Brainard, Diana M.; Frahm, Nicole; Knight, Heather L.; Eichbaum, Quentin; Walker, Bruce D.; Brander, Christian] MGH MIT & Harvard, Ragon Inst, Charlestown, MA 02129 USA. [Frahm, Nicole] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Seattle, WA 98109 USA. [Cariappa, Annaiah; Pillai, Shiv] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Charlestown, MA 02129 USA. [Bailey, Charles C.; Westmoreland, Susan V.] Harvard Univ, Div Comparat Pathol, Sch Med, New England Reg Primate Res Ctr, Southborough, MA 01772 USA. [Yang, Yong-Guang; Sykes, Megan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Brander, Christian] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. [Brander, Christian] Irsicaixa Fdn, Badalona, Spain. RP Luster, AD (reprint author), Harvard Univ, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp,Sch Med, Bldg 149-8301,149 13th St, Charlestown, MA 02129 USA. EM aluster@mgh.harvard.edu; amtager@partners.org OI Brander, Christian/0000-0002-0548-5778 FU Harvard University CFAR (HU CFAR) Scholar Award; HU CFAR Collaborative Feasibility Study Award; National Institutes of Health [K08 AI058857, R01 A1067077, AI064930, AI069458, P30 AI060354, P51 RR00168, T32 RR07000, P01 AI078897] FX This work was supported by a Harvard University CFAR (HU CFAR) Scholar Award and an HU CFAR Collaborative Feasibility Study Award to A. T. and by National Institutes of Health grants K08 AI058857 to D. B., R01 A1067077 to C. B., AI064930 and AI069458 to S. P., P30 AI060354 to B. W., P51 RR00168 and T32 RR07000 to S. V. W., and P01 AI078897 (Project 4) to A. L. NR 67 TC 124 Z9 125 U1 2 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL 15 PY 2009 VL 83 IS 14 BP 7305 EP 7321 DI 10.1128/JVI.02207-08 PG 17 WC Virology SC Virology GA 462LO UT WOS:000267354300033 PM 19420076 ER PT J AU Kumar, D Shadrach, JL Wagers, AJ Lassar, AB AF Kumar, Deepak Shadrach, Jennifer L. Wagers, Amy J. Lassar, Andrew B. TI Id3 Is a Direct Transcriptional Target of Pax7 in Quiescent Satellite Cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MUSCLE PROGENITOR CELLS; SKELETAL-MUSCLE; STEM-CELLS; FATE DETERMINATION; SOMITIC ORIGIN; SELF-RENEWAL; GENE; POPULATION; EXPRESSION; MYOGENESIS AB Pax7 is a key regulator of skeletal muscle stem cells and is required along with Pax3 to generate skeletal muscle precursors. We have identified a collection of genes induced by either Pax3 or Pax7 in C2C12 muscle cells. Two notable Pax3/7 targets are the inhibitory helix-loop-helix (HLH) proteins inhibitor of DNA binding (Id) 2 and Id3, both of which are coordinately expressed with Pax7 in quiescent satellite cells and are induced in quiescent C2C12 myogenic cells after ectopic expression of either Pax3 or Pax7. Ectopic Pax7 activates expression of a luciferase reporter driven by the Id3 promoter, and maximal induction of this reporter requires a conserved Pax7 binding site located upstream of the Id3 gene. Chromatin immunoprecipitation indicated that Pax7 is bound upstream of the Id3 promoter in quiescent satellite cells. In addition, short hairpin RNA-mediated knockdown of Pax7 expression in cultured satellite cells coordinately decreased both Id2 and Id3 expression. Together, these findings indicate that Id3 is a direct transcriptional target for Pax7 in quiescent satellite cells, and they suggest that Pax7 acts to block premature differentiation of quiescent satellite cells by inducing the expression of Id2 and Id3, which in turn may act to block either the precocious induction of myogenic basic (b) HLH proteins, the activity of myogenic bHLH proteins, or both. C1 [Kumar, Deepak; Lassar, Andrew B.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Shadrach, Jennifer L.; Wagers, Amy J.] Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, Boston, MA 02115 USA. [Shadrach, Jennifer L.; Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Shadrach, Jennifer L.; Wagers, Amy J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Lassar, AB (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM andrew_lassar@hms.harvard.edu FU National Institutes of Health [GM-054879]; Harvard Stem Cell Institute; Jain Foundation; Beckman Foundation; Muscular Dystrophy Association FX We thank Robert Lim for generously supplying the Id3 promoter; Michael Rudnicki for the Pax7 cDNA; Hyung-song Nam, Yvette Chin, and Robert Benezra for characterizing and supplying the anti-Id3 rabbit monoclonal antibody (now available from CalBioreagents, San Mateo, CA); and Robert Benezra for thoughtful comments on our work. This work was funded by National Institutes of Health grant GM-054879 (to A. B. L.) and grants from the Harvard Stem Cell Institute, Jain Foundation, and Beckman Foundation (to A. J. W.). D. K. was funded by a fellowship from the Muscular Dystrophy Association. NR 35 TC 56 Z9 58 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 15 PY 2009 VL 20 IS 14 BP 3170 EP 3177 DI 10.1091/mbc.E08-12-1185 PG 8 WC Cell Biology SC Cell Biology GA 470NL UT WOS:000267981600001 PM 19458195 ER PT J AU Bourgo, RJ Siddiqui, H Fox, S Solomon, D Sansam, CG Yaniv, M Muchardt, C Metzger, D Chambon, P Roberts, CWM Knudsen, ES AF Bourgo, Ryan J. Siddiqui, Hasan Fox, Sejal Solomon, David Sansam, Courtney G. Yaniv, Moshe Muchardt, Christian Metzger, Daniel Chambon, Pierre Roberts, Charles W. M. Knudsen, Erik S. TI SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID REMODELING COMPLEX; CHROMOSOME SEGREGATION; CANCER; GENE; BRG1; HETEROCHROMATIN; GENOME; BRM; HAPLOINSUFFICIENCY; TRANSCRIPTION AB Switch (SWI)/sucrose nonfermentable (SNF) is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity. C1 [Bourgo, Ryan J.; Knudsen, Erik S.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA. [Siddiqui, Hasan] Ohio State Univ, Coll Med & Publ Hlth, Ctr Comprehens Canc, Human Canc Genet Program,Dept Mol Virol Immunol &, Columbus, OH 43210 USA. [Fox, Sejal] Univ Cincinnati, Coll Med, Dept Cell & Canc Biol, Cincinnati, OH 45267 USA. [Solomon, David] Georgetown Univ, Sch Med, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Yaniv, Moshe; Muchardt, Christian] Inst Pasteur, Dept Dev Biol, CNRS, F-75724 Paris, France. [Metzger, Daniel; Chambon, Pierre] Inst Genet & Biol Mol & Cellulaire, Dept Funct Genom, F-67400 Illkirch Graffenstaden, France. [Metzger, Daniel; Chambon, Pierre] INSERM, U596, F-67400 Illkirch Graffenstaden, France. [Metzger, Daniel; Chambon, Pierre] CNRS, UMR 7104, F-67400 Illkirch Graffenstaden, France. [Metzger, Daniel; Chambon, Pierre] Univ Strasbourg, F-67000 Strasbourg, France. [Metzger, Daniel; Chambon, Pierre] Coll France, F-67400 Illkirch Graffenstaden, France. [Sansam, Courtney G.; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Bourgo, RJ (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA. EM ryan.bourgo@jefferson.edu FU National Cancer Institute [CA 104213] FX We thank members of the Erik and Karen Knudsen's laboratories for critical review of the manuscript and insightful discussion. We also thank Drs. Christian Muchardt and Moshe Yaniv for providing Brm nullizygous mice, Drs. Daniel Metzger and Pierre Chambon for providing Brg1f/f mice, and to Dr. Charles Roberts for providing SNF5f/f mouse embryonic fibroblasts and the pBABE-Puro and pBABE-Puro-Cre plasmids. Finally, we thank Dr. A. Kathleen McClendon for providing the p53DD retrovirus. E. S. K. is supported by National Cancer Institute grant CA 104213. NR 32 TC 37 Z9 38 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 15 PY 2009 VL 20 IS 14 BP 3192 EP 3199 DI 10.1091/mbc.E08-12-1224 PG 8 WC Cell Biology SC Cell Biology GA 470NL UT WOS:000267981600003 PM 19458193 ER PT J AU Gao, DM Inuzuka, H Korenjak, M Tseng, A Wu, T Wan, LX Kirschner, M Dyson, N Wei, WY AF Gao, Daming Inuzuka, Hiroyuki Korenjak, Michael Tseng, Alan Wu, Tao Wan, Lixin Kirschner, Marc Dyson, Nicholas Wei, Wenyi TI Cdh1 Regulates Cell Cycle through Modulating the Claspin/Chk1 and the Rb/E2F1 Pathways SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ANAPHASE-PROMOTING COMPLEX; ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE; UBIQUITIN LIGASE; HUMAN FIBROBLASTS; BINDING-PROTEIN; G(1) ARREST; CHECKPOINT; P53; DEGRADATION AB APC/Cdh1 is a major cell cycle regulator and its function has been implicated in DNA damage repair; however, its exact role remains unclear. Using affinity purification coupled with mass spectrometry, we identified Claspin as a novel Cdh1-interacting protein and further demonstrated that Claspin is a novel Cdh1 ubiquitin substrate. As a result, inactivation of Cdh1 leads to activation of the Claspin/Chk1 pathway. Previously, we demonstrated that Rb interacts with Cdh1 to influence its ability to degrade Skp2. Here, we report that Cdh1 reciprocally regulates the Rb pathway through competing with E2F1 to bind the hypophosphorylated form of Rb. Although inactivation of Cdh1 in HeLa cells, with defective p53/Rb pathways, led to premature S phase entry, acute depletion of Cdh1 in primary human fibroblasts resulted in premature senescence. Acute loss of many other major tumor suppressors, including PTEN and VHL, also induces premature senescence in a p53- or Rb-dependent manner. Similarly, we showed that inactivation of the p53/Rb pathways by overexpression of SV40 LT-antigen partially reversed Cdh1 depletion-induced growth arrest. Therefore, loss of Cdh1 is only beneficial to cells with abnormal p53 and Rb pathways, which helps explain why Cdh1 loss is not frequently found in many tumors. C1 [Gao, Daming; Inuzuka, Hiroyuki; Tseng, Alan; Wan, Lixin; Wei, Wenyi] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Wu, Tao; Kirschner, Marc] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02215 USA. [Korenjak, Michael; Dyson, Nicholas] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Korenjak, Michael; Dyson, Nicholas] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Wei, WY (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. EM wwei2@bidmc.harvard.edu RI Wan, Lixin/F-2124-2011; Wu, Tao/C-7533-2013 FU Harvard Medical School Milton Fund; Beth Israel Deaconess Medical Center; National Institutes of Health [R01 GM89763, R01 GM53203] FX We thank Alex Toker, Christoph Schorl, Shavali Shaik, and Susan Glueck for critical reading of the manuscript; James DeCaprio (Dana-Farber Cancer Institute, Boston, MA), Christoph Geisen (Dana-Farber Cancer Institute, Boston, MA), William Hahn, Bert Vogelstein (Johns Hopkins University, Baltimore, MD), Michele Pagano, and Peter Jackson for providing reagents; Michele Pagano for sharing unpublished data, and members of the Wei and Dyson labs for useful discussions. W. W. is V Scholar and Kimmel Scholar. M. K. is supported by the postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (German Research Foundation). This work is supported in part by the Harvard Medical School Milton Fund, the start-up package provided by the Beth Israel Deaconess Medical Center, and National Institutes of Health Grant R01 GM89763 to W. W, and National Institutes of Health Grant R01 GM53203 to N. D. NR 61 TC 35 Z9 35 U1 0 U2 8 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 15 PY 2009 VL 20 IS 14 BP 3305 EP 3316 DI 10.1091/mbc.E09-01-0092 PG 12 WC Cell Biology SC Cell Biology GA 470NL UT WOS:000267981600013 PM 19477924 ER PT J AU Simon, KC Chen, HL Gao, X Schwarzschild, MA Ascherio, A AF Simon, Kelly Claire Chen, Honglei Gao, Xiang Schwarzschild, Michael A. Ascherio, Alberto TI Reproductive Factors, Exogenous Estrogen Use, and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; estrogen; epidemiology; reproductive factors ID POSTMENOPAUSAL HORMONE USE; BREAST-CANCER; INDUCED NEUROPROTECTION; PREMENOPAUSAL WOMEN; CIGARETTE-SMOKING; AGE; GENDER; REPRODUCIBILITY; PROGESTERONE; CAFFEINE AB To determine if reproductive factors or exogenous estrogen are associated with risk of Parkinson's disease (PD), we conducted a prospective study with 22 years of follow-up among postmenopausal participants in the Nurses' Health Study. Relative risks (RRs) and 95% confidence intervals (CIs) of PD were estimated from a Cox proportional hazards model adjusting for potential confounders. Risk of PD was not significantly associated with any of the reproductive factors measured or exogenous estrogen use. Use of postmenopausal hormones, however, may modify the associations of smoking and caffeine intake with PD risk. The inverse relation between smoking and PD risk was attenuated among ever users of post-menopausal hormones (P for interaction = 0.05). Similar results were obtained for caffeine (P for interaction = 0.09). In exploratory analyses, women using progestin-only hormones were found to have an increased PD risk, but this result was based on a very small number of cases (n = 4). In this large longitudinal study, we found no evidence of a beneficial effect of exogenous or endogenous estrogens on risk of PD. The use of postmenopausal hormone use may interact with other risk factors, but findings are preliminary and need confirmation in other populations. (C) 2009 Movement Disorder Society C1 [Simon, Kelly Claire; Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Simon, KC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,3rd Floor, Boston, MA 02115 USA. EM ksimon@hsph.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU NIH/NINDS [ROI NS048517, T32 ES07069-26]; Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institute of Health [ZOIES1019]; DOD [W81XWH-091-0881] FX This work was funded by grant NIH/NINDS ROI NS048517 and training grant T32 ES07069-26 and was in part supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institute of Health (ZOIES1019) and DOD grant W81XWH-091-0881. We thank Eilis O'Reilly for technical support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 43 TC 30 Z9 30 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL 15 PY 2009 VL 24 IS 9 BP 1359 EP 1365 DI 10.1002/mds.22619 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 478UH UT WOS:000268613300015 PM 19424986 ER PT J AU Gass, N Porkka-Heiskanen, T Kalinchuk, AV AF Gass, Natalia Porkka-Heiskanen, Tarja Kalinchuk, Anna V. TI The role of the basal forebrain adenosine receptors in sleep homeostasis SO NEUROREPORT LA English DT Article DE adenosine; electrophysiology; in vivo microdialysis; sleep deprivation ID CENTRAL-NERVOUS-SYSTEM; BEHAVIORAL STATE; A(2A) RECEPTOR; A(1) RECEPTOR; NEURONS; RAT; MICRODIALYSIS; DEPRIVATION; WAKEFULNESS; MODULATION AB Multiple studies indicate that adenosine released in the basal forebrain during prolonged wakefulness could affect recovery sleep. It is still unclear which of adenosine receptors provide its sleep-modulating effects in the basal forebrain. We infused adenosine A(1) and A(2A) receptors antagonists into the rat basal forebrain during sleep deprivation and compared characteristics of recovery non-rapid eye movement (non-REM) sleep (its amount and non-REM sleep delta power) after sleep deprivation, and after sleep deprivation combined with perfusion of antagonists. A(1) receptor antagonist significantly reduced recovery sleep amount and delta power, whereas A(2A) receptor antagonist had no effect on recovery sleep. We conclude that adenosine can promote recovery non-REM sleep when acting through A(1) receptors in the basal forebrain. NeuroReport 20:1013-1018 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Kalinchuk, Anna V.] Harvard Univ, Sch Med, Dept Psychiat, Neurosci Lab, W Roxbury, MA 02132 USA. [Gass, Natalia; Porkka-Heiskanen, Tarja] Univ Helsinki, Dept Physiol, Inst Biomed, Helsinki, Finland. [Kalinchuk, Anna V.] VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. RP Kalinchuk, AV (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Neurosci Lab, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM anna_kalinchuk@hms.harvard.edu OI Stenberg, Tarja/0000-0003-1843-7625 FU Center for International Mobility (CIMO); Finnish Graduate School of Neuroscience and Academy of Finland FX The authors thank Mr Ernst Mecke, Mrs Pirjo Saarelainen, and Mrs Sari Levo-Siitari for their excellent technical assistance. This study was supported by grants from Center for International Mobility (CIMO), Finnish Graduate School of Neuroscience and Academy of Finland. NR 24 TC 13 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 15 PY 2009 VL 20 IS 11 BP 1013 EP 1018 DI 10.1097/WNR.0b013e32832d5859 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 468LQ UT WOS:000267820400008 PM 19491711 ER PT J AU Yeh, PH Simpson, K Durazzo, TC Gazdzinski, S Meyerhoff, DJ AF Yeh, Ping-Hong Simpson, Ken Durazzo, Timothy C. Gazdzinski, Stefan Meyerhoff, Dieter J. TI Tract-based spatial statistics (TBSS) of diffusion tensor imaging data in alcohol dependence: Abnormalities of the motivational neurocircuitry SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Alcohol use disorder; Cognition; Brain MRI; Diffusion tensor imaging, DTI; Tract-based spatial statistics, TBSS; Probabilistic tractography ID NATIONAL EPIDEMIOLOGIC SURVEY; CHRONIC CIGARETTE-SMOKING; DSM-IV ALCOHOL; WHITE-MATTER; WATER DIFFUSION; DRUG-ADDICTION; NEUROPSYCHIATRIC DISORDERS; MULTIPLE-SCLEROSIS; GENE-EXPRESSION; UNITED-STATES AB Previous diffusion tensor imaging (DTI) studies indicated microstructural disruption of white matter in alcohol dependence. To investigate the microstructure of primary neurocircuitry involved in alcohol use disorders, the present study used Tract-Based Spatial Statistics (TBSS) of DTI measures as well as probabilistic tractography. Eleven recovering alcoholics in their first week of abstinence from alcohol were compared with 10 light-drinking controls; diffusion measures were correlated with measures of neurocognition and drinking severity. Regions characterized by low fractional anisotropy and high mean diffusivity included cortico-striatal fibers and those in frontal white matter and limbic pathways. Greater diffusion abnormalities in sections of commissural fibers (inter-hemispheric connections) were associated with greater drinking severity, and lower fractional anisotropy measures in frontal and limbic fiber tracts correlated with lower visuospatial memory performance. These study findings provide direct evidence of compromised integrity of the motivational brain circuitry in alcohol use disorders. These abnormalities in fiber connections could be partially responsible for deficiencies in executive functions, behavioral regulation, and impulse control commonly described in alcohol dependence. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Yeh, Ping-Hong; Simpson, Ken; Durazzo, Timothy C.; Gazdzinski, Stefan; Meyerhoff, Dieter J.] San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA. [Durazzo, Timothy C.; Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. RP Yeh, PH (reprint author), San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis, 4150 Clement St 114M, San Francisco, CA 94121 USA. EM ping-hong_yeh@med.unc.edu FU NIH [AA10788] FX NIH AA10788 (DJM) and the Veteran's Administration research service supported this project We thank Mary Rebecca Young and Bill Clift of the San Francisco VA Substance Abuse Day Hospital, and Dr. David Pating, Karen Moise, and their colleagues at the San Francisco Kaiser Permanente Chemical Dependency Recovery Program for their valuable assistance in recruiting research participants. We also thank Dr. Hemanth Thayyullathil for assistance with data analyses, as well as Drs. Michael W. Weiner, Norbert Schuff, Wang Zhan, and Yu Zhang for valuable discussions. Last but not least, we thank our study volunteers, who made this research possible. NR 72 TC 50 Z9 52 U1 1 U2 6 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 JUL 15 PY 2009 VL 173 IS 1 BP 22 EP 30 DI 10.1016/j.pscychresns.2008.07.012 PG 9 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 463YF UT WOS:000267469400004 PM 19442492 ER PT J AU van Tulder, MW Suttorp, M Morton, S Bouter, LM Shekelle, P AF van Tulder, Maurits W. Suttorp, Marika Morton, Sally Bouter, Lex M. Shekelle, Paul TI Empirical Evidence of an Association Between Internal Validity and Effect Size in Randomized Controlled Trials of Low-Back Pain SO SPINE LA English DT Article DE Cochrane collaboration; randomized trials; low back pain; bias; effect size ID CLINICAL-TRIALS; SYSTEMATIC REVIEWS; QUALITY ASSESSMENT; METHOD GUIDELINES; CRITERIA LIST; METAANALYSES AB Study Design. We conducted a methodologic study. Objective. The objective of this study was to assess the validity of the criteria list recommended by the Cochrane Back Review Group Editorial Board by evaluating whether individual items and a total score are associated with effect sizes in randomized controlled trials of back-pain interventions. Summary of Background Data. There is concern that studies of low methodologic quality may exaggerate the effectiveness of treatments for low back pain. We performed this study to examine the association between a common measure of internal validity and the reported magnitude of treatment effects. Methods. We assessed the relationship between the 11 items contained in the Cochrane Back Review Group Internal Validity checklist and effect size in randomized trials of interventions for back pain. Of 267 trials in 15 Cochrane reviews that were eligible for inclusion, 51 were excluded, leaving 216 trials included in the analysis. The scores on the 11 items for each trial were taken from the original review. We extracted effect sizes from each low back pain trial. Results. We found that trials that fulfilled a specific item had smaller effect sizes compared with trials that did not fulfill that item for 10 of the 11 items, and for 6 of the criteria, the absolute difference in effect sizes was 0.10 or greater. The 95% confidence interval of the difference in effect sizes crossed the null value in each case. The number of items fulfilled showed that trials with higher scores consistently reported smaller effect sizes than trials with lower scores. At the thresholds of 5 or 6 items fulfilled, the difference in effect sizes was 0.20 in each case (95% confidence intervals 0.05-0.35 and 0.06-0.34, respectively). Stratified analyses did not support confounding by intervention. Conclusion. We conclude that the 11-item Internal Validity Checklist is associated with effect size in randomized trials of interventions for back pain, and that our data support the use of a sum score of the number of fulfilled items in this list. C1 [van Tulder, Maurits W.] Vrije Univ Amsterdam, Dept Hlth Sci, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [van Tulder, Maurits W.; Bouter, Lex M.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Suttorp, Marika; Shekelle, Paul] RAND Hlth, Santa Monica, CA USA. [Morton, Sally] RTI Int, Res Triangle Pk, NC USA. [Shekelle, Paul] W Los Angeles VA Med Ctr, Los Angeles, CA USA. RP van Tulder, MW (reprint author), Vrije Univ Amsterdam, Dept Hlth Sci, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. EM maurits.van.tulder@falw.vu.nl OI Bouter, Lex/0000-0002-2659-5482; van Tulder, Maurits/0000-0002-7589-8471 NR 39 TC 73 Z9 73 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JUL 15 PY 2009 VL 34 IS 16 BP 1685 EP 1692 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 527TX UT WOS:000272390900004 PM 19770609 ER PT J AU Hanekamp, JS Okumi, M Tena, A Arn, S Yamada, K Sachs, DH AF Hanekamp, John S. Okumi, Masayoshi Tena, Aseda Arn, Scott Yamada, Kazuhiko Sachs, David H. TI Cytoplasmic Inheritance of Transplantation Antigens in Animals Produced by Nuclear Transfer SO TRANSPLANTATION LA English DT Article DE Transplantation; Mitochondria; Transplantation antigens; Tolerance; Rejection ID MAJOR HISTOCOMPATIBILITY COMPLEX; MINIATURE SWINE; MITOCHONDRIAL-DNA; ALLOGRAFTS; TOLERANCE; INDUCTION; PIGS AB Background. Nuclear transfer has been used as a means of selectively modifying the mammalian genome. One possible consequence of this technology is that the oocytes used in nuclear transfer may provide additional antigens by cytoplasmic inheritance of maternally derived, mitochondrial DNA (mtDNA). These studies examine the potential consequences of such inheritance in a large animal transplantation model. Methods. Renal transplants were performed between major histocompatibility complex (MHC)-identical animals differing only in the source of their maternally derived cytoplasmic DNA, using a protocol, which uniformly leads to tolerance within standard MFIC-inbred lines. In an attempt to correlate transplant results with a putative marker for disparities in cytoplasmically inherited minor histocompatibility antigens, we examined one hypervariable region of mtDNA, designated hypervariable region 1 (HV1). Results. The mtDNA sequence of the HV1 region was found to be invariant among MGH miniature swine of different haplotypes, despite 25 years of selective breeding of the sublines of this colony. In contrast, swine derived by nuclear transfer into outbred oocytes differed in the HV1 region sequence from each other and from MGH swine. Renal transplants from standard, inbred. MGH swine to their MHC-identical knockout counterparts derived from outbred oocytes were rejected within 2 weeks, whereas transplants in the reverse direction were accepted for over 30 days. Conclusions. The HV1 sequence of mtDNA may serve as a marker for the level of diversity of mtDNA. These transplant data are consistent with the existence of mtDNA-encoded mitochondrial minor antigens with a level of diversity that can influence the outcome of renal transplantation. C1 [Hanekamp, John S.; Tena, Aseda; Arn, Scott; Yamada, Kazuhiko; Sachs, David H.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Hanekamp, John S.; Tena, Aseda; Arn, Scott; Yamada, Kazuhiko; Sachs, David H.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Okumi, Masayoshi] Osaka Univ, Grad Sch Med, Dept Urol, Osaka, Japan. RP Hanekamp, JS (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH East,Bldg 149,13th St, Boston, MA 02129 USA. EM John.hanekamp@tbrc.mgh.harvard.edu FU NIAID NIH HHS [R37 AI031046, R37 AI031046-19, R01 AI031046-10] NR 21 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2009 VL 88 IS 1 BP 30 EP 37 DI 10.1097/TP.0b013e3181a9ed5b PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 468UJ UT WOS:000267848000006 PM 19584677 ER PT J AU Thinda, S Tomlinson, JS AF Thinda, Sumeer Tomlinson, James S. TI Mesenteric rheumatoid nodules masquerading as an intra-abdominal malignancy: a case report and review of the literature SO WORLD JOURNAL OF SURGICAL ONCOLOGY LA English DT Article ID ACCELERATED NODULOSIS; ARTHRITIS; THERAPY AB Background: Rheumatoid nodules are the most common extra-articular findings in patients with rheumatoid arthritis. They occur most commonly at pressure points such as the extensor surfaces of the forearms, fingers, and occiput, but have also been reported to occur in unusual locations including the central nervous system, pericardium, pleura, and sclera. We present the unusual case of rheumatoid nodules in the small bowel mesentery masquerading as an intra-abdominal malignancy. Case presentation: A 65-year-old-male with a known history of longstanding erosive, nodular, seropositive rheumatoid arthritis was incidentally found to have a mesenteric mass on computed tomography (CT) exam of the abdomen. This mass had not been present on prior imaging studies and was worrisome for a malignancy. Attempts at noninvasive biopsy were nondiagnostic but consistent with a "spindle" cell neoplasm. Laparotomy revealed extensive thickening and fibrosis of the small bowel mesentery along with large, firm nodules throughout the mesentery. A limited bowel resection including a large, partially obstructing, nodule was performed. Pathology was consistent with an unusual presentation of rheumatoid nodules in the mesentery of the small bowel. Conclusion: Rheumatoid nodules should be considered in the differential diagnosis of a patient who presents with an intra-abdominal mass and a history of rheumatoid arthritis. Currently, no tests or imaging modality can discriminate with sufficient accuracy to rule out a malignancy in this difficult diagnostic delimma. Hopefully, this case will serve as impetus for further study and biomarker discovery to allow for improved diagnostic power. C1 [Tomlinson, James S.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Thinda, Sumeer; Tomlinson, James S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. RP Tomlinson, JS (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. EM sumeer.thinda@ucla.edu; jtomlinson@mednet.ucla.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7819 J9 WORLD J SURG ONCOL JI World J. Surg. Oncol. PD JUL 15 PY 2009 VL 7 AR 59 DI 10.1186/1477-7819-7-59 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA 488DP UT WOS:000269329600001 PM 19604347 ER PT J AU Drachman, DE AF Drachman, Douglas E. TI Drug-Eluting Stents in Animals and Patients Where Do We Stand Today? SO CIRCULATION LA English DT Editorial Material DE Editorials; animal model; paclitaxel; restenosis; sirolimus; stents; thrombosis ID INTRAVASCULAR ULTRASOUND; FOLLOW-UP; PACLITAXEL; IMPLANTATION; THROMBOSIS; MODEL C1 Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. RP Drachman, DE (reprint author), Massachusetts Gen Hosp, Div Cardiol, Dept Med, Gray Bigelow 800,55 Fruit St, Boston, MA 02114 USA. EM ddrachman@partners.org NR 19 TC 10 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 14 PY 2009 VL 120 IS 2 BP 101 EP 103 DI 10.1161/CIRCULATIONAHA.109.872473 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 469XI UT WOS:000267934700002 PM 19564555 ER PT J AU Yan, BP Kiernan, TJ Rosenfield, K Garasic, JM de Moor, M AF Yan, Bryan P. Kiernan, Thomas J. Rosenfield, Kenneth Garasic, Joseph M. de Moor, Michael TI Dynamic Left Main Coronary Artery Obstruction Associated With Williams Syndrome SO CIRCULATION LA English DT Editorial Material C1 [Yan, Bryan P.; Kiernan, Thomas J.; Rosenfield, Kenneth; Garasic, Joseph M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Sect Vasc Med, Boston, MA USA. [de Moor, Michael] Harvard Univ, Massachusetts Gen Hosp Children, Sch Med, Div Pediat Cardiol, Boston, MA USA. RP de Moor, M (reprint author), Massgen Hosp Children, CRP510,175 Cambridge St, Boston, MA 02114 USA. EM mdemoor@partners.org RI Yan, Bryan/P-5928-2015 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 JUL 14 PY 2009 VL 120 IS 2 BP 181 EP 182 DI 10.1161/CIRCULATIONAHA.108.831941 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 469XI UT WOS:000267934700012 PM 19597063 ER PT J AU Meeker, JD Missmer, SA Altshul, L Vitonis, AF Ryan, L Cramer, DW Hauser, R AF Meeker, John D. Missmer, Stacey A. Altshul, Larisa Vitonis, Allison F. Ryan, Louise Cramer, Daniel W. Hauser, Russ TI Serum and follicular fluid organochlorine concentrations among women undergoing assisted reproduction technologies SO ENVIRONMENTAL HEALTH LA English DT Article ID POLYCHLORINATED-BIPHENYLS; MATERNAL SERUM; CRITICAL WINDOWS; UNITED-STATES; EXPOSURE; PREGNANCY; BLOOD; PLASMA; DDT; PCB AB Background: Exposure to persistent organic pollutants, including polychlorinated biphenyls (PCBs) and organochlorine pesticides, is widespread among the general population. There is evidence of adverse effects on reproduction and early pregnancy in relation to organochlorine exposure but human studies remain limited. The increased use of assisted reproductive technologies (ART) presents unique opportunities for the assessment of environmental influences on early pregnancy outcomes not otherwise observable in humans, but studies need to be designed to maximize the efficiency of the exposure data collected while minimizing exposure measurement error. Methods: The present study was conducted to assess the correlation between concentrations of organochlorines in serum and follicular fluid samples collected from a subset of women undergoing ART in a large study that took place between 1994 and 2003, as well as the temporal reliability of serum organochlorine concentrations among women undergoing multiple ART cycles in the study. PCB congeners (118, 138, 153, and 180), 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p, p'-DDT), the DDT metabolite p, p'-DDE, hexachlorobenzene (HCB), oxychlordane, trans-nonachlor and mirex were measured in 72 follicular fluid samples and 265 serum samples collected from 110 women. Results: Organochlorine concentrations in paired serum and follicular fluid samples were correlated, with Pearson and Spearman coefficients ranging from 0.60 to 0.92. Serum organochlorine concentrations were two- to three-fold greater than in follicular fluid, and a significant inverse trend was observed in the distribution of follicular fluid: serum ratios with increasing molecular weight of the compound (p-value for trend < 0.0001). Serum organochlorine concentrations were highly reliable over the course of several months, with intraclass correlation coefficients ranging from 0.86 to 0.98. Finally, there was evidence for a declining trend in organochlorine concentrations between samples collected between years 1994-1998 and those collected in 1999-2003. Conclusion: Our results support the use of a single serum sample to adequately represent a more biologically relevant dose (concentrations in follicular fluid), as well as exposure levels over time, in epidemiological studies of ART outcomes in relation to organochlorine exposure. C1 [Meeker, John D.] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Missmer, Stacey A.; Vitonis, Allison F.; Cramer, Daniel W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Altshul, Larisa; Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Ryan, Louise] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Androl Lab, Boston, MA 02114 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vitro Fertilizat Unit, Boston, MA 02114 USA. RP Meeker, JD (reprint author), Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu; smissmer@hsph.harvard.edu; LALTSHUL@hsph.harvard.edu; avitonis@partners.org; lryan@hsph.harvard.edu; dcramer@partners.org; rhauser@hohp.harvard.edu RI Ryan, Louise/A-4562-2009; OI Ryan, Louise/0000-0001-5957-2490; Meeker, John/0000-0001-8357-5085 FU National Institute of Environmental Health Sciences [R01-ES013967]; National Institute of Child Health and Human Development [R01-HD32153] FX Work supported by grant R01-ES013967 from the National Institute of Environmental Health Sciences and grant R01-HD32153 from the National Institute of Child Health and Human Development. NR 42 TC 22 Z9 22 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD JUL 14 PY 2009 VL 8 AR 32 DI 10.1186/1476-069X-8-32 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 482AS UT WOS:000268856200001 PM 19594949 ER PT J AU Helfrich, CD Li, YF Sharp, ND Sales, AE AF Helfrich, Christian D. Li, Yu-Fang Sharp, Nancy D. Sales, Anne E. TI Organizational readiness to change assessment (ORCA): Development of an instrument based on the Promoting Action on Research in Health Services (PARIHS) framework SO IMPLEMENTATION SCIENCE LA English DT Article ID TOTAL-QUALITY-MANAGEMENT; THEORETICAL PERSPECTIVES; CONCEPTUAL-FRAMEWORK; IMPLEMENTATION; VETERANS; CONTEXT; IMPACT; CARE; FACILITATION; IMPROVEMENT AB Background: The Promoting Action on Research Implementation in Health Services, or PARIHS, framework is a theoretical framework widely promoted as a guide to implement evidence-based clinical practices. However, it has as yet no pool of validated measurement instruments that operationalize the constructs defined in the framework. The present article introduces an Organizational Readiness to Change Assessment instrument (ORCA), organized according to the core elements and sub-elements of the PARIHS framework, and reports on initial validation. Methods: We conducted scale reliability and factor analyses on cross-sectional, secondary data from three quality improvement projects (n = 80) conducted in the Veterans Health Administration. In each project, identical 77-item ORCA instruments were administered to one or more staff from each facility involved in quality improvement projects. Items were organized into 19 subscales and three primary scales corresponding to the core elements of the PARIHS framework: (1) Strength and extent of evidence for the clinical practice changes represented by the QI program, assessed with four subscales, (2) Quality of the organizational context for the QI program, assessed with six subscales, and (3) Capacity for internal facilitation of the QI program, assessed with nine subscales. Results: Cronbach's alpha for scale reliability were 0.74, 0.85 and 0.95 for the evidence, context and facilitation scales, respectively. The evidence scale and its three constituent subscales failed to meet the conventional threshold of 0.80 for reliability, and three individual items were eliminated from evidence subscales following reliability testing. In exploratory factor analysis, three factors were retained. Seven of the nine facilitation subscales loaded onto the first factor; five of the six context subscales loaded onto the second factor; and the three evidence subscales loaded on the third factor. Two subscales failed to load significantly on any factor. One measured resources in general (from the context scale), and one clinical champion role (from the facilitation scale). Conclusion: We find general support for the reliability and factor structure of the ORCA. However, there was poor reliability among measures of evidence, and factor analysis results for measures of general resources and clinical champion role did not conform to the PARIHS framework. Additional validation is needed, including criterion validation. C1 [Helfrich, Christian D.; Li, Yu-Fang; Sharp, Nancy D.] VA Puget Sound Healthcare Syst, NW HSR&D Ctr Excellence, Seattle, WA USA. [Helfrich, Christian D.; Sharp, Nancy D.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Helfrich, Christian D.; Sharp, Nancy D.] Univ Washington, Sch Nursing, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Sales, Anne E.] Univ Alberta, Fac Nursing, Edmonton, AB, Canada. RP Helfrich, CD (reprint author), VA Puget Sound Healthcare Syst, NW HSR&D Ctr Excellence, Seattle, WA USA. EM christian.helfrich@va.gov; yufang.li@va.gov; nancy.sharp@va.gov; anne.sales@ualberta.ca RI Sales, Anne/D-9678-2012; Helfrich, Christian/D-2382-2016; OI Helfrich, Christian/0000-0002-9827-4768; Sales, Anne/0000-0001-9360-3334 FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [RRP 07-280] FX The views expressed in this article are the authors' and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 41 TC 93 Z9 95 U1 1 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUL 14 PY 2009 VL 4 AR 38 DI 10.1186/1748-5908-4-38 PG 13 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 482LY UT WOS:000268891600001 PM 19594942 ER PT J AU Maron, BJ Maron, MS Wigle, ED Braunwald, E AF Maron, Barry J. Maron, Martin S. Wigle, E. Douglas Braunwald, Eugene TI The 50-Year History, Controversy, and Clinical Implications of Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy From Idiopathic Hypertrophic Subaortic Stenosis to Hypertrophic Cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cardiomyopathies; hypertrophic; cardiac surgery; heart catheterization; heart failure; heart failure treatment; hypertrophy ID SYSTOLIC ANTERIOR MOTION; DIMENSIONAL ECHOCARDIOGRAPHIC ASSESSMENT; SURGICAL SEPTAL MYECTOMY; MITRAL-VALVE; PRESSURE-GRADIENT; DOPPLER-ECHOCARDIOGRAPHY; SUDDEN-DEATH; MYOCARDIAL-METABOLISM; OPERATIVE TREATMENT; MYOTOMY-MYECTOMY AB Dynamic obstruction to left ventricular (LV) outflow was recognized from the earliest (50 years ago) clinical descriptions of hypertrophic cardiomyopathy (HCM) and has proved to be a complex phenomenon unique in many respects, as well as arguably the most visible and well-known pathophysiologic component of this heterogeneous disease. Over the past 5 decades, the clinical significance attributable to dynamic LV outflow tract gradients in HCM has triggered a periodic and instructive debate. Nevertheless, only recently has evidence emerged from observational analyses in large patient cohorts that unequivocally supports subaortic pressure gradients (and obstruction) both as true impedance to LV outflow and independent determinants of disabling exertional symptoms and cardiovascular mortality. Furthermore, abolition of subaortic gradients by surgical myectomy (or percutaneous alcohol septal ablation) results in profound and consistent symptomatic benefit and restoration of quality of life, with myectomy providing a long-term survival similar to that observed in the general population. These findings resolve the long-festering controversy over the existence of obstruction in HCM and whether outflow gradients are clinically important elements of this complex disease. These data also underscore the important principle, particularly relevant to clinical practice, that heart failure due to LV outflow obstruction in HCM is mechanically reversible and amenable to invasive septal reduction therapy. Finally, the recent observation that the vast majority of patients with HCM have the propensity to develop outflow obstruction (either at rest or with exercise) underscores a return to the characterization of HCM in 1960 as a predominantly obstructive disease. (J Am Coll Cardiol 2009; 54: 191-200) (C) 2009 by the American College of Cardiology Foundation C1 [Maron, Barry J.] Minneapolis Heart Inst Fdn, Hypertroph Cardiomyopathy Ctr, Minneapolis, MN 55407 USA. [Maron, Martin S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Hypertroph Cardiomyopathy Ctr,Tufts Med Ctr, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp, Boston, MA 02115 USA. [Wigle, E. Douglas] Toronto Gen Hosp, Div Cardiol, Toronto, ON, Canada. RP Maron, BJ (reprint author), Minneapolis Heart Inst Fdn, Hypertroph Cardiomyopathy Ctr, 920 E 28th St,Suite 620, Minneapolis, MN 55407 USA. EM hcm.maron@mhif.org NR 101 TC 115 Z9 124 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 14 PY 2009 VL 54 IS 3 BP 191 EP 200 DI 10.1016/j.jacc.2008.11.069 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 467SJ UT WOS:000267762400001 PM 19589431 ER PT J AU Khalil, AM Guttman, M Huarte, M Garber, M Raj, A Morales, DR Thomas, K Presser, A Bernstein, BE van Oudenaarden, A Regev, A Lander, ES Rinn, JL AF Khalil, Ahmad M. Guttman, Mitchell Huarte, Maite Garber, Manuel Raj, Arjun Morales, Dianali Rivea Thomas, Kelly Presser, Aviva Bernstein, Bradley E. van Oudenaarden, Alexander Regev, Aviv Lander, Eric S. Rinn, John L. TI Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE histone modifications; epigenetic regulation; polycomb ID HUMAN GENOME; DIFFERENTIATION; HETEROCHROMATIN; CELLS; FATE AB We recently showed that the mammalian genome encodes >1,000 large intergenic noncoding (linc) RNAs that are clearly conserved across mammals and, thus, functional. Gene expression patterns have implicated these lincRNAs in diverse biological processes, including cell-cycle regulation, immune surveillance, and embryonic stem cell pluripotency. However, the mechanism by which these lincRNAs function is unknown. Here, weexpand the catalog of human lincRNAs to approximate to 3,300 by analyzing chromatin-state maps of various human cell types. Inspired by the observation that the well-characterized lincRNA HOTAIR binds the polycomb repressive complex (PRC) 2, we tested whether many lincRNAs are physically associated with PRC2. Remarkably, we observe that approximate to 20% of lincRNAs expressed in various cell types are bound by PRC2, and that additional lincRNAs are bound by other chromatin-modifying complexes. Also, we show that siRNA-mediated depletion of certain lincRNAs associated with PRC2 leads to changes in gene expression, and that the up-regulated genes are enriched for those normally silenced by PRC2. We propose a model in which some lincRNAs guide chromatin-modifying complexes to specific genomic loci to regulate gene expression. C1 [Khalil, Ahmad M.; Guttman, Mitchell; Huarte, Maite; Garber, Manuel; Morales, Dianali Rivea; Thomas, Kelly; Presser, Aviva; Bernstein, Bradley E.; Regev, Aviv; Lander, Eric S.; Rinn, John L.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Khalil, Ahmad M.; Guttman, Mitchell; Huarte, Maite; Garber, Manuel; Morales, Dianali Rivea; Thomas, Kelly; Presser, Aviva; Bernstein, Bradley E.; Regev, Aviv; Lander, Eric S.; Rinn, John L.] MIT, Cambridge, MA 02142 USA. [Khalil, Ahmad M.; Huarte, Maite; Morales, Dianali Rivea; Thomas, Kelly; Rinn, John L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Guttman, Mitchell; Regev, Aviv; Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Raj, Arjun; van Oudenaarden, Alexander] MIT, Dept Phys, Cambridge, MA 02139 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. RP Lander, ES (reprint author), Broad Inst Harvard, Cambridge, MA 02142 USA. EM lander@broad.mit.edu; jrinn@broad.mit.edu RI Huarte, Maite/J-6903-2014; jia, xu/A-8386-2016; OI Huarte, Maite/0000-0003-3753-6493; Raj, Arjun/0000-0002-2915-6960 FU National Institutes of Health [HL007893]; National Human Genome Research Institute; Broad Institute of MIT and Harvard. FX We thank Yang Shi and Shigeki Iwase (Harvard Medical School) for antibodies to SMCX and their input on the manuscript; J. P. Mesirov and Pablo Tamayo [The Broad Institute of Harvard and Massachusetts Institute of Technology ( MIT)] for discussions and statistical insights; and Miguel Rivera for access to hEK ChIP-Seq data. A. M. K. is supported by National Institutes of Health Training Grant HL007893. M. Guttman is a Vertex scholar. J. L. R is a Damon Runyon-Rachleff Innovation and Smith Family Foundation Scholar. J. L. R. and A. Regev are Investigators of the Richard Merkin Foundation for Stem Cell Research at the Broad Institute. A. R. is supported by the Pioneer award and by the Burroughs Wellcome Fund. This work was supported by the National Human Genome Research Institute, and the Broad Institute of MIT and Harvard. NR 27 TC 1228 Z9 1292 U1 13 U2 128 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 JUL 14 PY 2009 VL 106 IS 28 BP 11667 EP 11672 DI 10.1073/pnas.0904715106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 470KD UT WOS:000267972700045 PM 19571010 ER PT J AU Chan, YM de Guillebon, A Lang-Muritano, M Plummer, L Cerrato, F Tsiaras, S Gaspert, A Lavoie, HB Wu, CH Crowley, WF Amory, JK Pitteloud, N Seminara, SB AF Chan, Yee-Ming de Guillebon, Adelaide Lang-Muritano, Mariarosaria Plummer, Lacey Cerrato, Felecia Tsiaras, Sarah Gaspert, Ariana Lavoie, Helene B. Wu, Ching-Hui Crowley, William F., Jr. Amory, John K. Pitteloud, Nelly Seminara, Stephanie B. TI GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE GnRH; luteinizing hormone-releasing hormone; LHRH ID GONADOTROPIN-RELEASING-HORMONE; KALLMANN-SYNDROME; LUTEINIZING-HORMONE; MESSENGER-RNA; GENE; RECEPTOR; DEFICIENCY; PROTEIN; MOUSE; PROKINETICIN-2 AB Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH. C1 [Chan, Yee-Ming; de Guillebon, Adelaide; Plummer, Lacey; Cerrato, Felecia; Tsiaras, Sarah; Crowley, William F., Jr.; Pitteloud, Nelly; Seminara, Stephanie B.] Massachusetts Gen Hosp, Harvard Reprod Sci Ctr, Boston, MA 02114 USA. [Chan, Yee-Ming; de Guillebon, Adelaide; Plummer, Lacey; Cerrato, Felecia; Tsiaras, Sarah; Crowley, William F., Jr.; Pitteloud, Nelly; Seminara, Stephanie B.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Chan, Yee-Ming] Childrens Hosp, Div Endocrinol, Dept Med, Boston, MA 02115 USA. [Lang-Muritano, Mariarosaria] Univ Childrens Hosp Zurich, Pediat Endocrine Unit, CH-8032 Zurich, Switzerland. [Gaspert, Ariana] Univ Zurich Hosp, Dept Pathol, CH-8091 Zurich, Switzerland. [Lavoie, Helene B.] CHU Montreal, Div Endocrinol, Dept Med, Montreal, PQ H2X 3J4, Canada. [Lavoie, Helene B.] PROCREA Clin, Montreal, PQ H4P 2R2, Canada. [Amory, John K.] Univ Washington, Med Ctr, Div Gen Internal Med, Seattle, WA 98195 USA. RP Seminara, SB (reprint author), Massachusetts Gen Hosp, Harvard Reprod Sci Ctr, 55 Fruit St,BHX 5, Boston, MA 02114 USA. EM seminara.stephanie@mgh.harvard.edu RI PITTELOUD, Nelly/K-2709-2014 FU National Institutes of Health/National Institute of Child Health and Human Development [U54 HD028138, F32 HD056759] FX We thank Martin Dym for assistance with interpretation of testicular histology. This work was supported by National Institutes of Health/National Institute of Child Health and Human Development Grant U54 HD028138. Y.-M. C. received support from National Institutes of Health/National Institute of Child Health and Human Development Grant F32 HD056759. NR 46 TC 86 Z9 88 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 14 PY 2009 VL 106 IS 28 BP 11703 EP 11708 DI 10.1073/pnas.0903449106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 470KD UT WOS:000267972700051 PM 19567835 ER PT J AU Ho, O Larsen, K Polacino, P Li, Y Anderson, D Song, RJ Ruprecht, RM Hu, SL AF Ho, On Larsen, Kay Polacino, Patricia Li, Yun Anderson, David Song, Ruijiang Ruprecht, Ruth M. Hu, Shiu-Lok TI Pathogenic infection of Macaca nemestrina with a CCR5-tropic subtype-C simian-human immunodeficiency virus SO RETROVIROLOGY LA English DT Article ID CD4(+) T-CELLS; NEUTRALIZING ANTIBODY-RESPONSES; PIG-TAILED MACAQUES; ACUTE SIV INFECTION; RHESUS MACAQUES; IN-VIVO; HIV-1 INFECTION; GASTROINTESTINAL-TRACT; AIDS PATHOGENESIS; VIRAL REPLICATION AB Background: Although pig-tailed macaques (Macaca nemestrina) have been used in AIDS research for years, less is known about the early immunopathogenic events in this species, as compared to rhesus macaques (Macaca mulatta). Similarly, the events in early infection are well-characterized for simian immunodeficiency viruses (SIV), but less so for chimeric simian-human immunodeficiency viruses (SHIV), although the latter have been widely used in HIV vaccine studies. Here, we report the consequences of intrarectal infection with a CCR5-tropic clade C SHIV-1157ipd3N4 in pig-tailed macaques. Results: Plasma and cell-associated virus was detectable in peripheral blood and intestinal tissues of all four pig-tailed macaques following intrarectal inoculation with SHIV-1157ipd3N4. We also observed a rapid and irreversible loss of CD4(+) T cells at multiple mucosal sites, resulting in a marked decrease of CD4:CD8 T cell ratios 0.5-4 weeks after inoculation. This depletion targeted subsets of CD4(+) T cells expressing the CCR5 coreceptor and having a CD28-CD95(+) effector memory phenotype, consistent with the R5-tropism of SHIV-1157ipd3N4. All three animals that were studied beyond the acute phase seroconverted as early as week 4, with two developing cross-clade neutralizing antibody responses by week 24. These two animals also demonstrated persistent plasma viremia for > 48 weeks. One of these animals developed AIDS, as shown by peripheral blood CD4(+) T-cell depletion starting at 20 weeks post inoculation. Conclusion: These findings indicate that SHIV-1157ipd3N4-induced pathogenesis in pig-tailed macaques followed a similar course as SIV-infected rhesus macaques. Thus, R5 SHIV-C-infection of pig-tailed macaques could provide a useful and relevant model for AIDS vaccine and pathogenesis research. C1 [Ho, On; Li, Yun; Hu, Shiu-Lok] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. [Larsen, Kay; Polacino, Patricia; Anderson, David; Hu, Shiu-Lok] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98121 USA. [Song, Ruijiang; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Song, Ruijiang; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Song, Ruijiang] Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. RP Hu, SL (reprint author), Univ Washington, Dept Pharmaceut, Box 357610, Seattle, WA 98195 USA. EM onh@bart.rprc.washington.edu; kayl@bart.rprc.washington.edu; patf@bart.rprc.washington.edu; yunli@bart.rprc.washington.edu; davea@bart.rprc.washington.edu; rsong@adarc.org; ruth_ruprecht@dfci.harvard.edu; hus@bart.rprc.washington.edu RI Hu, Shiu-Lok/A-3196-2008 OI Hu, Shiu-Lok/0000-0003-4336-7964 FU NIH [P51 RR0166, P01 AI24048] FX We thank the veterinary and animal care staff at the WaNPRC for excellent care of the macaques; Drs. Steve Kelley and Keith Vogel, and Leon Flanary and Joel Ahrens for mucosal sample collections; Dr. Robert Murnane for histopathological analyses; Heather Mack, Ryan Wallerstedt, Valerie Teske, Xuebing Li, Taryn Urion, and Modou Mbowe for expert technical assistance; and Drs. Don Sodora, Ron Veazey, Louis Picker, and John Fanton, and Kiran Mir and Amanda Leone for helpful discussions. This study is supported in part by NIH grants and contracts P51 RR0166 ( WaNPRC) and P01 AI24048 ( RMR and SLH). NR 80 TC 13 Z9 14 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUL 14 PY 2009 VL 6 AR 65 DI 10.1186/1742-4690-6-65 PG 16 WC Virology SC Virology GA 487TR UT WOS:000269299800001 PM 19602283 ER PT J AU Kruse, GR Chapula, BT Ikeda, S Nkhoma, M Quiterio, N Pankratz, D Mataka, K Chi, BH Bond, V Reid, SE AF Kruse, Gina R. Chapula, Bushimbwa Tambatamba Ikeda, Scott Nkhoma, Mavis Quiterio, Nicole Pankratz, Debra Mataka, Kaluba Chi, Benjamin H. Bond, Virginia Reid, Stewart E. TI Burnout and use of HIV services among health care workers in Lusaka District, Zambia: a cross-sectional study SO HUMAN RESOURCES FOR HEALTH LA English DT Article ID SOUTH-AFRICA; ANTIRETROVIRAL TREATMENT; SCALING-UP; HIV/AIDS; OUTCOMES; THERAPY; JOB; PERCEPTIONS; MORTALITY; COUNTRIES AB Background: Well-documented shortages of health care workers in sub-Saharan Africa are exacerbated by the increased human resource demands of rapidly expanding HIV care and treatment programmes. The successful continuation of existing programmes is threatened by health care worker burnout and HIV-related illness. Methods: From March to June 2007, we studied occupational burnout and utilization of HIV services among health providers in the Lusaka public health sector. Providers from 13 public clinics were given a 36-item, self-administered questionnaire and invited for focus group discussions and key-informant interviews. Results: Some 483 active clinical staff completed the questionnaire (84% response rate), 50 staff participated in six focus groups, and four individuals gave interviews. Focus group participants described burnout as feeling overworked, stressed and tired. In the survey, 51% reported occupational burnout. Risk factors were having another job (RR 1.4 95% CI 1.2-1.6) and knowing a co-worker who left in the last year (RR 1.6 95% CI 1.3-2.2). Reasons for co-worker attrition included: better pay (40%), feeling overworked or stressed (21%), moving away (16%), death (8%) and illness (5%). When asked about HIV testing, 370 of 456 (81%) reported having tested; 240 (50%) tested in the last year. In contrast, discussion groups perceived low testing rates. Both discussion groups and survey respondents identified confidentiality as the prime reason for not undergoing HIV testing. Conclusion: In Lusaka primary care clinics, overwork, illness and death were common reasons for attrition. Programmes to improve access, acceptability and confidentiality of health care services for clinical providers and to reduce workplace stress could substantially affect workforce stability. C1 [Kruse, Gina R.; Ikeda, Scott; Nkhoma, Mavis; Quiterio, Nicole; Pankratz, Debra; Mataka, Kaluba; Chi, Benjamin H.; Reid, Stewart E.] CIDRZ, Lusaka, Zambia. [Kruse, Gina R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chapula, Bushimbwa Tambatamba] Zambian Minist Hlth, Lusaka Dist Hlth Management Team, Lusaka, Zambia. [Ikeda, Scott] Montefiore Med Ctr, Dept Family & Social Med, Bronx, NY 10467 USA. [Quiterio, Nicole] Robert Wood Johnson Univ Hosp, Bristol Myers Squibb Childrens Hosp, Dept Pediat, New Brunswick, NJ USA. [Chi, Benjamin H.] Univ Alabama, Dept Obstet & Gynecol, Sch Med, Birmingham, AL 35294 USA. [Chi, Benjamin H.] Univ Alabama, Dept Obstet & Gynecol, Sch Publ Hlth, Birmingham, AL 35294 USA. [Bond, Virginia] ZAMBART Project, Lusaka, Zambia. [Bond, Virginia] London Sch Hyg & Trop Med, Dept Publ Hlth & Policy, Hlth Policy Unit, London WC1, England. [Reid, Stewart E.] Univ Alabama, Sch Med, Div Infect Dis, Birmingham, AL USA. RP Reid, SE (reprint author), CIDRZ, Lusaka, Zambia. EM gkruse@partners.org; bushitamba@doctors.org.uk; scott.ikeda@gmail.com; mavis.nkhoma@cidrz.org; nicole.quiterio@gmail.com; debra.pankratz@cidrz.org; kaluba.mataka@cidrz.org; benjamin.chi@cidrz.org; gbond@zambart.org.zm; stewart.reid@cidrz.org OI Reid, Stewart/0000-0001-7779-4820 FU FIC NIH HHS [K01 TW006670] NR 30 TC 30 Z9 30 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1478-4491 J9 HUM RESOUR HEALTH JI Hum. Resour. Health PD JUL 13 PY 2009 VL 7 AR 55 DI 10.1186/1478-4491-7-55 PG 10 WC Health Policy & Services; Industrial Relations & Labor SC Health Care Sciences & Services; Business & Economics GA 482LM UT WOS:000268890400002 PM 19594917 ER PT J AU Holmans, P Green, EK Pahwa, JS Ferreira, MAR Purcell, SM Sklar, P Owen, MJ O'Donovan, MC Craddock, N AF Holmans, Peter Green, Elaine K. Pahwa, Jaspreet Singh Ferreira, Manuel A. R. Purcell, Shaun M. Sklar, Pamela Owen, Michael J. O'Donovan, Michael C. Craddock, Nick CA Wellcome Trust Case Control Consor TI Gene Ontology Analysis of GWA Study Data Sets Provides Insights into the Biology of Bipolar Disorder SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; COMMON DISEASES; MOOD DISORDERS; LINKS; AXIS; PRIORITIZATION; SCHIZOPHRENIA; PATHOGENESIS; VARIANTS AB We present a method for testing overrepresentation of biological pathways, indexed by gene-ontology terms, in lists of significant SNPs from genome-wide association studies. This method corrects for linkage disequilibrium between SNPs, variable gene size, and multiple testing of nonindependent pathways. The method was applied to the Wellcome Trust Case-Control Consortium Crohn disease (CD) data set. At a general level, the biological basis of CD is relatively well known for a complex genetic trait, and it thus acted as a test of the method. The method, known as ALIGATOR (Association LIst Go AnnoTatOR), successfully detected biological pathways implicated in CD. The method was also applied to a meta-analysis of bipolar disorder, and it implicated the modulation of transcription and cellular activity, including that which occurs via hormonal action, as an important player in pathogenesis. C1 [Holmans, Peter; Green, Elaine K.; Pahwa, Jaspreet Singh; Owen, Michael J.; O'Donovan, Michael C.; Craddock, Nick] Sch Med, Dept Psychol Med & Neurol, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF23 6BQ, S Glam, Wales. [Ferreira, Manuel A. R.; Purcell, Shaun M.; Sklar, Pamela] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ferreira, Manuel A. R.; Purcell, Shaun M.; Sklar, Pamela] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Ferreira, Manuel A. R.; Purcell, Shaun M.; Sklar, Pamela] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Ferreira, Manuel A. R.; Purcell, Shaun M.; Sklar, Pamela] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Ferreira, Manuel A. R.; Purcell, Shaun M.; Sklar, Pamela] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Ferreira, Manuel A. R.] Genet Epidemiol Queensland Inst Med Res, Brisbane, Qld 4029, Australia. RP Holmans, P (reprint author), Sch Med, Dept Psychol Med & Neurol, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF23 6BQ, S Glam, Wales. EM holmanspa@cardiff.ac.uk RI Ferreira, Manuel/D-3609-2013; Holmans, Peter/F-4518-2015; OI Holmans, Peter/0000-0003-0870-9412; O'Donovan, Michael/0000-0001-7073-2379 FU Medical Research Council; Wellcome Trust NR 42 TC 244 Z9 250 U1 3 U2 22 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 JUL 10 PY 2009 VL 85 IS 1 BP 13 EP 24 DI 10.1016/j.ajhg.2009.05.011 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 470RO UT WOS:000267997600004 PM 19539887 ER PT J AU Lee, JH Ryu, H Kowall, NW AF Lee, Junghee Ryu, Hoon Kowall, Neil W. TI Motor neuronal protection by L-arginine prolongs survival of mutant SOD1 (G93A) ALS mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Amyotrophic lateral sclerosis (ALS); L-Arginine; Motor neuron; Polyamines; Superoxide dismutase 1 (SOD1) ID AMYOTROPHIC-LATERAL-SCLEROSIS; HYPERCHOLESTEROLEMIC MICE; SUPEROXIDE-DISMUTASE; INHIBITION; POLYAMINES; GLUTAMATE; ARGINASE; GROWTH AB Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. Despite the fact that many different therapeutic strategies have been applied to prevent disease progression, no cure or effective therapy is currently available for ALS. We found that L-arginine protects cultured motor neurons from excitotoxic injury. We also found that L-arginine supplementation both prior to and after the onset of motor neuron degeneration in mtSOD1 (G93A) transgenic ALS mice significantly slowed the progression of neuropathology in lumbar spinal cord, delayed onset of motor dysfunction, and prolonged life span. Moreover, L-arginine treatment was associated with preservation of arginase I activity and neuroprotective polyamines in spinal cord motor neurons. Our findings show that L-arginine has potent in vitro and in vivo neuroprotective properties and may be a candidate for therapeutic trials in ALS. Published by Elsevier Inc C1 [Lee, Junghee; Ryu, Hoon; Kowall, Neil W.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Kowall, Neil W.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [Lee, Junghee; Ryu, Hoon; Kowall, Neil W.] VA Boston Healthcare Syst, Neurol Serv, Boston, MA 02130 USA. [Lee, Junghee; Ryu, Hoon; Kowall, Neil W.] VA Boston Healthcare Syst, Geriatr Res & Educ & Clin Ctr, Boston, MA 02130 USA. RP Lee, JH (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. EM junghee@bu.edu; nkowall@bu.edu RI Kowall, Neil/G-6364-2012 OI Kowall, Neil/0000-0002-6624-0213 FU NIA NIH HHS [P30 AG013846-09, P30 AG013846, P30 AG13846]; NINDS NIH HHS [R01 NS052724-03, R01 NS052724, NS52724] NR 23 TC 14 Z9 14 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 JUL 10 PY 2009 VL 384 IS 4 BP 524 EP 529 DI 10.1016/j.bbrc.2009.05.015 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 454NN UT WOS:000266689300024 PM 19427829 ER PT J AU Svendsen, JM Smogorzewska, A Sowa, ME O'Connell, BC Gygi, SP Elledge, SJ Harper, JW AF Svendsen, Jennifer M. Smogorzewska, Agata Sowa, Mathew E. O'Connell, Brenda C. Gygi, Steven P. Elledge, Stephen J. Harper, J. Wade TI Mammalian BTBD12/SLX4 Assembles A Holliday Junction Resolvase and Is Required for DNA Repair SO CELL LA English DT Article ID STRUCTURE-SPECIFIC ENDONUCLEASE; SACCHAROMYCES-CEREVISIAE; MEIOTIC CROSSOVERS; MUS81-EME1; IDENTIFICATION; RESOLUTION; MECHANISM; PROTEINS; DAMAGE; YEAST AB Structure-specific endonucleases mediate cleavage of DNA structures formed during repair of collapsed replication forks and double-strand breaks (DSBs). Here, we identify BTBD12 as the human ortholog of the budding yeast DNA repair factor Slx4p and D. melanogaster MUS312. Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases and also associates with MSH2/MSH3 mismatch repair complex, telomere binding complex TERF2(TRF2)-TERF2IP(RAP1), the protein kinase PLK1 and the uncharacterized protein C20orf94. Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin and reduces the efficiency of DSB repair in vivo. SLX4 complexes cleave 3' flap, 5' flap, and replication fork structures; yet unlike other endonucleases associated with SLX4, the SLX1-SLX4 module promotes symmetrical cleavage of static and migrating Holliday junctions (HJs), identifying SLX1-SLX4 as a HJ resolvase. Thus, SLX4 assembles a modular toolkit for repair of specific types of DNA lesions and is critical for cellular responses to replication fork failure. C1 [Svendsen, Jennifer M.; Sowa, Mathew E.; O'Connell, Brenda C.; Harper, J. Wade] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Smogorzewska, Agata; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Smogorzewska, Agata; Elledge, Stephen J.] Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Med, Div Genet, Boston, MA 02115 USA. [Smogorzewska, Agata] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Harper, JW (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM wade_harper@hms.harvard.edu RI Smogorzewska, Agata/B-8891-2011 FU National Institutes of Health; Centers for Medical Countermeasures Against Radiation; Stewart Trust; Burroughs Wellcome Fund; American Cancer Society; [T32CA09216] FX We thank Clare McGowan, Richard Wood, Orlando Scharer, Joyce Reardon, Laura Niedernhofer, Maria Jasin, Steve West, and Guang Hu for reagents, John Rouse, Jim Haber, Jeff Sekelsky, Monica Colaiacovo, and Pierre- Henri Gaillard for communicating results prior to publication, and Alberto Ciccia and Maria Jasin for discussions. This work was supported by grants from the National Institutes of Health to S.J.E., S.P.G., and J.W.H., a Centers for Medical Countermeasures Against Radiation grant to S.J.E., and by a grant from the Stewart Trust to J.W.H.A.S. is supported by T32CA09216 to the Pathology Department at the Massachusetts General Hospital and by an award from the Burroughs Wellcome Fund. B.C.O. is supported by a postdoctoral fellowship from the American Cancer Society. S.J.E. is an investigator of the Howard Hughes Medical Institute. NR 34 TC 252 Z9 263 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 10 PY 2009 VL 138 IS 1 BP 63 EP 77 DI 10.1016/j.cell.2009.06.030 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 468UN UT WOS:000267848600015 PM 19596235 ER PT J AU Emery, B Agalliu, D Cahoy, JD Watkins, TA Dugas, JC Mulinyawe, SB Ibrahim, A Ligon, KL Rowitch, DH Barres, BA AF Emery, Ben Agalliu, Dritan Cahoy, John D. Watkins, Trent A. Dugas, Jason C. Mulinyawe, Sara B. Ibrahim, Adilijan Ligon, Keith L. Rowitch, David H. Barres, Ben A. TI Myelin Gene Regulatory Factor Is a Critical Transcriptional Regulator Required for CNS Myelination SO CELL LA English DT Article ID OLIGODENDROCYTE DIFFERENTIATION; NERVOUS-SYSTEM; NKX2.2; BRAIN; SOX10; OLIG1; EXPRESSION; LINEAGE; BINDING; PROTEIN AB The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named myelin gene regulatory factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, premyelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities and die because of seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination. C1 [Emery, Ben; Agalliu, Dritan; Cahoy, John D.; Watkins, Trent A.; Dugas, Jason C.; Mulinyawe, Sara B.; Ibrahim, Adilijan; Barres, Ben A.] Stanford Univ, Sch Med, Dept Neurobiol, Stanford, CA 94305 USA. [Ligon, Keith L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Rowitch, David H.] Univ Calif San Francisco, Dept Pediat, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Rowitch, David H.] Univ Calif San Francisco, Inst Regenerat Med, San Francisco, CA 94143 USA. RP Emery, B (reprint author), Stanford Univ, Sch Med, Dept Neurobiol, Stanford, CA 94305 USA. EM bemery@stanford.edu RI Emery, Ben/I-6223-2013; OI Emery, Ben/0000-0002-9132-3045 FU National Eye Institute [RO1 EY10257]; Australian NHMRC CJ Martin FX We thank Professor Klaus-Armin Nave for kindly providing the CNP-Cre mouse line. We are indebted to Lydia-Marie Joubert for processing samples for TEM and Elizabeth Zou for processing samples for Affymetrix analysis. This work was funded by the National Eye Institute (RO1 EY10257, B. A. B.) and the Myelin Repair Foundation. B. E. is supported by an Australian NHMRC CJ Martin award. NR 27 TC 141 Z9 145 U1 3 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 10 PY 2009 VL 138 IS 1 BP 172 EP 185 DI 10.1016/j.cell.2009.04.031 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 468UN UT WOS:000267848600023 PM 19596243 ER PT J AU Kleiner, S Nguyen-Tran, V Bare, O Huang, XM Spiegelman, B Wu, ZD AF Kleiner, Sandra Nguyen-Tran, Van Bare, Olivia Huang, Xueming Spiegelman, Bruce Wu, Zhidan TI PPAR delta Agonism Activates Fatty Acid Oxidation via PGC-1 alpha but Does Not Increase Mitochondrial Gene Expression and Function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SKELETAL-MUSCLE; COACTIVATOR PGC-1-ALPHA; TRANSCRIPTIONAL CONTROL; METABOLIC SYNDROME; ENERGY-METABOLISM; RECEPTOR; CELLS; GAMMA; OBESITY; ALPHA AB PPAR delta (peroxisome proliferator-activated receptor delta) is a regulator of lipid metabolism and has been shown to induce fatty acid oxidation (FAO). PPAR delta transgenic and knock-out mice indicate an involvement of PPAR delta in regulating mitochondrial biogenesis and oxidative capacity; however, the precise mechanisms by which PPAR delta regulates these pathways in skeletal muscle remain unclear. In this study, we determined the effect of selective PPAR delta agonism with the synthetic ligand, GW501516, on FAO and mitochondrial gene expression in vitro and in vivo. Our results show that activation of PPAR delta by GW501516 led to a robust increase in mRNA levels of key lipid metabolism genes. Mitochondrial gene expression and function were not induced under the same conditions. Additionally, the activation of Pdk4 transcription by PPAR delta was coactivated by PGC-1 alpha. PGC-1 alpha, but not PGC-1 beta, was essential for full activation of Cpt-1b and Pdk4 gene expression via PPAR beta agonism. Furthermore, the induction of FAO by PPAR delta agonism was completely abolished in the absence of both PGC-1 alpha and PGC-1 beta Conversely, PGC-1 alpha-driven FAO was independent of PPAR delta. Neither GW501516 treatment nor knockdown of PPAR delta affects PGC-1 alpha-induced mitochondrial gene expression in primary myotubes. These results demonstrate that pharmacological activation of PPAR delta induces FAO via PGC-1 alpha. However, PPAR delta agonism does not induce mitochondrial gene expression and function. PGC-1 alpha-induced FAO and mitochondrial biogenesis appear to be independent of PPAR delta. C1 [Nguyen-Tran, Van] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Kleiner, Sandra; Spiegelman, Bruce] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kleiner, Sandra; Spiegelman, Bruce] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kleiner, Sandra; Bare, Olivia; Huang, Xueming; Wu, Zhidan] Novartis Inst Biomed Res Inc, Cardiovasc & Metab Dis Area, Cambridge, MA 02139 USA. RP Wu, ZD (reprint author), 100 Technol Sq, Cambridge, MA 02139 USA. EM zhidan.wu@novartis.com NR 25 TC 67 Z9 69 U1 1 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 JUL 10 PY 2009 VL 284 IS 28 BP 18624 EP 18633 DI 10.1074/jbc.M109.008797 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 467BP UT WOS:000267711500011 PM 19435887 ER PT J AU Kwak, SY Wiedemann-Bidlack, FB Beniash, E Yamakoshi, Y Simmer, JP Litman, A Margolis, HC AF Kwak, Seo-Young Wiedemann-Bidlack, Felicitas B. Beniash, Elia Yamakoshi, Yasuo Simmer, James P. Litman, Amy Margolis, Henry C. TI Role of 20-kDa Amelogenin (P148) Phosphorylation in Calcium Phosphate Formation in Vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PORCINE-AMELOGENINS; MOUSE AMELOGENINS; ENAMEL; HYDROXYAPATITE; GROWTH; CRYSTALS; NUCLEATION; PARTICLES; CARBONATE; PROTEINS AB The potential role of amelogenin phosphorylation in enamel formation is elucidated through in vitro mineralization studies. Studies focused on the native 20-kDa porcine amelogenin proteolytic cleavage product P148 that is prominent in developing enamel. Experimental conditions supported spontaneous calcium phosphate precipitation with the initial formation of amorphous calcium phosphate (ACP). In the absence of protein, ACP was found to undergo relatively rapid transformation to randomly oriented plate-like apatitic crystals. In the presence of non-phosphorylated recombinant full-length amelogenin, rP172, a longer induction period was observed during which relatively small ACP nanoparticles were transiently stabilized. In the presence of rP172, these nanoparticles were found to align to form linear needle-like particles that subsequently transformed and organized into parallel arrays of apatitic needle-like crystals. In sharp contrast to these findings, P148, with a single phosphate group on serine 16, was found to inhibit calcium phosphate precipitation and stabilize ACP formation for more than 1 day. Additional studies using non- phosphorylated recombinant (rP147) and partially dephosphorylated forms of P148 (dephoso-P148) showed that the single phosphate group in P148 was responsible for the profound effect on mineral formation in vitro. The present study has provided, for the first time, evidence suggesting that the native proteolytic cleavage product P148 may have an important functional role in regulating mineralization during enamel formation by preventing unwanted mineral formation within the enamel matrix during the secretory stage of amelogenesis. Results obtained have also provided new insights into the functional role of the highly conserved hydrophilic C terminus found in full-length amelogenin. found in full-length amelogenin. C1 [Kwak, Seo-Young; Wiedemann-Bidlack, Felicitas B.; Litman, Amy; Margolis, Henry C.] Forsyth Inst, Dept Biomineralizat, Boston, MA 02115 USA. [Beniash, Elia] Univ Pittsburgh, Dept Oral Biol, Pittsburgh, PA 15261 USA. [Yamakoshi, Yasuo; Simmer, James P.] Univ Michigan, Dent Res Lab, Ann Arbor, MI 48109 USA. RP Margolis, HC (reprint author), 140 Fenway, Boston, MA 02115 USA. EM hmargolis@forsyth.org FU National Institutes of Health [DE-016376, T32 DE-007327] FX Supported in part by National Institutes of Health Grant T32 DE-007327. NR 43 TC 49 Z9 52 U1 1 U2 13 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 JUL 10 PY 2009 VL 284 IS 28 BP 18972 EP 18979 DI 10.1074/jbc.M109.020370 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 467BP UT WOS:000267711500047 PM 19443653 ER PT J AU Goodwin, PJ Ligibel, JA Stambolic, V AF Goodwin, Pamela J. Ligibel, Jennifer A. Stambolic, Vuk TI Metformin in Breast Cancer: Time for Action SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ACTIVATED PROTEIN-KINASE; INSULIN; TARGET; PATHWAY; RISK C1 [Goodwin, Pamela J.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Goodwin, Pamela J.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Ligibel, Jennifer A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Stambolic, Vuk] Univ Hlth Network, Ontario Canc Inst, Div Signaling Biol, Toronto, ON, Canada. RP Goodwin, PJ (reprint author), Mt Sinai Hosp, Samuel Lunenfeld Res Inst, 600 Univ Ave, Toronto, ON M5G 1X5, Canada. RI Goodwin, Pamela/K-1477-2013 NR 19 TC 120 Z9 128 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2009 VL 27 IS 20 BP 3271 EP 3273 DI 10.1200/JCO.2009.22.1630 PG 3 WC Oncology SC Oncology GA 468LZ UT WOS:000267821400003 PM 19487373 ER PT J AU Colman, RJ Anderson, RM Johnson, SC Kastman, EK Kosmatka, KJ Beasley, TM Allison, DB Cruzen, C Simmons, HA Kemnitz, JW Weindruch, R AF Colman, Ricki J. Anderson, Rozalyn M. Johnson, Sterling C. Kastman, Erik K. Kosmatka, Kristopher J. Beasley, T. Mark Allison, David B. Cruzen, Christina Simmons, Heather A. Kemnitz, Joseph W. Weindruch, Richard TI Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys SO SCIENCE LA English DT Article ID DIETARY RESTRICTION; ADULT MALE; LIFE-SPAN; MACAQUES AB Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species. C1 [Colman, Ricki J.; Anderson, Rozalyn M.; Johnson, Sterling C.; Cruzen, Christina; Simmons, Heather A.; Kemnitz, Joseph W.; Weindruch, Richard] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Johnson, Sterling C.; Kastman, Erik K.; Kosmatka, Kristopher J.; Kemnitz, Joseph W.; Weindruch, Richard] Univ Wisconsin, Dept Med, Madison, WI 53706 USA. [Johnson, Sterling C.; Kastman, Erik K.; Kosmatka, Kristopher J.; Weindruch, Richard] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI 53705 USA. [Beasley, T. Mark; Allison, David B.] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. [Kemnitz, Joseph W.] Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA. RP Colman, RJ (reprint author), Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. EM rcolman@primate.wisc.edu; rhweindr@wisc.edu RI Kastman, Erik/N-6645-2016; OI Kastman, Erik/0000-0001-7221-9042; Allison, David/0000-0003-3566-9399 FU NIH [P01 AG-11915, P51 RR000167]; Research Facilities Improvement Program [RR15459-01, RR020141-01]; William S. Middleton Memorial Veterans Hospital FX We acknowledge the excellent technical assistance provided by S. Baum, J. Christensen, J. A. Adriansjach, C. E. Armstrong, D. G. McLaren, C. Dizack, D. Shanmuganayagam, J. Root, and the Animal Care, Veterinary and Pathology Staff of the WNPRC. R.W. is a cofounder and member of the board of LifeGen Technologies, a company focused on nutritional genomics, including the impact of dietary interventions on the aging process. This work was supported by NIH grants P01 AG-11915 and P51 RR000167. This research was conducted in part at the WNPRC, which received support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01. This research was supported in part by facilities and resources at the William S. Middleton Memorial Veterans Hospital. NR 19 TC 940 Z9 963 U1 22 U2 192 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 JUL 10 PY 2009 VL 325 IS 5937 BP 201 EP 204 DI 10.1126/science.1173635 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468FK UT WOS:000267802000047 PM 19590001 ER PT J AU Brockman, MA Kwon, DS Tighe, DP Pavlik, DF Rosato, PC Sela, J Porichis, F Le Gall, S Waring, MT Moss, K Jessen, H Pereyra, F Kavanagh, DG Walker, BD Kaufmann, DE AF Brockman, Mark A. Kwon, Douglas S. Tighe, Daniel P. Pavlik, David F. Rosato, Pamela C. Sela, Jennifer Porichis, Filippos Le Gall, Sylvie Waring, Michael T. Moss, Kristin Jessen, Heiko Pereyra, Florencia Kavanagh, Daniel G. Walker, Bruce D. Kaufmann, Daniel E. TI IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC VIRAL-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; INTERLEUKIN-10 PRODUCTION; CYTOKINE PRODUCTION; IMMUNE DYSFUNCTION; PD-1 EXPRESSION; IFN-GAMMA; TNF-ALPHA AB Murine models indicate that interleukin-10 (IL-10) can suppress viral clearance, and interventional blockade of IL-10 activity has been proposed to enhance immunity in chronic viral infections. Increased IL-10 levels have been observed during HIV infection and IL-10 blockade has been shown to enhance T-cell function in some HIV-infected subjects. However, the categories of individuals in whom the IL-10 pathway is up-regulated are poorly defined, and the cellular sources of IL-10 in these subjects remain to be determined. Here we report that blockade of the IL-10 pathway augmented in vitro proliferative capacity of HIV-specific CD4 and CD8 T cells in individuals with ongoing viral replication. IL-10 blockade also increased cytokine secretion by HIV-specific CD4 T cells. Spontaneous IL-10 expression, measured as either plasma IL-10 protein or IL-10 mRNA in peripheral blood mononuclear cells (PBMCs), correlated positively with viral load and diminished after successful antiretroviral therapy. IL-10 mRNA levels were up-regulated in multiple PBMC subsets in HIV-infected subjects compared with HIV-negative controls, particularly in T, B, and natural killer (NK) cells, whereas monocytes were a major source of IL-10 mRNA in HIV-infected and -uninfected individuals. These data indicate that multiple cell types contribute to IL-10-mediated immune suppression in the presence of uncontrolled HIV viremia. (Blood. 2009; 114: 346-356) C1 [Brockman, Mark A.; Kwon, Douglas S.; Tighe, Daniel P.; Pavlik, David F.; Rosato, Pamela C.; Sela, Jennifer; Porichis, Filippos; Le Gall, Sylvie; Waring, Michael T.; Moss, Kristin; Pereyra, Florencia; Kavanagh, Daniel G.; Walker, Bruce D.; Kaufmann, Daniel E.] Massachusetts Gen Hosp, MIT & Harvard, Ragon Inst, Charlestown, MA USA. [Brockman, Mark A.; Kwon, Douglas S.; Porichis, Filippos; Le Gall, Sylvie; Pereyra, Florencia; Kavanagh, Daniel G.; Walker, Bruce D.; Kaufmann, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Kwon, Douglas S.; Waring, Michael T.; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Jessen, Heiko] Jessen Praxis, Berlin, Germany. [Pereyra, Florencia] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kaufmann, DE (reprint author), Massachusetts Gen Hosp E, Partners AIDS Res Ctr, Rm 6618B,149 13th St, Charlestown, MA 02129 USA. EM dkaufmann@partners.org OI Brockman, Mark/0000-0001-6432-1426 FU National Heart, Lung and Blood Institute of the National Institutes of Health (Bethesda, MD) [R01-HL092565]; AIDS Research Foundation; Howard Hughes Medical Institute; Bill and Melinda Gates Foundation FX This study was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health (Bethesda, MD; R01-HL092565 [D. E. K.]), the Concerned Parents for AIDS Research Foundation (D. E. K., B. D. W.), the Howard Hughes Medical Institute (B. D. W.), the Bill and Melinda Gates Foundation (Seattle, WA), and a gift from the Mark and Lisa Schwartz Foundation. NR 61 TC 128 Z9 131 U1 0 U2 12 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 JUL 9 PY 2009 VL 114 IS 2 BP 346 EP 356 DI 10.1182/blood-2008-12-191296 PG 11 WC Hematology SC Hematology GA 471MK UT WOS:000268061700020 PM 19365081 ER PT J AU Fulciniti, M Tassone, P Hideshima, T Vallet, S Nanjappa, P Ettenberg, SA Shen, ZX Patel, N Tai, YT Chauhan, D Mitsiades, C Prabhala, R Raje, N Anderson, KC Stover, DR Munshi, NC AF Fulciniti, Mariateresa Tassone, Pierfrancesco Hideshima, Teru Vallet, Sonia Nanjappa, Puru Ettenberg, Seth A. Shen, Zhenxin Patel, Nipun Tai, Yu-tzu Chauhan, Dharminder Mitsiades, Constantine Prabhala, Rao Raje, Noopur Anderson, Kenneth C. Stover, David R. Munshi, Nikhil C. TI Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma SO BLOOD LA English DT Article ID CANCER BONE METASTASES; MARROW STROMAL CELLS; GROWTH IN-VIVO; NF-KAPPA-B; WNT PATHWAY; OSTEOBLAST DIFFERENTIATION; SERUM CONCENTRATIONS; TUMOR PROGRESSION; BETA-CATENIN; MURINE MODEL AB Decreased activity of osteoblasts (OBs) contributes to osteolytic lesions in multiple myeloma (MM). The production of the soluble Wnt inhibitor Dickkopf-1 (DKK1) by MM cells inhibits OB activity, and its serum level correlates with focal bone lesions in MM. Therefore, we have evaluated bone anabolic effects of a DKK1 neutralizing antibody (BHQ880) in MM. In vitro BHQ880 increased OB differentiation, neutralized the negative effect of MM cells on osteoblastogenesis, and reduced IL-6 secretion. In a severe combined immunodeficiency (SCID)-hu murine model of human MM, BHQ880 treatment led to a significant increase in OB number, serum human osteocalcin level, and trabecular bone. Although BHQ880 had no direct effect on MM cell growth, it significantly inhibited growth of MM cells in the presence of bone marrow stromal cells (BMSCs) in vitro. This effect was associated with inhibition of BMSC/MM cell adhesion and production of IL-6. In addition, BHQ880 up-regulated beta-catenin level while down-regulating nuclear factor-kappa B (NF-kappa B) activity in BMSC. Interestingly, we also observed in vivo inhibition of MM cell growth by BHQ880 treatment in the SCID-hu murine model. These results confirm DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth. (Blood. 2009; 114: 371-379) C1 [Fulciniti, Mariateresa; Hideshima, Teru; Vallet, Sonia; Nanjappa, Puru; Tai, Yu-tzu; Chauhan, Dharminder; Mitsiades, Constantine; Raje, Noopur; 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.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Cambridge, MA 02138 USA. [Fulciniti, Mariateresa; Tassone, Pierfrancesco] Magna Graecia Univ Catanzaro, Catanzaro, Italy. [Ettenberg, Seth A.; Stover, David R.] Novartis Inst Biomed Res, Cambridge, MA USA. [Shen, Zhenxin; Patel, Nipun] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Munshi, NC (reprint author), Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St,M1B28, Boston, MA 02115 USA. EM Nikhil_Munshi@DFCI.Harvard.edu FU Department of Veterans Affairs Merit Review Awards; National Institutes of Health [RO1-124929, P50-100007, PO1-78378]; Associazione Italiana per la Ricerca sul Cancro (AIRC) FX This work was supported in part by grants from the Department of Veterans Affairs Merit Review Awards, the National Institutes of Health (grant nos. RO1-124929 [N.C.M.], P50-100007, and PO1-78378 [N.C.M. and K. C. A.]), and Associazione Italiana per la Ricerca sul Cancro (AIRC). NR 51 TC 184 Z9 202 U1 3 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 9 PY 2009 VL 114 IS 2 BP 371 EP 379 DI 10.1182/blood-2008-11-191577 PG 9 WC Hematology SC Hematology GA 471MK UT WOS:000268061700023 PM 19417213 ER PT J AU Shen, YP Nunes, F Stemmer-Rachamimov, A James, M Mohapatra, G Plotkin, S Betensky, RA Engler, DA Roy, J Ramesh, V Gusella, JF AF Shen, Yiping Nunes, Fabio Stemmer-Rachamimov, Anat James, Marianne Mohapatra, Gayatry Plotkin, Scott Betensky, Rebecca A. Engler, David A. Roy, Jennifer Ramesh, Vijaya Gusella, James F. TI Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas SO BMC MEDICAL GENOMICS LA English DT Article ID GENE-EXPRESSION; ANAPLASTIC MENINGIOMAS; OLIGONUCLEOTIDE MICROARRAYS; INTRACRANIAL MENINGIOMAS; NEUROFIBROMATOSIS TYPE-2; DISTINCT PATTERNS; TUMOR-SUPPRESSOR; NF2 GENE; HYBRIDIZATION; DNA AB Background: Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas. Methods: We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH). Results: Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the NF2 tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors. Conclusion: Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members. C1 [Shen, Yiping; James, Marianne; Ramesh, Vijaya; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Nunes, Fabio] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Stemmer-Rachamimov, Anat; Mohapatra, Gayatry; Roy, Jennifer] Massachusetts Gen Hosp, Mol Neurooncol Lab, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat; Mohapatra, Gayatry; Roy, Jennifer] Massachusetts Gen Hosp, Pathol Lab, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat; Mohapatra, Gayatry; Roy, Jennifer] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat; Mohapatra, Gayatry; Plotkin, Scott; Roy, Jennifer] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Plotkin, Scott] Massachusetts Gen Hosp, Pappas Ctr Neuro Oncol, NF Clin, Boston, MA 02114 USA. [Betensky, Rebecca A.; Engler, David A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Gusella, JF (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. EM yshen3@partners.org; fnunes@partners.org; ASTEMMERRACHAMIMOV@PARTNERS.ORG; james@helix.mgh.harvard.edu; gmohapatra@partners.org; splotkin@partners.org; betensky@hsph.harvard.edu; engler@byu.edu; royj@helix.mgh.harvard.edu; ramesh@helix.mgh.harvard.edu; gusella@helix.mgh.harvard.edu FU S. Sydney De Young Foundation [DAMD17-02-1-0646]; National Institutes of Health [NS24279]; Armenise Foundation, NF Inc.; Children's Tumor Foundation [2005-01-004] FX Support for this project was received from the S. Sydney De Young Foundation, the Department of Defense Neurofibromatosis Research Program (DAMD17-02-1-0646), the National Institutes of Health (NS24279), the Armenise Foundation, NF Inc. NE, and by a Young Investigator Award (2005-01-004) from the Children's Tumor Foundation (to YS). NR 55 TC 16 Z9 16 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD JUL 9 PY 2009 VL 2 AR 42 DI 10.1186/1755-8794-2-42 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 533HA UT WOS:000272813100002 PM 19589153 ER PT J AU Vlajkovic, SM Housley, GD Thorne, PR Gupta, R Enjyoji, K Cowan, PJ Liberman, MC Robson, SC AF Vlajkovic, Srdjan M. Housley, Gary D. Thorne, Peter R. Gupta, Rita Enjyoji, Keiichi Cowan, Peter J. Liberman, M. Charles Robson, Simon C. TI Preservation of cochlear function in Cd39 deficient mice SO HEARING RESEARCH LA English DT Article DE CD39; NTPDase1; Ectonucleotidase; Purinergic signalling; Knockout mice; Hearing ID NUCLEOSIDE TRIPHOSPHATE DIPHOSPHOHYDROLASE-1; RAT COCHLEA; UP-REGULATION; CATALYTIC PROPERTIES; PROTECTION; ECTONUCLEOTIDASES; RECEPTOR; INJURY; EXPRESSION; ADENOSINE AB Signalling actions of extracellular nucleotides via P2 receptors influence cellular function in most tissues. In the inner ear, P2 receptor signaling is involved in many processes including the regulation of hearing sensitivity and the cochlea's response to noise stress. CD39 (NTPDase1/ENTPD1) is an ectonucleotidase (ecto-nucleoside triphosphate diphosphohydrolase) that can hydrolyse purine and pyrimidine nucleoside tri- and di-phosphates to generate monophosphate nucleosides. Mice null for Cd39 exhibit major alterations in haemostasis and profound alterations in inflammatory and thrombotic reactions. Studies in the cochlea have suggested the involvement of purinergic-type signals that could be modulated by CD39 in regulation of cochlear blood flow and also auditory neurotransmission. This study aimed to determine the auditory phenotype of adult Cd39 null mice on the C57BL6 background. Auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) were unaffected in Cd39-deficient mice across the range of test frequencies, suggesting normal neural and outer hair cell function. Mutant mice also showed little difference to wild type mice in vulnerability to acoustic trauma. Gene expression analysis of other membrane-bound NTPDases with comparable hydrolytic activity demonstrated an up-regulation of Entpd2 and Entpd8 in the cochleae of Cd39 deficient mice. These findings suggest that Cd39 deletion alone does not adversely affect cochlear function, possibly as compensatory up-regulation of other surface located NTPDases may offset predicted alterations in cochlear homeostasis. (C) 2009 Elsevier B.V. All rights reserved. C1 [Vlajkovic, Srdjan M.; Housley, Gary D.; Thorne, Peter R.; Gupta, Rita] Univ Auckland, Fac Med & Hlth Sci, Dept Physiol, Auckland 1142, New Zealand. [Thorne, Peter R.] Univ Auckland, Fac Med & Hlth Sci, Discipline Audiol, Auckland 1142, New Zealand. [Enjyoji, Keiichi; Robson, Simon C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Cowan, Peter J.] Univ Melbourne, St Vincents Hosp Melbourne, Immunol Res Ctr, Melbourne, Vic, Australia. [Cowan, Peter J.] Univ Melbourne, Dept Med, Melbourne, Vic, Australia. [Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Vlajkovic, SM (reprint author), Univ Auckland, Fac Med & Hlth Sci, Dept Physiol, 85 Pk Rd,Private Bag 92019, Auckland 1142, New Zealand. EM s.vlajkovic@auckland.ac.nz; g.housley@unsw.edu.au; pr.thorne@auckland.ac.nz; r.gupta@aucklan-d.ac.nz; kenjoji@caregroup.harvard.edu; Peter.COWAN@svh-m.org.au; Charles_Liberman@meei.harvard.edu; srobson@bidmc.harvard.edu OI Cowan, Peter/0000-0001-9016-4954; Housley, Gary/0000-0002-8413-588X; Vlajkovic, Srdjan/0000-0001-8548-6844 FU Health Research Council (NZ); Deafness Research Foundation (NZ); Auckland Medical Research Foundation; National Institute on Deafness and other Communicative Disorders [DC RO1 00188]; RNID FX This study was supported by the Health Research Council (NZ), Deafness Research Foundation (NZ), Auckland Medical Research Foundation, the National Institute on Deafness and other Communicative Disorders (DC RO1 00188 to MCQ, and RNID (UK). NR 35 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUL 9 PY 2009 VL 253 IS 1-2 BP 77 EP 82 DI 10.1016/j.heares.2009.03.009 PG 6 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 471SR UT WOS:000268079100009 PM 19327391 ER PT J AU Rosowski, JJ Cheng, JT Ravicz, ME Hulli, N Hernandez-Montes, M Harrington, E Furlong, C AF Rosowski, John J. Cheng, Jeffrey Tao Ravicz, Michael E. Hulli, Nesim Hernandez-Montes, Maria Harrington, Ellery Furlong, Cosme TI Computer-assisted time-averaged holograms of the motion of the surface of the mammalian tympanic membrane with sound stimuli of 0.4-25 kHz SO HEARING RESEARCH LA English DT Article DE Tympanic membrane; Middle-ear sound transmission; Middle-ear models ID HUMAN MIDDLE-EAR; FINITE-ELEMENT METHOD; VIBRATION MEASUREMENT; TEMPORAL BONES; CAT EARDRUM; MODEL; TRANSMISSION; GERBIL; MECHANICS AB Time-averaged holograms describing the sound-induced motion of the tympanic membrane (TM) in cadaveric preparations from three mammalian species and one live ear were measured using opto-electronic holography. This technique allows rapid measurements of the magnitude of motion of the tympanic membrane surface at frequencies as high as 25 kHz. The holograms measured in response to low and middle-frequency sound stimuli are similar to previously reported time-averaged holograms. However, at higher frequencies (f > 4 kHz), our holograms reveal unique TM surface displacement patterns that consist of highly-ordered arrangements of multiple local displacement magnitude maxima, each of which is surrounded by nodal areas of low displacement magnitude. These patterns are similar to modal patterns (two-dimensional standing waves) produced by either the interaction of surface waves traveling in multiple directions or the uniform stimulation of modes of motion that are determined by the structural properties and boundary conditions of the TM. From the ratio of the displacement magnitude peaks to nodal valleys in these apparent surface waves, we estimate a Standing Wave Ratio of at least 4 that is consistent with energy reflection coefficients at the TM boundaries of at least 0.35. It is also consistent with small losses within the uniformly stimulated modal surface waves. We also estimate possible TM surface wave speeds that vary with frequency and species from 20 to 65 m/s, consistent with other estimates in the literature. The presence of standing. wave or modal phenomena has previously been intuited from measurements of TM function, but is ignored in some models of tympanic membrane function. Whether these standing waves result either from the interactions of multiple surface waves that travel along the membrane, or by uniformly excited modal displacement patterns of the entire TM surface is still to be determined. (C) 2009 Elsevier B.V. All rights reserved. C1 [Rosowski, John J.; Cheng, Jeffrey Tao; Ravicz, Michael E.; Furlong, Cosme] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Hulli, Nesim; Hernandez-Montes, Maria; Harrington, Ellery; Furlong, Cosme] Worcester Polytech Inst, Dept Mech Engn, Worcester, MA 01609 USA. [Hulli, Nesim; Hernandez-Montes, Maria; Harrington, Ellery; Furlong, Cosme] Worcester Polytech Inst, Ctr Holog Studies & Laser MicromechaTron, Worcester, MA 01609 USA. [Rosowski, John J.; Cheng, Jeffrey Tao; Ravicz, Michael E.; Furlong, Cosme] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Rosowski, John J.] MIT, Harvard Mit Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol Program, Cambridge, MA 02139 USA. RP Rosowski, JJ (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM john_rosowski@meei.harvard.edu FU NIDCD; WPI; MEEI FX This work was funded by the NIDCD, the WPI, the MEEI and a generous donor. NR 53 TC 57 Z9 58 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUL 9 PY 2009 VL 253 IS 1-2 BP 83 EP 96 DI 10.1016/j.heares.2009.03.010 PG 14 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 471SR UT WOS:000268079100010 PM 19328841 ER PT J AU Wang, JH Gostissa, M Yan, CT Goff, P Hickernell, T Hansen, E Difilippantonio, S Wesemann, DR Zarrin, AA Rajewsky, K Nussenzweig, A Alt, FW AF Wang, Jing H. Gostissa, Monica Yan, Catherine T. Goff, Peter Hickernell, Thomas Hansen, Erica Difilippantonio, Simone Wesemann, Duane R. Zarrin, Ali A. Rajewsky, Klaus Nussenzweig, Andre Alt, Frederick W. TI Mechanisms promoting translocations in editing and switching peripheral B cells SO NATURE LA English DT Article ID END-JOINING PATHWAY; CHROMOSOMAL TRANSLOCATIONS; V(D)J RECOMBINATION; RECEPTOR REVISION; BONE-MARROW; DNA BREAKS; LYMPHOCYTE DEVELOPMENT; GENE-REGULATION; AID; EXPRESSION AB Variable, diversity and joining gene segment (V(D) J) recombination assembles immunoglobulin heavy or light chain (IgH or IgL) variable region exons in developing bone marrow B cells, whereas class switch recombination (CSR) exchanges IgH constant region exons in peripheral B cells. Both processes use directed DNA double-strand breaks (DSBs) repaired by non-homologous end-joining (NHEJ). Errors in either V(D) J recombination or CSR can initiate chromosomal translocations, including oncogenic IgH locus (Igh) to c-myc (also known as Myc) translocations of peripheral B cell lymphomas. Collaboration between these processes has also been proposed to initiate translocations. However, the occurrence of V(D) J recombination in peripheral B cells is controversial. Here we show that activated NHEJ-deficient splenic B cells accumulate V(D) J-recombination-associated breaks at the lambda IgL locus (Igl), as well as CSR-associated Igh breaks, often in the same cell. Moreover, Igl and Igh breaks are frequently joined to form translocations, a phenomenon associated with specific Igh-Igl co-localization. Igh and c-myc also co-localize in these cells; correspondingly, the introduction of frequent c-myc DSBs robustly promotes Igh-c-myc translocations. Our studies show peripheral B cells that attempt secondary V(D) J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours. C1 [Wang, Jing H.; Gostissa, Monica; Yan, Catherine T.; Goff, Peter; Hickernell, Thomas; Hansen, Erica; Wesemann, Duane R.; Zarrin, Ali A.; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Wang, Jing H.; Gostissa, Monica; Yan, Catherine T.; Goff, Peter; Hickernell, Thomas; Hansen, Erica; Wesemann, Duane R.; Zarrin, Ali A.; Alt, Frederick W.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Wang, Jing H.; Gostissa, Monica; Yan, Catherine T.; Goff, Peter; Hickernell, Thomas; Hansen, Erica; Wesemann, Duane R.; Zarrin, Ali A.; Rajewsky, Klaus; Alt, Frederick W.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Wang, Jing H.; Gostissa, Monica; Yan, Catherine T.; Goff, Peter; Hickernell, Thomas; Hansen, Erica; Wesemann, Duane R.; Zarrin, Ali A.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Difilippantonio, Simone; Nussenzweig, Andre] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI Wang, Jing/M-7813-2015 OI Wang, Jing/0000-0003-4343-2527 FU National Insitutes of Health (NIH) [5P01CA92625]; Leukemia and Lymphoma Society of America (LLS) SCORE; NCI FX We thank Alt laboratory members for discussions, and Y. L. Chen, J. M. Bianco and M. Moghimi for technical assistance. This work was supported by the National Insitutes of Health (NIH) grant 5P01CA92625 and a Leukemia and Lymphoma Society of America (LLS) SCORE grant to F. W. A. and K. R. M. G. is and J. H. W. was a Special Fellow of the LLS. J. H. W. and D. R. W. are supported by an NIH training grant and C. T. Y. was supported by an NCI training grant. A. N. is supported by the Intramural Research program of the NIH, NCI, Center for Cancer Research. F. W. A. is an Investigator of the Howard Hughes Medical Institute. NR 50 TC 87 Z9 90 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 9 PY 2009 VL 460 IS 7252 BP 231 EP U94 DI 10.1038/nature08159 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 467RV UT WOS:000267761000035 PM 19587764 ER PT J AU Naveiras, O Nardi, V Wenzel, PL Hauschka, PV Fahey, F Daley, GQ AF Naveiras, Olaia Nardi, Valentina Wenzel, Pamela L. Hauschka, Peter V. Fahey, Frederic Daley, George Q. TI Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment SO NATURE LA English DT Article ID STEM-CELL NICHE; INSULIN-RESISTANCE; PROGENITOR CELLS; SELF-RENEWAL; IN-VIVO; DIFFERENTIATION; GROWTH; IDENTIFICATION; ROSIGLITAZONE; ADIPONECTIN AB Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow(1-3). Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia(4). To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 'fatless' mice, which are genetically incapable of forming adipocytes(5), and in mice treated with the peroxisome proliferator-activated receptor-c inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis(6), marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation. C1 [Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Daley, George Q.] Harvard Univ, Stem Cell Inst, Boston, MA 02115 USA. [Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Daley, George Q.] Manton Ctr Orphan Dis, Boston, MA 02115 USA. [Hauschka, Peter V.] Harvard Univ, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. [Hauschka, Peter V.] Harvard Univ, Sch Med, Dept Oral & Dev Biol, Boston, MA 02115 USA. [Hauschka, Peter V.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Fahey, Frederic] Harvard Univ, Childrens Hosp, Sch Med, Dept Radiol,Div Nucl Med PET, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Div Pediat Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu RI Wenzel, Pamela/A-2992-2010 FU Barrie de la Maza Foundation; National Institutes of Health (NIH) [T32-HL-7623]; Burroughs Wellcome Fund; Leukemia and Lymphoma Society FX We thank S. Lazo-Kallanian, J. Daley, G. Losyev and R. Mathieu for assistance with flow cytometry; R. Bronson for assistance with pathological analysis; P. Dunning, E. Snay and S. Carlton for assistance with small animal imaging; S. Loewer for translation of historical references; and S. McKinney-Freeman, A. Yabuuchi, K. Ng and R. Chapman for mouse and technical assistance. O.N. was partially funded by the Barrie de la Maza Foundation. P. L. W. was supported by a Hematology Training Grant from the National Institutes of Health (NIH T32-HL-7623). G. Q. D. was supported by grants from the NIH and the NIH Director's Pioneer Award of the NIH Roadmap for Medical Research. G. Q. D. is the recipient of the Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and is an Investigator of the Howard Hughes Medical Institute. NR 33 TC 369 Z9 392 U1 0 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 9 PY 2009 VL 460 IS 7252 BP 259 EP U124 DI 10.1038/nature08099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 467RV UT WOS:000267761000041 PM 19516257 ER PT J AU Ganem, NJ Godinho, SA Pellman, D AF Ganem, Neil J. Godinho, Susana A. Pellman, David TI A mechanism linking extra centrosomes to chromosomal instability SO NATURE LA English DT Article ID MEROTELIC KINETOCHORE ORIENTATION; MAMMALIAN TISSUE-CELLS; CANCER-CELLS; CLONAL EVOLUTION; ANEUPLOIDY; AMPLIFICATION; MITOSIS; POPULATIONS; ABERRATIONS; PROGRESSION AB Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes(1-4). However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstrate that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. In contrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, but display a significantly increased frequency of lagging chromosomes during anaphase. To define the mechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number. We demonstrate that extra centrosomes alone are sufficient to promote chromosome missegregation during bipolar cell division. These segregation errors are a consequence of cells passing through a transient 'multipolar spindle intermediate' in which merotelic kinetochore-microtubule attachment errors accumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic link between extra centrosomes and CIN, two common characteristics of solid tumours. We propose that this mechanism may be a common underlying cause of CIN in human cancer. C1 [Ganem, Neil J.; Godinho, Susana A.; Pellman, David] Harvard Univ, Sch Med,Dept Pediat Oncol, Dana Farber Canc Inst,Dept Cell Biol, Howard Hughes Med Inst,Childrens Hosp, Boston, MA 02115 USA. RP Pellman, D (reprint author), Harvard Univ, Sch Med,Dept Pediat Oncol, Dana Farber Canc Inst,Dept Cell Biol, Howard Hughes Med Inst,Childrens Hosp, 44 Binney St, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu FU Leukemia and Lymphoma Society; NIH [GM083299] FX We would like to thank D. Compton, R. King, D. Livingston, A. Manning, T. Rapoport, J. Shah, T. Stukenberg and members of the Pellman laboratory for comments and discussion of the manuscript; L. Cameron for setting up the confocal microscope; P. Schow for help with FACS; D. Neuberg for help with statistical analysis; C. King for help with the model figure; J. Iwasa for creating the animations; and L. Moreau and S. Thompson for technical advice on chromosome spreads and FISH analysis. Reagents were provided by D. Compton, S. Gollin, R. King, A. Khodjakov, E. Nigg and G. Wahl. N.J.G. is a fellow of the Leukemia and Lymphoma Society and D. P. is an HHMI Investigator. This work was supported by NIH grant GM083299. NR 30 TC 583 Z9 595 U1 16 U2 57 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 9 PY 2009 VL 460 IS 7252 BP 278 EP U146 DI 10.1038/nature08136 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 467RV UT WOS:000267761000045 PM 19506557 ER PT J AU Neilson, EG Farris, AB AF Neilson, Eric G. Farris, Alton B. TI A Woman with Abdominal Pain, Weight Loss, and Renal Failure Acute and chronic tubulointerstitial nephritis associated with uveitis (TINU or Dobrin's syndrome). SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POLYARTERITIS-NODOSA; HELICOBACTER-PYLORI; INTERSTITIAL NEPHRITIS; FANCONI-SYNDROME; AUTOANTIBODIES; VASCULITIS; DIAGNOSIS; CELLS C1 [Neilson, Eric G.] Vanderbilt Univ Sch Med, Nashville, TN USA. [Neilson, Eric G.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Farris, Alton B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Farris, Alton B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Neilson, EG (reprint author), Vanderbilt Univ Sch Med, Nashville, TN USA. NR 30 TC 2 Z9 3 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 9 PY 2009 VL 361 IS 2 BP 179 EP 187 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 467OS UT WOS:000267748900013 PM 19587344 ER PT J AU Iglehart, JD Silver, DP AF Iglehart, J. Dirk Silver, Daniel P. TI Synthetic Lethality -- A New Direction in Cancer-Drug Development. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HOMOLOGOUS RECOMBINATION; PARP INHIBITOR; SENSITIVITY; RESISTANCE; REPAIR; MUTATIONS; THERAPY; SCREEN C1 [Iglehart, J. Dirk] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Iglehart, J. Dirk] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Silver, Daniel P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Boston, MA 02115 USA. RP Iglehart, JD (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. NR 13 TC 88 Z9 91 U1 3 U2 12 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 JUL 9 PY 2009 VL 361 IS 2 BP 189 EP 191 DI 10.1056/NEJMe0903044 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 467OS UT WOS:000267748900014 PM 19553640 ER PT J AU Vavvas, D Brodowska, K AF Vavvas, Demetrios Brodowska, Katarzyna TI Traumatic Bleb. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Vavvas, Demetrios; Brodowska, Katarzyna] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Vavvas, D (reprint author), Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. EM dvavvas@partners.org OI Vavvas, Demetrios/0000-0002-8622-6478 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 9 PY 2009 VL 361 IS 2 BP E2 EP E2 DI 10.1056/NEJMicm0802306 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 467OS UT WOS:000267748900012 PM 19587336 ER PT J AU Chauhan, VP Lanning, RM Diop-Frimpong, B Mok, W Brown, EB Padera, TP Boucher, Y Jain, RK AF Chauhan, Vikash P. Lanning, Ryan M. Diop-Frimpong, Benjamin Mok, Wilson Brown, Edward B. Padera, Timothy P. Boucher, Yves Jain, Rakesh K. TI Multiscale Measurements Distinguish Cellular and Interstitial Hindrances to Diffusion In Vivo SO BIOPHYSICAL JOURNAL LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; SOLID TUMORS; EXTRACELLULAR-SPACE; TRANSPORT; COLLAGEN; ENVIRONMENT; MICROSCOPY; MUSCLE; BRAIN; PORE AB Molecular cancer therapy relies on interstitial diffusion for drug distribution in solid tumors. A mechanistic understanding of how tumor components affect diffusion is necessary to advance cancer drug development. Yet, because of limitations in current techniques, it is unclear how individual tissue components hinder diffusion. We developed multiscale fluorescence recovery after photobleaching (MS-FRAP) to address this deficiency. Diffusion measurements facilitated by MS-FRAP distinguish the diffusive hindrance of the interstitial versus cellular constituents in living tissue. Using multiscale diffusion measurements in vivo, we resolved the contributions of these two major tissue components toward impeding diffusive transport in solid tumors and subcutaneous tissue in mice. We further used MS-FRAP in interstitial matrix-mimetic gels and in vivo to show the influence of physical interactions between collagen and hyaluronan on diffusive hindrance through the interstitium. Through these studies, we show that interstitial hyaluronan paradoxically improves diffusion and that reducing cellularity enhances diffusive macromolecular transport in solid tumors. C1 [Chauhan, Vikash P.; Lanning, Ryan M.; Diop-Frimpong, Benjamin; Mok, Wilson; Padera, Timothy P.; Boucher, Yves; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Chauhan, Vikash P.; Lanning, Ryan M.; Diop-Frimpong, Benjamin; Mok, Wilson; Padera, Timothy P.; Boucher, Yves; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chauhan, Vikash P.; Diop-Frimpong, Benjamin] Harvard Univ, Harvard Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Lanning, Ryan M.; Diop-Frimpong, Benjamin] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Brown, Edward B.] Univ Rochester, Med Ctr, Dept Biomed Engn, New York, NY 14642 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu RI Chauhan, Vikash/H-8172-2013; OI Chauhan, Vikash/0000-0001-9126-2302; Padera, Timothy/0000-0002-3453-9384 FU National Institutes of Health [5P01CA080124-08, 2T32CA073479-11]; Department of Defense Breast Cancer Research Program [W81X-WH-06-1-0436] FX This work was supported by the National Institutes of Health (grants 5P01CA080124-08 and 2T32CA073479-11 to R.K.J.) and Department of Defense Breast Cancer Research Program (grant W81X-WH-06-1-0436 to R.M.L.). NR 25 TC 30 Z9 30 U1 2 U2 11 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 JUL 8 PY 2009 VL 97 IS 1 BP 330 EP 336 DI 10.1016/j.bpj.2009.03.064 PG 7 WC Biophysics SC Biophysics GA 469BV UT WOS:000267871000033 PM 19580771 ER PT J AU Peterson, PN Ambardekar, AV Jones, PG Krumholz, HM Schelbert, E Spertus, JA Rumsfeld, JS Masoudi, FA AF Peterson, Pamela N. Ambardekar, Amrut V. Jones, Philip G. Krumholz, Harlan M. Schelbert, Erik Spertus, John A. Rumsfeld, John S. Masoudi, Frederick A. TI Increased Mortality among Survivors of Myocardial Infarction with Kidney Dysfunction: the Contribution of Gaps in the use of Guideline-Based Therapies SO BMC CARDIOVASCULAR DISORDERS LA English DT Article ID ACUTE CORONARY SYNDROMES; STAGE RENAL-DISEASE; CARDIOVASCULAR-DISEASE; HEART-FAILURE; INSUFFICIENCY; OUTCOMES; ASSOCIATION; INHIBITORS; ASPIRIN; EVENTS AB Background: We assessed the degree to which differences in guideline-based medical therapy for acute myocardial infarction (AMI) contribute to the higher mortality associated with kidney disease. Methods: In the PREMIER registry, we evaluated patients from 19 US centers surviving AMI. Cox regression evaluated the association between estimated glomerular filtration rate (GFR) and time to death over two years, adjusting for demographic and clinical variables. The contribution of variation in guideline-based medical therapy to differences in mortality was then assessed by evaluating the incremental change in the hazard ratios after further adjustment for therapy. Results: Of 2426 patients, 26% had GFR >= 90, 44% had GFR = 60- < 90, 22% had GFR = 30- < 60, and 8% had GFR < 30 ml/min/1.73 m(2). Greater degrees of renal dysfunction were associated with greater 2-year mortality and lower rates of guideline-based therapy among eligible patients. For patients with severely decreased GFR, adjustment for differences in guideline-based therapy did not significantly attenuate the relationship with mortality (HR 3.82, 95% CI 2.39-6.11 partially adjusted; HR = 3.90, 95% CI 2.42-6.28 after adjustment for treatment differences). Conclusion: Higher mortality associated with reduced GFR after AMI is not accounted for by differences in treatment factors, underscoring the need for novel therapies specifically targeting the pathophysiological abnormalities associated with kidney dysfunction to improve survival. C1 [Peterson, Pamela N.; Masoudi, Frederick A.] Denver Hlth Med Ctr, Denver, CO USA. [Peterson, Pamela N.; Ambardekar, Amrut V.; Rumsfeld, John S.; Masoudi, Frederick A.] Univ Colorado Denver, Aurora, CO USA. [Jones, Philip G.; Spertus, John A.] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Schelbert, Erik] Natl Inst Hlth, Bethesda, MD USA. [Spertus, John A.] Univ Missouri, Kansas City, MO 64110 USA. [Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. RP Peterson, PN (reprint author), Denver Hlth Med Ctr, Denver, CO USA. EM pamela.peterson@uchsc.edu; Amrut.Ambardekar@uchsc.edu; pgjones@saint-lukes.org; Harlan.Krumholz@yale.edu; Schelberteb@nhlbi.nih.gov; spertusj@umkc.edu; John.Rumsfeld@uchsc.edu; Fred.Masoudi@uchsc.edu OI Schelbert, Erik/0000-0003-0356-4437 NR 26 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD JUL 8 PY 2009 VL 9 AR 29 DI 10.1186/1471-2261-9-29 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 477AN UT WOS:000268488400001 PM 19586550 ER PT J AU Fjell, AM Westlye, LT Amlien, I Espeseth, T Reinvang, I Raz, N Agartz, I Salat, DH Greve, DN Fischl, B Dale, AM Walhovd, KB AF Fjell, Anders M. Westlye, Lars T. Amlien, Inge Espeseth, Thomas Reinvang, Ivar Raz, Naftali Agartz, Ingrid Salat, David H. Greve, Doug N. Fischl, Bruce Dale, Anders M. Walhovd, Kristine B. TI Minute Effects of Sex on the Aging Brain: A Multisample Magnetic Resonance Imaging Study of Healthy Aging and Alzheimer's Disease SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; DEMENTIA RATING CDR; ADULT HUMAN BRAIN; IN-VIVO; CORTICAL THICKNESS; GRAY-MATTER; WHITE-MATTER; YOUNG ADULTS AB Age is associated with substantial macrostructural brain changes. While some recent magnetic resonance imaging studies have reported larger age effects in men than women, others find no sex differences. As brain morphometry is a potentially important tool in diagnosis and monitoring of age-related neurological diseases, e.g., Alzheimer's disease (AD), it is important to know whether sex influences brain aging. We analyzed cross-sectional magnetic resonance scans from 1143 healthy participants from seven subsamples provided by four independent research groups. In addition, 96 patients with mild AD were included. Estimates of cortical thickness continuously across the brain surface, as well as volume of 17 subcortical structures, were obtained by use of automated segmentation tools (FreeSurfer). In the healthy participants, no differences in aging slopes between women and men were found in any part of the cortex. Pallidum corrected for intracranial volume showed slightly higher age correlations for men. The analyses were repeated in each of the seven subsamples, and the lack of age x sex interactions was largely replicated. Analyses of the AD sample showed no interactions between sex and age for any brain region. We conclude that sex has negligible effects on the age slope of brain volumes both in healthy participants and in AD. C1 [Fjell, Anders M.; Westlye, Lars T.; Amlien, Inge; Espeseth, Thomas; Reinvang, Ivar; Walhovd, Kristine B.] Univ Oslo, Dept Psychol, Ctr Study Human Cognit, N-0317 Oslo, Norway. [Agartz, Ingrid] Univ Oslo, Dept Psychiat, N-0317 Oslo, Norway. [Fjell, Anders M.; Walhovd, Kristine B.] Ullevaal Univ Hosp, Dept Neuropsychiat, N-0317 Oslo, Norway. [Raz, Naftali] Wayne State Univ, Dept Psychol, Detroit, MI 48202 USA. [Raz, Naftali] Wayne State Univ, Inst Gerontol, Detroit, MI 48202 USA. [Agartz, Ingrid] Diakonhjemmet Hosp, Dept Psychiat Res, N-0319 Oslo, Norway. [Agartz, Ingrid] Karolinska Hosp & Inst, Psychiat Sect, Dept Clin Neurosci, S-17176 Stockholm, Sweden. [Salat, David H.; Greve, Doug N.; Fischl, Bruce] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr,Dept Radiol, Charlestown, MA 02129 USA. [Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Dale, Anders M.] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Fjell, AM (reprint author), Univ Oslo, Dept Psychol, Ctr Study Human Cognit, Pb 1094 Blindern, N-0317 Oslo, Norway. EM andersmf@psykologi.uio.no RI Dale, Anders/A-5180-2010; OI Agartz, Ingrid/0000-0002-9839-5391; Westlye, Lars T./0000-0001-8644-956X FU Howard Hughes Medical Institute; NCRR NIH HHS [P41 RR014075, P41 RR014075-075751, P41 RR014075-075752, P41 RR014075-075753, P41 RR014075-086765, P41 RR014075-086766, P41 RR014075-086767, P41 RR014075-098601, P41 RR014075-098602, P41 RR014075-098603, P41 RR014075-105995, P41 RR014075-105996, P41 RR014075-105997, P41-RR14075, R01 RR016594, R01 RR016594-01A1, R01 RR016594-02, R01 RR016594-03, R01 RR016594-04, R01 RR16594-01A1, R01-RR13609, RR 16594, RR14075, U24 RR021382]; NIA NIH HHS [P01 AG003991, P01 AG003991-219005, P01 AG003991-229005, P01 AG003991-239005, P01 AG003991-249005, P01 AG003991-259005, P01 AG03991, P50 AG005681, P50 AG005681-170029, P50 AG005681-180029, P50 AG005681-18S10029, P50 AG005681-18S20029, P50 AG005681-18S30029, P50 AG005681-190029, P50 AG005681-19S10029, P50 AG005681-19S20029, P50 AG05681, R01 AG034556, R37 AG011230, R37-AG11230]; NIBIB NIH HHS [R01EB006758, R01 EB001550, R01 EB006758, R01 EB006758-01A1, R01 EB006758-02, R01 EB006758-03, R01 EB006758-03S1, U54 EB005149]; NIMH NIH HHS [P20 MH071616, P50 MH071616]; NINDS NIH HHS [R01 NS052585, R01 NS052585-01, R01 NS052585-01A1, R01 NS052585-02, R01 NS052585-02S1, R01 NS052585-03, R01 NS052585-04, R01-NS39581] NR 76 TC 47 Z9 48 U1 2 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 8 PY 2009 VL 29 IS 27 BP 8774 EP 8783 DI 10.1523/JNEUROSCI.0115-09.2009 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 468KY UT WOS:000267818400018 PM 19587284 ER PT J AU Hogberg, B Liedl, T Shih, WM AF Hogberg, Bjorn Liedl, Tim Shih, William M. TI Folding DNA Origami from a Double-Stranded Source of Scaffold SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID THERMODYNAMICS; FORMAMIDE; SHAPES AB Combined heat and chemical denaturation of double-stranded DNA scaffold strands in the presence of staple strands, followed by a sudden temperature drop and then stepwise dialysis to remove the chemical denaturant, leads to self-assembly of two distinct DNA-origami structures. C1 [Hogberg, Bjorn] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Hogberg, B (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM Bjorn_Hogberg@dfci.harvard.edu; Tim_Liedl@dfci.harvard.edu; William_Shih@dfci.harvard.edu RI Liedl, Tim/O-7539-2014; OI Liedl, Tim/0000-0002-0040-0173; Hogberg, Bjorn/0000-0003-2715-7887 FU NIH HHS [1DP2OD004641-01, DP2 OD004641, DP2 OD004641-01] NR 10 TC 54 Z9 55 U1 2 U2 36 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 JUL 8 PY 2009 VL 131 IS 26 BP 9154 EP + DI 10.1021/ja902569x PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 466AT UT WOS:000267633300011 PM 19566089 ER PT J AU Ahmad, M Zhang, YQ Liu, H Rose, ME Graham, SH AF Ahmad, Muzamil Zhang, Yuquin Liu, Hao Rose, Marie E. Graham, Steven H. TI Prolonged opportunity for neuroprotection in experimental stroke with selective blockade of cyclooxygenase-2 activity SO BRAIN RESEARCH LA English DT Article DE Cerebral ischemia; Therapeutic window; Clinical significance; Valdecoxib; COX-2 inhibitor ID FOCAL CEREBRAL-ISCHEMIA; BRAIN-DAMAGE; NEURONS; COX-2; INHIBITION; RECEPTORS; RATS; NEUROTOXICITY; INFLAMMATION; CONTRIBUTES AB The post-treatment effects of the selective cyclooxygenase (COX)-2 inhibitor, valdecoxib, were investigated in a rat model of temporary focal ischemia. Valdecoxib reduced basal brain prostaglandin E(2) concentrations at dosages that did not affect serum thromboxane B(2), consistent with a selective COX-2 effect. Temporary focal cerebral ischemia was produced in rats by middle cerebral artery occlusion for 90 min. There was increased expression of COX-2 protein detected by Western blot and immunocytochemistry within neurons in the ischemic cortex at 4 and 24 h after ischemia. Rats were treated with vehicle or valdecoxib IS min before or 1.5, 3 and 6 h after cerebral ischemia. Rats were sacrificed and brain infarction volume determined 24 h after ischemia. Valdecoxib treatment was associated with a decrease in infarction volume when administered 15 min before, and 1.5 or 3 h but not 6 h after cerebral ischemia, There were no differences in physiological parameters during the procedure. Valdecoxib administered at 1.5 h after ischemia significantly reduced the concentrations of prostaglandin E(2) in ischemic penumbral cortex as compared to the vehicle-treated group and contralateral non-ischemic cortex. These results suggest that COX-2 inhibition with valdecoxib is effective when initiated both before and after middle cerebral artery occlusion. Published by Elsevier B.V. C1 VA Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. RP Graham, SH (reprint author), VA Pittsburgh Healthcare, Geriatr Res Educ & Clin Ctr 00GRH, Highland Dr, Pittsburgh, PA 15205 USA. EM sgra@pitt.edu FU NIH [R01 NS37459] FX This work was supported by NIH R01 NS37459 (SHG). NR 27 TC 19 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 7 PY 2009 VL 1279 BP 168 EP 173 DI 10.1016/j.brainres.2009.05.020 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 466PI UT WOS:000267674100018 PM 19446533 ER PT J AU Grant, RW Middleton, B AF Grant, Richard W. Middleton, Blackford TI Improving primary care for patients with complex chronic diseases: Can health information technology play a role? SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID DECISION-SUPPORT-SYSTEMS; QUALITY C1 [Grant, Richard W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Grant, Richard W.; Middleton, Blackford] Harvard Univ, Sch Med, Boston, MA USA. [Middleton, Blackford] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Middleton, Blackford] Partners HealthCare Syst, Clin Informat Res & Dev, Wellesley, MA USA. RP Grant, RW (reprint author), 50-9 Staniford St, Boston, MA 02114 USA. EM rgrant@partners.org RI Tao, Youyou/D-2367-2014; OI Grant, Richard/0000-0002-6164-8025 NR 10 TC 5 Z9 5 U1 0 U2 0 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JUL 7 PY 2009 VL 181 IS 1-2 BP 17 EP 18 DI 10.1503/cmaj.091101 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 464XJ UT WOS:000267542600003 PM 19581613 ER PT J AU Sgroi, DC AF Sgroi, Dennis C. TI Breast Cancer Src Activity: Bad to the Bone SO CANCER CELL LA English DT Editorial Material ID METASTASIS C1 [Sgroi, Dennis C.] Massachusetts Gen Hosp, Mol Pathol Res Unit, Boston, MA 02129 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02129 USA. [Sgroi, Dennis C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. RP Sgroi, DC (reprint author), Massachusetts Gen Hosp, Mol Pathol Res Unit, Boston, MA 02129 USA. EM dsgroi@partners.org NR 8 TC 6 Z9 6 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUL 7 PY 2009 VL 16 IS 1 BP 1 EP 2 DI 10.1016/j.ccr.2009.06.010 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 468AR UT WOS:000267786100001 PM 19573804 ER PT J AU Vasudevan, KM Barbie, DA Davies, MA Rabinovsky, R McNear, CJ Kim, JJ Hennessy, BT Tseng, H Pochanard, P Kim, SY Dunn, IF Schinzel, AC Sandy, P Hoersch, S Sheng, Q Gupta, PB Boehm, JS Reiling, JH Silver, S Lu, YL Stemke-Hale, K Dutta, B Joy, C Sahin, AA Gonzalez-Angulo, AM Lluch, A Rameh, LE Jacks, T Root, DE Lander, ES Mills, GB Hahn, WC Sellers, WR Garraway, LA AF Vasudevan, Krishna M. Barbie, David A. Davies, Michael A. Rabinovsky, Rosalia McNear, Chontelle J. Kim, Jessica J. Hennessy, Bryan T. Tseng, Hsiuyi Pochanard, Panisa Kim, So Young Dunn, Ian F. Schinzel, Anna C. Sandy, Peter Hoersch, Sebastian Sheng, Qing Gupta, Piyush B. Boehm, Jesse S. Reiling, Jan H. Silver, Serena Lu, Yiling Stemke-Hale, Katherine Dutta, Bhaskar Joy, Corwin Sahin, Aysegul A. Gonzalez-Angulo, Ana Maria Lluch, Ana Rameh, Lucia E. Jacks, Tyler Root, David E. Lander, Eric S. Mills, Gordon B. Hahn, William C. Sellers, William R. Garraway, Levi A. TI AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer SO CANCER CELL LA English DT Article ID 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE-1; MAMMARY EPITHELIAL-CELLS; HYDROPHOBIC MOTIF PHOSPHORYLATION; BREAST-CANCER; PHOSPHATIDYLINOSITOL 3-KINASES; CAENORHABDITIS-ELEGANS; HOMOLOGY DOMAIN; HIGH-FREQUENCY; MTOR COMPLEX; ACTIVATION AB Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations. C1 [Vasudevan, Krishna M.; Barbie, David A.; Rabinovsky, Rosalia; McNear, Chontelle J.; Kim, Jessica J.; Tseng, Hsiuyi; Pochanard, Panisa; Kim, So Young; Dunn, Ian F.; Schinzel, Anna C.; Sheng, Qing; Hahn, William C.; Sellers, William R.; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Vasudevan, Krishna M.; Rabinovsky, Rosalia; McNear, Chontelle J.; Kim, Jessica J.; Kim, So Young; Dunn, Ian F.; Schinzel, Anna C.; Hahn, William C.; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Vasudevan, Krishna M.; Rabinovsky, Rosalia; Dunn, Ian F.; Sheng, Qing; Hahn, William C.; Garraway, Levi A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Dunn, Ian F.; Sheng, Qing; Hahn, William C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Barbie, David A.; Kim, So Young; Dunn, Ian F.; Schinzel, Anna C.; Gupta, Piyush B.; Boehm, Jesse S.; Silver, Serena; Root, David E.; Lander, Eric S.; Hahn, William C.; Garraway, Levi A.] Broad Inst MIT & Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Sellers, William R.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Davies, Michael A.; Hennessy, Bryan T.; Lu, Yiling; Stemke-Hale, Katherine; Dutta, Bhaskar; Joy, Corwin; Sahin, Aysegul A.; Gonzalez-Angulo, Ana Maria; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Sandy, Peter; Hoersch, Sebastian; Jacks, Tyler] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Reiling, Jan H.] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. [Lluch, Ana] Univ Valencia, Clin Hosp, Valencia 46010, Spain. [Rameh, Lucia E.] Boston Biomed Res Inst, Watertown, MA 02472 USA. [Barbie, David A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Garraway, LA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM levi_garraway@dfci.harvard.edu RI Stemke-Hale, Katherine/K-9113-2013; OI Stemke-Hale, Katherine/0000-0002-1231-4192; Boehm, Jesse/0000-0002-6795-6336 FU Prostate Cancer Foundation; Burroughs-Wellcome Fund; Department of Defense [PC073284]; American Society for Clinical Oncology; Human Frontier Fellowship Organization; National Human Genome Research Institute; Susan Madden Fund; Starr Cancer Consortium [1A-1 1]; National Institutes of Health [T32CA09172-33, P50CA093459, R33CA128625, P01CA050661, P50CA112967, P30CA14051, R01CA085912, DP20DO02750-01]; Novartis, Inc FX We thank Erica Bauerlein for shRNA constructs; Len Pennacchio, Jan-Fang Cheng, Mandy Madiredio, Stefan Frohling, Claudia Scholl, and Raymond Wadlow for technical assistance; Tamas Balla for the PH-AKT GFP construct; Pablo Tamayo for statistical help; and Payman Amin, Stephen Basham, Amit Duft, Matthew Meyerson, David Livingston, DavidSabatini, and members of the Garraway laboratory for helpful discussions. This work was supported by the Prostate Cancer Foundation, the Burroughs-Wellcome Fund (L.A.G.), the Department of Defense grant PC073284(K.M.V.), the American Society for Clinical Oncology (M.A. D.); the Human Frontier Fellowship Organization (J.H.R.); the National Human Genome Research Institute (E.S.L.); the Susan Madden Fund (D.A.B.); the Starr Cancer Consortium 1A-1 1 (W.C.H.); and the National Institutes of Health grants T32CA09172-33 (D.A.B.), P50CA093459 (M.A.D.), R33CA128625, P01CA050661 (W.C.H.), P50CA112967, P30CA14051 (T.J.), R01CA085912 ("W.R.S. and L.A.G.), and DP20DO02750-01 (L.A.G.). G.B.M. is a consultant for Amira Pharmaceuticals, Inc., Arcxis Biotech nologies, Catena Pharmaceuticals, Genentech, Inc., GlaxoSmith Kline, Lpath Therapeutics, PTV Sciences, QLT, Inc., Sernafore Pharmaceuticals, and Signal Pharmaceuticals. W.R.S. is an employee for Novartis, Inc. W.C.H. and L.A.G. are consultants for and received sponsored research support from Novartis, Inc. NR 56 TC 273 Z9 281 U1 2 U2 19 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 JUL 7 PY 2009 VL 16 IS 1 BP 21 EP 32 DI 10.1016/j.ccr.2009.04.012 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 468AR UT WOS:000267786100006 PM 19573809 ER PT J AU McGillicuddy, LT Fromm, JA Hollstein, PE Kubek, S Beroukhim, R De Raedt, T Johnson, BW Williams, SMG Nghiemphu, P Liau, LM Cloughesy, TF Mischel, PS Parret, A Seiler, J Moldenhauer, G Scheffzek, K Stemmer-Rachamimov, AO Sawyers, CL Brennan, C Messiaen, L Mellinghoff, IK Cichowski, K AF McGillicuddy, Lauren T. Fromm, Jody A. Hollstein, Pablo E. Kubek, Sara Beroukhim, Rameen De Raedt, Thomas Johnson, Bryan W. Williams, Sybil M. G. Nghiemphu, Phioanh Liau, Linda M. Cloughesy, Tim F. Mischel, Paul S. Parret, Annabel Seiler, Jeanette Moldenhauer, Gerd Scheffzek, Klaus Stemmer-Rachamimov, Anat O. Sawyers, Charles L. Brennan, Cameron Messiaen, Ludwine Mellinghoff, Ingo K. Cichowski, Karen TI Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in Gliomagenesis SO CANCER CELL LA English DT Article ID NEUROFIBROMATOSIS TYPE-1 GENE; PROTEIN-KINASE-C; HUMAN GLIOBLASTOMA-MULTIFORME; SOMATIC MUTATIONS; UBIQUITIN LIGASE; BRAIN-TUMORS; CELLS; SENESCENCE; ACTIVATION; PATHWAY AB Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity. C1 [McGillicuddy, Lauren T.; Fromm, Jody A.; Hollstein, Pablo E.; De Raedt, Thomas; Johnson, Bryan W.; Williams, Sybil M. G.; Cichowski, Karen] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [McGillicuddy, Lauren T.; Fromm, Jody A.; Hollstein, Pablo E.; Beroukhim, Rameen; De Raedt, Thomas; Johnson, Bryan W.; Williams, Sybil M. G.; Cichowski, Karen] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [McGillicuddy, Lauren T.; Fromm, Jody A.; Hollstein, Pablo E.; Beroukhim, Rameen; De Raedt, Thomas; Johnson, Bryan W.; Williams, Sybil M. G.; Stemmer-Rachamimov, Anat O.; Cichowski, Karen] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kubek, Sara; Mellinghoff, Ingo K.] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA. [Beroukhim, Rameen] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [De Raedt, Thomas; Johnson, Bryan W.; Cichowski, Karen] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA. [Nghiemphu, Phioanh; Cloughesy, Tim F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Liau, Linda M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurosurg, Los Angeles, CA 90095 USA. [Mischel, Paul S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Parret, Annabel; Seiler, Jeanette; Scheffzek, Klaus] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany. [Parret, Annabel; Seiler, Jeanette; Scheffzek, Klaus] European Mol Biol Lab, Dev Biol Unit, D-69117 Heidelberg, Germany. [Moldenhauer, Gerd] German Canc Res Ctr, Translat Immunol Unit, D-69120 Heidelberg, Germany. [Stemmer-Rachamimov, Anat O.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sawyers, Charles L.; Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Brennan, Cameron] Cornell Univ, Weill Cornell Med Coll, Dept Neurosurg, New York, NY 10021 USA. [Brennan, Cameron] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [Messiaen, Ludwine] Univ Alabama, Dept Genet, Med Genom Lab, Birmingham, AL 35242 USA. [Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10065 USA. RP Cichowski, K (reprint author), Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM kcichowski@rics.bwh.harvard.edu RI Sawyers, Charles/G-5327-2016; OI Brennan, Cameron/0000-0003-4064-8891; Parret, Annabel/0000-0003-0635-8890 FU Brain Tumor Funders' Collaborative; NCI [R01 CA111754-01]; DOD [W81XWH-08-1-0136]; Children's Tumor Foundation; Landesstiftung Baden-Wuerttemberg, Germany FX We thank Wade Harper, Steve Elledge, Gerard Evan, and Bill Hahn for helpful discussions and Maria Debiec-Rychter for samples. This work was supported by grants from the Brain Tumor Funders' Collaborative (I.K.M., T.F.C., and P.S.M.), NCI (R01 CA111754-01) (K.C.), DOD (W81XWH-08-1-0136) (K.C.), The Children's Tumor Foundation (L.T.M., S.M.G.W., and A.P.), and Landesstiftung Baden-Wuerttemberg, Germany (K.S.). NR 49 TC 69 Z9 71 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUL 7 PY 2009 VL 16 IS 1 BP 44 EP 54 DI 10.1016/j.ccr.2009.05.009 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 468AR UT WOS:000267786100008 PM 19573811 ER PT J AU Reddy, VY Neuzil, P Themistoclakis, S Danik, SB Bonso, A Rossillo, A Raviele, A Schweikert, R Ernst, S Kuck, KH Natale, A AF Reddy, Vivek Y. Neuzil, Petr Themistoclakis, Sakis Danik, Stephan B. Bonso, Aldo Rossillo, Antonio Raviele, Antonio Schweikert, Robert Ernst, Sabine Kuck, Karl-Heinz Natale, Andrea TI Visually-Guided Balloon Catheter Ablation of Atrial Fibrillation Experimental Feasibility and First-in-Human Multicenter Clinical Outcome SO CIRCULATION LA English DT Article; Proceedings Paper CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc DE ablation; atrial fibrillation; catheter ablation; lasers; pulmonary veins ID PULMONARY VEIN ISOLATION; CIRCUMFERENTIAL ULTRASOUND ABLATION; CONDUCTION; OSTIUM; LESIONS; SYSTEM AB Background-Electric isolation of the pulmonary veins (PVs) can successfully treat patients with paroxysmal atrial fibrillation. However, it remains technically challenging to identify the left atrial-PV junction and sequentially position the ablation catheter in a point-by-point contiguous fashion to isolate the PVs. In this study, a novel endoscopic ablation system was used to directly visualize and ablate tissue at the left atrial-PV junction with laser energy. Methods and Results-This study consisted of 2 phases: a short-term (n = 9) and long-term (n = 11) canine experimental validation phase and a multicenter clinical feasibility phase (n = 30 paroxysmal atrial fibrillation patients). After transseptal puncture, the balloon-based endoscopic ablation system was advanced to each PV ostium, and arcs of laser energy (90 to 360) were projected onto the target left atrial-PV junction. Electric PV isolation was defined with a circular multielectrode catheter. In the short-term preclinical experimental phase, 15 of 17 targeted PVs (88%) were successfully isolated. Pathological examination revealed well-demarcated circumferential lesions with minimal endothelial disruption. In the long-term experiments, 9 of 10 targeted veins (90%) remained persistently isolated (at 4 to 8 weeks). In the clinical phase, 105 of 116 PVs (91%) were successfully isolated. After a single procedure, the 12-month drug-free rate of freedom from atrial fibrillation was 60% (18 of 30 patients). There were no significant PV stenoses, but adverse events included 1 episode of cardiac tamponade, 1 stroke without residual defect, and 1 asymptomatic phrenic nerve palsy. Conclusion-This study establishes the feasibility of a novel paradigm for AF ablation: direct visualization to guide catheter ablation of the left atrial-PV junction. (Circulation. 2009; 120: 12-20.) C1 [Reddy, Vivek Y.] Mt Sinai Sch Med, New York, NY USA. [Reddy, Vivek Y.; Danik, Stephan B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Reddy, Vivek Y.; Danik, Stephan B.] Harvard Univ, Sch Med, Boston, MA USA. [Reddy, Vivek Y.; Neuzil, Petr] Homolka Hosp, Prague, Czech Republic. [Themistoclakis, Sakis; Bonso, Aldo; Rossillo, Antonio; Raviele, Antonio; Natale, Andrea] Umberto Hosp, Venice, Italy. [Schweikert, Robert] Akron Gen Med Ctr, Akron, OH USA. [Ernst, Sabine; Kuck, Karl-Heinz] St Georg Hosp, Hamburg, Germany. [Natale, Andrea] Texas Cardiac Arrhythmia Inst, Austin, TX USA. RP Reddy, VY (reprint author), Univ Miami, Miller Sch Med, 1400 NW 12th Ave,Suite 4062, Miami, FL 33136 USA. EM vreddy@med.miami.edu NR 18 TC 49 Z9 49 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 7 PY 2009 VL 120 IS 1 BP 12 EP 20 DI 10.1161/CIRCULATIONAHA.108.840587 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 468BO UT WOS:000267788500004 PM 19546385 ER PT J AU Wills, AM Cronin, S Slowik, A Kasperaviciute, D Van Es, MA Morahan, JM Valdmanis, PN Meininger, V Melki, J Shaw, CE Rouleau, GA Fisher, EMC Shaw, PJ Morrison, KE Pamphlett, R Van den Berg, LH Figlewicz, DA Andersen, PM Al-Chalabi, A Hardiman, O Purcell, S Landers, JE Brown, RH AF Wills, A-M. Cronin, S. Slowik, A. Kasperaviciute, D. Van Es, M. A. Morahan, J. M. Valdmanis, P. N. Meininger, V. Melki, J. Shaw, C. E. Rouleau, G. A. Fisher, E. M. C. Shaw, P. J. Morrison, K. E. Pamphlett, R. Van den Berg, L. H. Figlewicz, D. A. Andersen, P. M. Al-Chalabi, A. Hardiman, O. Purcell, S. Landers, J. E. Brown, R. H., Jr. TI A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; GENOME-WIDE ASSOCIATION; CLUSTER POLYMORPHISMS; DISEASE; SUSCEPTIBILITY; POPULATION; LINKAGE; DIAGNOSIS; CRITERIA AB Background: Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding. Methods: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls. Results: The combined fixed effects odds ratio (OR) for rs662(PON1Q192R) was 1.09(95% confidence interval [CI], 1.02-1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07-1.45, p = 0.0004); the combined OR for rs854560(PON1L55M) was 0.97(95% CI, 0.86-1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92-1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97-1.16, p = 0.22). Conclusions: In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS. Neurology (R) 2009; 73: 16-24 C1 [Wills, A-M.; Landers, J. E.; Brown, R. H., Jr.] Massachusetts Gen Hosp, Neuromuscular Res Lab, Charlestown, MA USA. [Cronin, S.; Hardiman, O.] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland. [Slowik, A.] Jagiellonian Univ, Dept Neurol, Krakow, Poland. [Kasperaviciute, D.; Fisher, E. M. C.] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England. [Van Es, M. A.; Van den Berg, L. H.] Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Neurol, Netherlands ALS Ctr, Utrecht, Netherlands. [Morahan, J. M.; Pamphlett, R.] Univ Sydney, Dept Pathol, Stacey MND Lab, Sydney, NSW 2006, Australia. [Morahan, J. M.] Royal Prince Alfred Hosp, Dept Mol & Clin Genet, Sydney, NSW, Australia. [Valdmanis, P. N.; Rouleau, G. A.] Univ Montreal, CHUM Res Ctr, Ctr Excellence Neur, Montreal, PQ H3C 3J7, Canada. [Valdmanis, P. N.; Rouleau, G. A.] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Meininger, V.] Hop La Pitie Salpetriere, Ctr Referent SLA, Paris, France. [Melki, J.] Hadassah Univ Hosp, Dept Human Genet, IL-91120 Jerusalem, Israel. [Shaw, C. E.; Al-Chalabi, A.] Kings Coll London, Inst Psychiat, Dept Clin Neurosci, MRC Ctr Neurodegenerat Res, London WC2R 2LS, England. [Shaw, P. J.] Univ Sheffield, Sch Med, Acad Neurol Unit, Sheffield S10 2TN, S Yorkshire, England. [Morrison, K. E.] Univ Birmingham, Sch Med, Inst Biomed Res, Dept Clin Neurosci, Birmingham B15 2TT, W Midlands, England. [Figlewicz, D. A.] Univ Michigan, Ann Arbor, MI USA. [Figlewicz, D. A.] ALS Soc Canada, Ann Arbor, MI USA. [Andersen, P. M.] Umea Univ Hosp, Dept Neurol, Umea, Sweden. [Hardiman, O.] Trinity Coll Dublin, Inst Neurosci, Dublin, Ireland. [Purcell, S.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Wills, AM (reprint author), CNY 114-3125,114 16th St, Charlestown, MA 02129 USA. EM awills@partners.org RI Kasperaviciute, Dalia/D-1493-2009; Shaw, Pamela/A-7620-2010; Al-Chalabi, Ammar/E-5361-2010; Shaw, Pamela/E-6193-2010; OI Al-Chalabi, Ammar/0000-0002-4924-7712; Hardiman, Orla/0000-0003-2610-1291 FU Medical Research Council [G0500289, , G0600974, G0400149, G0900688]; NIEHS NIH HHS [R01 ES013482-01]; Wellcome Trust [, 089701] NR 37 TC 35 Z9 35 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 JUL 7 PY 2009 VL 73 IS 1 BP 16 EP 24 DI 10.1212/WNL.0b013e3181a18674 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 463VP UT WOS:000267461000005 PM 19321847 ER PT J AU Zhu, XP El Fakhri, G AF Zhu, Xuping El Fakhri, Georges TI Monte Carlo modeling of cascade gamma rays in Y-86 PET imaging: preliminary results SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID YTTRIUM-86; RADIATION; I-124; BR-76; 2D AB Y-86 is a PET agent that could be used as an ideal surrogate to allow personalized dosimetry in Y-90 radionuclide therapy. However, Y-86 also emits cascade gamma rays. We have developed a Monte Carlo program based on SimSET (Simulation System for Emission Tomography) to model cascade gamma rays in PET imaging. The new simulation was validated with the GATE simulation package. Agreements within 15% were found in spatial resolution, apparent scatter fraction (ratio of coincidences outside peak regions in line source sinograms), single and coincidence statistics and detected photons energy distribution within the PET energy window. A discrepancy of 20% was observed in the absolute scatter fraction, likely caused by differences in the tracking of higher energy cascade gamma photons. On average, the new simulation is 6 times faster than GATE, and the computing time can be further improved by using variance reduction techniques currently available in SimSET. Comparison with phantom acquisitions showed agreements in spatial resolutions and the general shape of projection profiles; however, the standard scatter correction method on the scanner is not directly applicable to Y-86 PET as it leads to incorrect scatter fractions. The new simulation was used to characterize Y-86 PET. Compared with conventional F-18 PET, in which major contamination at low count rates comes from scattered events, cascade gamma-involved events are more important in Y-86 PET. The two types of contaminations have completely different distribution patterns, which should be considered for the corrections of their effects. Our approach will be further improved in the future in the modeling of random coincidences and tracking of high-energy photons, and simulation results will be used for the development of correction methods in Y-86 PET. C1 [Zhu, Xuping] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Zhu, XP (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM xzhu4@Partners.org; elfakhri@pet.mgh.harvard.edu FU NIH [R21-CA134812]; Society of Nuclear Medicine Pilot Research Grant FX This work is supported by NIH grant R21-CA134812 and a Society of Nuclear Medicine Pilot Research Grant. NR 16 TC 4 Z9 4 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2009 VL 54 IS 13 BP 4181 EP 4193 DI 10.1088/0031-9155/54/13/014 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 459UW UT WOS:000267137200014 PM 19521011 ER PT J AU Shackelford, DB Vasquez, DS Corbeil, J Wu, SL Leblanc, M Wu, CL Vera, DR Shaw, RJ AF Shackelford, David B. Vasquez, Debbie S. Corbeil, Jacqueline Wu, Shulin Leblanc, Mathias Wu, Chin-Lee Vera, David R. Shaw, Reuben J. TI mTOR and HIF-1 alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AMPK; FDG-PET; glycolysis; hamartoma; polyposis ID TUBEROUS SCLEROSIS COMPLEX; GROWTH-FACTOR EXPRESSION; CELL-GROWTH; MAMMALIAN TARGET; STK11 DELETIONS; MESSENGER-RNA; CANCER-CELLS; RAPAMYCIN; POLYPOSIS; KINASE AB Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/STK11 serine/threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice. Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/- mice. However, the key targets of mTORC1 in LKB1-deficient tumors remain unknown. We demonstrate here that these polyps, and LKB1- and AMPK-deficient mouse embryonic fibroblasts, show dramatic up-regulation of the HIF-1 alpha transcription factor and its downstream transcriptional targets in an rapamycin-suppressible manner. The HIF-1 alpha targets hexokinase II and Glut1 are up-regulated in these polyps, and using FDG-PET, we demonstrate that LKB1+/- mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal hamartomas. Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1 alpha, and GLUT1 levels. Furthermore, like HIF-1 alpha and its target genes, the FDG-PET signal in the GI tract of these mice is abolished by rapamycin treatment. These findings suggest a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients, and potential for the screening and treatment of the 30% of sporadic human lung cancers bearing LKB1 mutations. C1 [Shackelford, David B.; Vasquez, Debbie S.; Leblanc, Mathias; Shaw, Reuben J.] Salk Inst Biol Studies, Dulbecco Ctr Canc Res, La Jolla, CA 92037 USA. [Shackelford, David B.; Vasquez, Debbie S.; Shaw, Reuben J.] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA. [Corbeil, Jacqueline; Vera, David R.] Univ Calif San Diego, Moores Canc Ctr, Mol Imaging Program, Dept Radiol, La Jolla, CA 92093 USA. [Wu, Shulin; Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Wu, Shulin; Wu, Chin-Lee] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Shaw, RJ (reprint author), Salk Inst Biol Studies, Dulbecco Ctr Canc Res, La Jolla, CA 92037 USA. EM shaw@salk.edu FU National Institutes of Health [P01 CA120964]; National Cancer Institute [P50 CA128346]; American Cancer Society; V Foundation for Cancer Research; [T32 CA009370] FX We thank Lauri Aaltonen and Sini Marttinen (Biomedicum Helsinki, Helsinki) for the Finnish Peutz-Jeghers patient samples, Keith Laderoute (SRI International, Menlo Park, CA) and Benoit Viollet (Institut Cochin, Paris) for their generous donation of the isogenic SV40-immortalized wild-type and AMPKa1/a2 double deficient MEFs, and Dr. Carl Ho (University of California San Diego, La Jolla, CA) for his assistance in analyzing the FDG-PET data. We thank Katja Lamia for critical reading of the manuscript. This work was supported in part from grants from the National Institutes of Health (P01 CA120964 to R. J. S. and C.- L. W.), National Cancer Institute (P50 CA128346 to D. R. V.), American Cancer Society (R. J. S.), and V Foundation for Cancer Research (R. J. S). D. B. S. was supported by training grant T32 CA009370 to the Salk Institute Center for Cancer Research. NR 59 TC 102 Z9 106 U1 4 U2 12 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 JUL 7 PY 2009 VL 106 IS 27 BP 11137 EP 11142 DI 10.1073/pnas.0900465106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468DX UT WOS:000267796100050 PM 19541609 ER PT J AU He, CW Qu, XY Cui, LB Wang, JD Kang, JX AF He, Chengwei Qu, Xiying Cui, Libin Wang, Jingdong Kang, Jing X. TI Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cognitive function; omega-3 fatty acids; transgenic fat-1 mice; neural stem cells ID POLYUNSATURATED FATTY-ACIDS; PROLIFERATOR-ACTIVATED RECEPTOR; RETINOID-X-RECEPTOR; GENE-EXPRESSION; IN-VITRO; NEURONAL DIFFERENTIATION; ADULT NEUROGENESIS; ARACHIDONIC-ACID; DENTATE GYRUS; GRANULE CELLS AB Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LC-PUFA), highly enriched in the central nervous system, is critical for brain development and function. It has been shown that DHA deficiency impairs cognitive performance whereas DHA supplementation improves the condition. However, the mechanisms underlying the role of DHA in brain development and function remain to be elucidated. By using transgenic fat-1 mice rich in endogenous n-3 PUFA, we show that increased brain DHA significantly enhances hippocampal neurogenesis shown by an increased number of proliferating neurons and neuritogenesis, evidenced by increased density of dendritic spines of CA1 pyramidal neurons in the hippocampus. Concurrently, fat-1 mice exhibit a better spatial learning performance in the Morris water maze compared with control WT littermates. In vitro experiments further demonstrate that DHA promotes differentiation and neurite outgrowth of neuronal cells derived from mouse ES cells and increases the proliferation of cells undergoing differentiation into neuronal lineages from the ES cells. These results together provide direct evidence for a promoting effect of DHA on neurogenesis and neuritogenesis and suggest that this effect may be a mechanism underlying its beneficial effect on behavioral performance. C1 [He, Chengwei; Qu, Xiying; Wang, Jingdong; Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Charlestown, MA 02129 USA. [Cui, Libin] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Cui, Libin] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kang, JX (reprint author), Massachusetts Gen Hosp, Dept Med, 149 13th St,Room 4433, Charlestown, MA 02129 USA. EM kang.jing@mgh.harvard.edu FU National Institutes of Health [CA113605] FX We thank Dr. Alexander Leaf for critically reviewing the manuscript, Anna Kreshock for histopathology services, Piet Habbel for assistance in the analysis of neurite, and Zerong You and Jinsheng Yang for technical assistance in Morris water maze test. This work was partially supported by National Institutes of Health Grant CA113605. NR 40 TC 98 Z9 108 U1 5 U2 14 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 JUL 7 PY 2009 VL 106 IS 27 BP 11370 EP 11375 DI 10.1073/pnas.0904835106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468DX UT WOS:000267796100090 PM 19549874 ER PT J AU Park, SM Kim, SY Earle, CC Jeong, SY Yun, YH AF Park, Sang Min Kim, Sun-Young Earle, Craig C. Jeong, Seung-Yong Yun, Young Ho TI What is the most cost-effective strategy to screen for second primary colorectal cancers in male cancer survivors in Korea? SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Cost-effectiveness; Second primary colorectal cancer; Screening; Cancer survivor ID CONTRAST BARIUM ENEMA; SURVEILLANCE GUIDELINES; ENDOSCOPIC PERFORATION; RISK; COLONOSCOPY; POLYPS; COLON; POPULATION; SOCIETY; RECTUM AB AIM: To identify a cost-effective strategy of second primary colorectal cancer (CRC) screening for cancer survivors in Korea using a decision-analytic model. METHODS: A Markov model estimated the clinical and economic consequences of a simulated 50-year-old male cancer survivors' cohort, and we compared the results of eight screening strategies: no screening, fecal occult blood test (FOBT) annually, FOBT every 2 years, sigmoidoscopy every 5 years, double contrast barium enema every 5 years, and colonoscopy every 10 years (COL10), every 5 years (COL5), and every 3 years (COL3). We included only direct medical costs, and our main outcome measures were discounted lifetime costs, life expectancy, and incremental cost-effectiveness ratio (ICER). RESULTS: In the base-case analysis, the non-dominated strategies in cancer survivors were COL5, and COL3. The ICER for COL3 in cancer survivors was $5593/life-year saved (LYS), and did not exceed $10000/LYS in one-way sensitivity analyses. If the risk of CRC in cancer survivors is at least two times higher than that in the general population, COL5 had an ICER of less than $10500/LYS among both good and poor prognosis of index cancer. If the age of cancer survivors starting CRC screening was decreased to 40 years, the ICER of COL5 was less than $7400/LYS regardless of screening compliance. CONCLUSION: Our study suggests that more strict and frequent recommendations for colonoscopy such as COL5 and COL3 could be considered as economically reasonable second primary CRC screening strategies for Korean male cancer survivors. (C) 2009 The WIG Press and Baishideng. All rights reserved. C1 [Yun, Young Ho] Natl Canc Ctr, Div Canc Control, Goyang 411769, Gyeonggi Do, South Korea. [Park, Sang Min] Seoul Natl Univ, Coll Med, Dept Family Med, Seoul Natl Univ Hosp, Seoul 110799, South Korea. [Park, Sang Min] Harvard Univ, Sch Publ Hlth, Dept Populat & Int Hlth, Boston, MA 02115 USA. [Park, Sang Min] Natl Canc Ctr, Div Canc Control, Goyang, Gyeonggi, South Korea. [Kim, Sun-Young] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Program Hlth Decis Sci, Boston, MA 02115 USA. [Earle, Craig C.] Harvard Univ, Dana Farber Canc Inst, Div Populat Sci, Dept Med Oncol,Med Sch, Boston, MA 02108 USA. [Jeong, Seung-Yong] Seoul Natl Univ, Coll Med, Dept Surg, Seoul Natl Univ Hosp, Seoul 110799, South Korea. RP Yun, YH (reprint author), Natl Canc Ctr, Div Canc Control, 809 Madu Dong, Goyang Si 411769, Gyeonggi Do, South Korea. EM lawyun08@ncc.re.kr RI Yun, Young Ho/J-5560-2012; Park, Sang Min/J-5484-2012; Jeong, Seung-Yong/J-5643-2012 FU Harvard School of Public Health; National Cancer Center [07104221] FX Supported by Takemi Program in International Health at Harvard School of Public Health and by National Cancer Center Grant, No. 07104221 NR 46 TC 4 Z9 6 U1 0 U2 3 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 7 PY 2009 VL 15 IS 25 BP 3153 EP 3160 DI 10.3748/wjg.15.3153 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 468YT UT WOS:000267861500011 PM 19575496 ER PT J AU Mao, YD Sun, QM Wang, XF Ouyang, Q Han, L Jiang, L Han, D AF Mao, Youdong Sun, Quanmei Wang, Xiufeng Ouyang, Qi Han, Li Jiang, Lei Han, Dong TI In vivo nanomechanical imaging of blood-vessel tissues directly in living mammals using atomic force microscopy SO APPLIED PHYSICS LETTERS LA English DT Article ID CELLS; STRESS; STIFFNESS; MECHANICS; NETWORKS AB Atomic force microscopy (AFM) is difficult to achieve in living mammals but is necessary for understanding mechanical properties of tissues in their native form in organisms. Here we report in vivo nanomechanical imaging of blood-vessel tissues directly in living mammalians by AFM combined with surgical operations. Nanomechanical heterogeneity of blood vessels is observed across the diverse microenvironments of the same tissues in vivo. This method is further used to measure the counteractive nanomechanical changes in real time during drug-induced vasodilation and vasoconstriction in vivo, demonstrating appealing potential in characterization of in vivo nanomechanical dynamics of native tissues. (C) 2009 American Institute of Physics. [DOI:10.1063/1.3167546] C1 [Mao, Youdong; Sun, Quanmei; Han, Dong] Natl Ctr Nanosci & Technol, Beijing 100080, Peoples R China. [Mao, Youdong] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Mao, Youdong] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Wang, Xiufeng] Tsinghua Univ, Dept Phys, Beijing 100084, Peoples R China. [Ouyang, Qi] Peking Univ, Sch Phys, Beijing 100871, Peoples R China. [Han, Li] Chinese Acad Sci, Inst Elect Engn, Beijing 100190, Peoples R China. [Jiang, Lei] Chinese Acad Sci, Inst Chem, Beijing 100190, Peoples R China. RP Han, D (reprint author), Natl Ctr Nanosci & Technol, Beijing 100080, Peoples R China. EM jianglei@iccas.ac.cn; dhan@nanoctr.cn RI jiang, lei/E-8437-2010; Jiang, Lei/B-1066-2011 FU National Science Foundation of China [90709054]; Ministry of Science and Technology of China [2006CB705600, 2009CB930200] FX We thank J.H. Wang, L. Chen, and P. Chen for their assistance during experiment. This work was supported by the National Science Foundation of China (Grant No. 90709054) and the project of 973 in Ministry of Science and Technology of China (Grant Nos. 2006CB705600 and 2009CB930200). NR 15 TC 22 Z9 27 U1 7 U2 31 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD JUL 6 PY 2009 VL 95 IS 1 AR 013704 DI 10.1063/1.3167546 PG 3 WC Physics, Applied SC Physics GA 470NV UT WOS:000267983200102 ER PT J AU Bienvenu, OJ Wang, Y Shugart, YY Welch, JM Grados, MA Fyer, AJ Rauch, SL McCracken, JT Rasmussen, SA Murphy, DL Cullen, B Valle, D Hoehn-Saric, R Greenberg, BD Pinto, A Knowles, JA Piacentini, J Pauls, DL Liang, KY Willour, VL Riddle, M Samuels, JF Feng, G Nestadt, G AF Bienvenu, O. J. Wang, Y. Shugart, Y. Y. Welch, J. M. Grados, M. A. Fyer, A. J. Rauch, S. L. McCracken, J. T. Rasmussen, S. A. Murphy, D. L. Cullen, B. Valle, D. Hoehn-Saric, R. Greenberg, B. D. Pinto, A. Knowles, J. A. Piacentini, J. Pauls, D. L. Liang, K. Y. Willour, V. L. Riddle, M. Samuels, J. F. Feng, G. Nestadt, G. TI Sapap3 and Pathological Grooming in Humans: Results From the OCD Collaborative Genetics Study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genes; Dlgap3; obsessive-compulsive disorder; nail biting; trichotillomania ID OBSESSIVE-COMPULSIVE DISORDER; SPECTRUM DISORDERS; PEDIATRIC PROBANDS; ANXIETY DISORDERS; TRANSPORTER GENE; LINKAGE ANALYSIS; MESSENGER-RNA; TRICHOTILLOMANIA; FAMILY; ASSOCIATION AB SAP90/PSD95-associated protein (SAPAP) family proteins are post-synaptic density (PSD) components that interact with other proteins to form a key scaffolding complex at excitatory (glutamatergic) synapses. A recent study found that mice with a deletion of the Sapap3 gene groomed themselves excessively, exhibited increased anxiety-like behaviors, and had cortico-striatal synaptic defects, all of which were preventable with lentiviral-mediated expression of Sapap3 in the striatum; the behavioral abnormalities were also reversible with fluoxetine. In the current study, we sought to determine whether variation within the human Sapap3 gene was associated with grooming disorders (GDs: pathologic nail biting, pathologic skin picking, and/or trichotillomania) and/or obsessive-compulsive disorder (OCD) in 383 families thoroughly phenotyped for OCD genetic studies. We conducted family-based association analyses using the FBAT and GenAssoc statistical packages. Thirty-two percent of the 1,618 participants met criteria for a GD, and 65% met criteria for OCD. Four of six SNPs were nominally associated (P < 0.05) with at least one GD (genotypic relative risks: 1.6-3.3), and all three haplotypes were nominally associated with at least one GD (permuted P < 0.05). None of the SNPs or haplotypes were significantly associated with OCD itself. We conclude that Sapap3 is a promising functional candidate gene for human GDs, though further work is necessary to confirm this preliminary evidence of association. (C) 2008 Wiley-Liss, Inc. C1 [Bienvenu, O. J.; Wang, Y.; Grados, M. A.; Cullen, B.; Hoehn-Saric, R.; Willour, V. L.; Riddle, M.; Samuels, J. F.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Shugart, Y. Y.] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Welch, J. M.; Feng, G.] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. [Fyer, A. J.; Knowles, J. A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Fyer, A. J.; Knowles, J. A.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Rauch, S. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, S. L.; Pauls, D. L.] Harvard Univ, Sch Med, Boston, MA USA. [McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles Sch Med, Los Angeles, CA 90024 USA. [Rasmussen, S. A.; Greenberg, B. D.; Pinto, A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Valle, D.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. [Pauls, D. L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Liang, K. Y.] Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. RP Bienvenu, OJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 600 N Wolfe St,Meyer 115, Baltimore, MD 21287 USA. EM jbienven@jhmi.edu RI Piacentini, John/C-4645-2011; Citations, TLC SAB/C-4006-2011; Liang, Kung-Yee/F-8299-2011; Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU NIH [MH50125, RR00052, NS42609, MH64543, MH66284] FX NIH grants MH50125, RR00052, NS42609, MH64543, and MH66284 supported this study. The authors thank the many families who have participated in the OCD Collaborative Genetics Study (OCGS); the Obsessive-Compulsive Foundation; Ann Pulver, PhD, Kathleen Merikangas, PhD, David Houseman, MD, and Alec Wilson, PhD, for consultation; and clinicians and coordinators at each OCGS site: Providence (Maria Mancebo, PhD, Richard Marsland, RN, and Shirley Yen, PhD); New York (Renee Goodwin, PhD, Joshua Lipsitz, PhD, and Jessica Page, PsyD); Baltimore (Laura Eisen, BS, Karan Lamb, PsyD, Tracey Lichner, PhD, Yung-mei Leong, PhD, and Krista Vermillion, BA); Boston (Dan Geller, MD, Anne Chosak, PhD, Michelle Wedig, BS, Evelyn Stewart, MD, Michael Jenike, MD, Beth Gershuny, PhD, and Sabine Wilhelm, PhD); Bethesda (Lucy Justement, Diane Kazuba, V. Holland LaSalle-Ricci, and Theresa B. DeGuzman); and Los Angeles (R. Lindsey Bergman, PhD, Susanna Chang, PhD, Audra Langley, PhD, and Amanda Pearlman, BA). NR 63 TC 70 Z9 75 U1 2 U2 12 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL 5 PY 2009 VL 150B IS 5 BP 710 EP 720 DI 10.1002/ajmg.b.30897 PG 11 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 464BZ UT WOS:000267481100010 PM 19051237 ER PT J AU Doyle, AE Ferreira, MAR Sklar, PB Lasky-Su, J Petty, C Fusillo, SJ Seidman, LJ Willcutt, EG Smoller, JW Purcel, S Biederman, J Faraone, SV AF Doyle, Alysa E. Ferreira, Manuel A. R. Sklar, Pamela B. Lasky-Su, Jessica Petty, Carter Fusillo, Steven J. Seidman, Larry J. Willcutt, Erik G. Smoller, Jordan W. Purcel, Shaun Biederman, Joseph Faraone, Stephen V. TI Multivariate Genomewide Linkage Scan of Neurocognitive Traits and ADHD Symptoms: Suggestive Linkage to 3q13 (vol 147B, pg 1399, 2008) SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Correction C1 [Doyle, Alysa E.; Petty, Carter; Fusillo, Steven J.; Seidman, Larry J.; Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. [Doyle, Alysa E.; Ferreira, Manuel A. R.; Sklar, Pamela B.; Smoller, Jordan W.; Purcel, Shaun] Massachusetts Gen Hosp, Psychiat & Neurodevel Genet Unit, Boston, MA 02114 USA. [Doyle, Alysa E.; Ferreira, Manuel A. R.; Sklar, Pamela B.; Seidman, Larry J.; Smoller, Jordan W.; Purcel, Shaun; Biederman, Joseph] Harvard Univ, Sch Med, Boston, MA USA. [Ferreira, Manuel A. R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Lasky-Su, Jessica] Brigham & Womens Hosp, Channing Labs, Boston, MA 02115 USA. [Seidman, Larry J.] Div Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr Publ Psychiat, Boston, MA USA. [Willcutt, Erik G.] Univ Colorado, Boulder, CO 80309 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Neurosci & Physiol, Syracuse, NY USA. RP Doyle, AE (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL 5 PY 2009 VL 150B IS 5 BP 751 EP 751 DI 10.1002/ajmg.b.30997 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 464BZ UT WOS:000267481100015 ER PT J AU Mega, JL Braunwald, E Mohanavelu, S Burton, P Poulter, R Misselwitz, F Hricak, V Barnathan, ES Bordes, P Witkowski, A Markov, V Oppenheimer, L Gibson, CM AF Mega, J. L. Braunwald, E. Mohanavelu, S. Burton, P. Poulter, R. Misselwitz, F. Hricak, V. Barnathan, E. S. Bordes, P. Witkowski, A. Markov, V. Oppenheimer, L. Gibson, C. M. CA ATLAS ACS-TIMI 46 Study Grp TI Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial SO LANCET LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; TOTAL KNEE ARTHROPLASTY; ANTITHROMBOTIC THERAPY; HIP-ARTHROPLASTY; UNSTABLE ANGINA; LONG-TERM; ASPIRIN; WARFARIN; ENOXAPARIN; THROMBOPROPHYLAXIS AB Background Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. Methods In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. Findings Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% Cl 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). Interpretation The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. C1 [Mega, J. L.; Braunwald, E.] Harvard Univ, Div Cardiovasc, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Mega, J. L.; Braunwald, E.; Mohanavelu, S.] TIMI Study Grp, Boston, MA USA. [Burton, P.; Barnathan, E. S.; Oppenheimer, L.] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. [Poulter, R.] Univ Queensland, Royal Brisbane Hosp, Herston, Qld, Australia. [Misselwitz, F.] Bayer HealthCare, Wuppertal, Germany. [Hricak, V.] Natl Heart Inst, Bratislava, Slovakia. [Bordes, P.] Hosp Gen Univ Alicante, Alicante, Spain. [Witkowski, A.] Inst Cardiol, Warsaw, Poland. [Markov, V.] State Inst Res Cardiol Inst, Tomsk, Russia. [Gibson, C. M.] Harvard Univ, Sch Med, Beth Israel Hosp, Div Cardiovasc, Boston, MA USA. RP Mega, JL (reprint author), Harvard Univ, Div Cardiovasc, Brigham & Womens Hosp, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM jmega@partners.org RI Walters, Darren/A-7069-2011; Sinkiewicz, Wladyslaw/G-5169-2014; Ponikowski, Piotr/O-6454-2015 OI Ponikowski, Piotr/0000-0002-3391-7064 FU Johnson & Johnson Pharmaceutical Research Development; Bayer Healthcare AG FX This study is supported by research grants from Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG. NR 22 TC 219 Z9 228 U1 1 U2 29 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 JUL 4 PY 2009 VL 374 IS 9683 BP 29 EP 38 DI 10.1016/S0140-6736(09)60738-8 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 467UO UT WOS:000267768800031 ER PT J AU Adamovich, DA Nakamura, F Worth, A Burns, S Thrasher, AJ Hartwig, JH Snapper, SB AF Adamovich, David A. Nakamura, Fumihiko Worth, Austen Burns, Siobhan Thrasher, Adrian J. Hartwig, John H. Snapper, Scott B. TI Activating mutations of N-WASP alter Shigella pathogenesis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE N-WASP; Shigella; Actin tails; Bacterial pathogenesis; Autophagy; Actin polymerization ID ACTIN-BASED MOTILITY; ALDRICH-SYNDROME PROTEIN; CONGENITAL NEUTROPENIA; ARP2/3 COMPLEX; FLEXNERI; PHOSPHORYLATION; POLYMERIZATION; AUTOINHIBITION; CELLS AB The pathogenesis of Shigella requires binding to the host protein N-WASP. To examine the roles of structural conformation and phospho-regulation of N-WASP during Shigello pathogenesis, mutant N-WASP constructs predicted to result in a constitutively open conformation (L229P and L232P) or either a phospho-mimicking (Y253E) or phospho-disruptive (Y253F) Structure were constructed. Pyrene actin assays demonstrated that the N-WASP L229P and L232P constructs are Constitutively active. Despite the increase in actin polymerization seen in vitro, cell lines expressing N-WASP L229P and L232P Supported shorter actin tails when infected with Shigella. Shigella actin tails were unchanged in cells expressing N-WASP phospho-regulation mutant proteins. Shigella invasion, intracellular, and intercellular motility were not altered in cells expressing N-WASP L229P or L232P. However, plaque numbers were increased in cells expressing N-WASP L229P and L232P. These data demonstrate that N-WASP Structural conformation is an important regulator of Shigella pathogenesis in distinct segments of its lifecycle. (C) 2009 Elsevier Inc. All rights reserved C1 [Adamovich, David A.; Snapper, Scott B.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Nakamura, Fumihiko; Hartwig, John H.; Snapper, Scott B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Nakamura, Fumihiko; Hartwig, John H.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Worth, Austen; Burns, Siobhan; Thrasher, Adrian J.] UCL, Mol Immunol Unit, Inst Child Hlth, London WC1N 1EH, England. [Adamovich, David A.] Harvard Univ, Sch Med, Biol & Biomed Sci Grad Program, Boston, MA 02115 USA. RP Snapper, SB (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. EM ssnapper@hms.harvard.edu RI Nakamura, Fumihiko/N-5476-2016 FU NIH [5R01 AI052354, 5P01 HL59561] FX This work was supported by NIH 5R01 AI052354 and 5P01 HL59561 to S.B.S. NR 23 TC 6 Z9 6 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 JUL 3 PY 2009 VL 384 IS 3 BP 284 EP 289 DI 10.1016/j.bbrc.2009.04.050 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 453XY UT WOS:000266647400003 PM 19379711 ER PT J AU Carnemolla, A Fossale, E Agostoni, E Michelazzi, S Calligaris, R De Maso, L Del Sal, G MacDonald, ME Persichetti, F AF Carnemolla, Alisia Fossale, Elisa Agostoni, Elena Michelazzi, Silvia Calligaris, Raffaella De Maso, Luca Del Sal, Giannino MacDonald, Marcy E. Persichetti, Francesca TI Rrs1 Is Involved in Endoplasmic Reticulum Stress Response in Huntington Disease SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KNOCK-IN MICE; PROTEIN L11-BINDING PROTEIN; CAG REPEAT INSTABILITY; 5S RIBOSOMAL-RNA; SACCHAROMYCES-CEREVISIAE; CELL-DEATH; NEURODEGENERATIVE DISEASE; NUCLEAR-ENVELOPE; GENE-EXPRESSION; ER STRESS AB The induction of Rrs1 expression is one of the earliest events detected in a presymptomatic knock-in mouse model of Huntington disease (HD). Rrs1 up-regulation fulfills the HD criteria of dominance, striatal specificity, and polyglutamine dependence. Here we show that mammalian Rrs1 is localized both in the nucleolus as well as in the endoplasmic reticulum ( ER) of neurons. This dual localization is shared with its newly identified molecular partner 3D3/lyric. We then show that both genes are induced by ER stress in neurons. Interestingly, we demonstrate that ER stress is an early event in a presymptomatic HD mouse model that persists throughout the life span of the rodent. We further show that ER stress also occurs in postmortem brains of HD patients. C1 [Carnemolla, Alisia; Agostoni, Elena; Michelazzi, Silvia; Calligaris, Raffaella; De Maso, Luca; Persichetti, Francesca] Scuola Int Super Studi Avanzati, Sector Neurobiol, I-34151 Trieste, Italy. [Fossale, Elisa; MacDonald, Marcy E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Del Sal, Giannino] Area Sci Pk Padriciano, Lab Nazl CIB, I-34149 Trieste, Italy. [Del Sal, Giannino] Univ Trieste, Dipartimento Sci Vita, I-34127 Trieste, Italy. RP Persichetti, F (reprint author), Univ Piemonte Orientale, Dipartimento Sci Ambiente & Vita, Alessandria, Italy. EM persiche@sissa.it OI DEL SAL, GIANNINO/0000-0003-2185-6003 FU Telethon Foundation of Italy [GGP06264]; Italian Government; Comitato Interministerale per la Programmazione Economica/Friuli Venezia Giulia, Italy FX This work was supported by Telethon Foundation of Italy Grant GGP06264, by the Italian Government ( Brain Gain Program, Ministero dell'Istruzione, dell'Universita e della Ricerca), and by Comitato Interministerale per la Programmazione Economica/Friuli Venezia Giulia, Italy Grant GRAND. NR 32 TC 57 Z9 57 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 JUL 3 PY 2009 VL 284 IS 27 BP 18167 EP 18173 DI 10.1074/jbc.M109.018325 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 467BW UT WOS:000267712400028 PM 19433866 ER PT J AU Abdel-Wahab, O Mullally, A Hedvat, C Garcia-Manero, G Patel, J Wadleigh, M Malinge, S Yao, JJ Kilpivaara, O Bhat, R Huberman, K Thomas, S Dolgalev, I Heguy, A Paietta, E Le Beau, MM Beran, M Tallman, MS Ebert, BL Kantarjian, HM Stone, RM Gilliland, DG Crispino, JD Levine, RL AF Abdel-Wahab, Omar Mullally, Ann Hedvat, Cyrus Garcia-Manero, Guillermo Patel, Jay Wadleigh, Martha Malinge, Sebastien Yao, JinJuan Kilpivaara, Outi Bhat, Rukhmi Huberman, Kety Thomas, Sabrena Dolgalev, Igor Heguy, Adriana Paietta, Elisabeth Le Beau, Michelle M. Beran, Miloslav Tallman, Martin S. Ebert, Benjamin L. Kantarjian, Hagop M. Stone, Richard M. Gilliland, D. Gary Crispino, John D. Levine, Ross L. TI Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies SO BLOOD LA English DT Article ID TYROSINE KINASE JAK2; ACTIVATING MUTATION; POLYCYTHEMIA-VERA; MYELOPROLIFERATIVE DISORDERS; ESSENTIAL THROMBOCYTHEMIA; HIGH-THROUGHPUT; LEUKEMIA; SEQUENCE; MYELOFIBROSIS; METAPLASIA AB Disease alleles that activate signal transduction are common in myeloid malignancies; however, there are additional unidentified mutations that contribute to myeloid transformation. Based on the recent identification of TET2 mutations, we evaluated the mutational status of TET1, TET2, and TET3 in myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Sequencing of TET2 in 408 paired tumor/normal samples distinguished between 68 somatic mutations and 6 novel single nucleotide polymorphisms and identified TET2 mutations in MPN (27 of 354, 7.6%), CMML (29 of 69, 42%), AML (11 of 91, 12%), and M7 AML (1 of 28, 3.6%) samples. We did not identify somatic TET1 or TET3 mutations or TET2 promoter hypermethylation in MPNs. TET2 mutations did not cluster in genetically defined MPN, CMML, or AML subsets but were associated with decreased overall survival in AML (P = .029). These data indicate that TET2 mutations are observed in different myeloid malignancies and may be important in AML prognosis. (Blood. 2009; 114:144-147) C1 [Abdel-Wahab, Omar; Patel, Jay; Kilpivaara, Outi; Huberman, Kety; Thomas, Sabrena; Dolgalev, Igor; Heguy, Adriana; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Abdel-Wahab, Omar; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, Dept Med, New York, NY 10065 USA. [Mullally, Ann; Wadleigh, Martha; Stone, Richard M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mullally, Ann; Ebert, Benjamin L.; Gilliland, D. Gary] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Hedvat, Cyrus; Yao, JinJuan] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Garcia-Manero, Guillermo; Beran, Miloslav; Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Malinge, Sebastien; Bhat, Rukhmi; Tallman, Martin S.; Crispino, John D.] Northwestern Univ, Div Hematol Oncol, Feinberg Sch Med, Chicago, IL 60611 USA. [Paietta, Elisabeth] New York Med Coll, Montefiore Med Ctr, North Div, New York, NY USA. [Le Beau, Michelle M.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Ebert, Benjamin L.; Gilliland, D. Gary] Harvard Stem Cell Inst, Boston, MA USA. [Ebert, Benjamin L.] Harvard & Massachusetts Inst Technol, Broad Inst, Boston, MA USA. [Gilliland, D. Gary] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Levine, RL (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave,Box 20, New York, NY 10065 USA. EM leviner@mskcc.org OI HEDVAT, CYRUS/0000-0003-0045-3491; Dolgalev, Igor/0000-0003-4451-126X; Yao, JinJuan/0000-0003-4692-9969; Abdel-Wahab, Omar/0000-0002-3907-6171; Crispino, John/0000-0002-8182-8306 FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA101774-07, CA10863101, R01 CA101774, U10 CA021115, U24 CA114737]; NHLBI NIH HHS [HL082677, K08 HL082677] NR 22 TC 322 Z9 332 U1 1 U2 26 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 JUL 2 PY 2009 VL 114 IS 1 BP 144 EP 147 DI 10.1182/blood-2009-03-210039 PG 4 WC Hematology SC Hematology GA 468CA UT WOS:000267789800022 PM 19420352 ER PT J AU Desmedt, C Giobbie-Hurder, A Neven, P Paridaens, R Christiaens, MR Smeets, A Lallemand, F Haibe-Kains, B Viale, G Gelber, RD Piccart, M Sotiriou, C AF Desmedt, Christine Giobbie-Hurder, Anita Neven, Patrick Paridaens, Robert Christiaens, Marie-Rose Smeets, Ann Lallemand, Francoise Haibe-Kains, Benjamin Viale, Giuseppe Gelber, Richard D. Piccart, Martine Sotiriou, Christos TI The Gene expression Grade Index: a potential predictor of relapse for endocrine-treated breast cancer patients in the BIG 1-98 trial SO BMC MEDICAL GENOMICS LA English DT Article ID POSTMENOPAUSAL WOMEN; ADJUVANT TAMOXIFEN; RANDOMIZED-TRIAL; LETROZOLE; ANASTROZOLE AB Background: We have previously shown that the Gene expression Grade Index (GGI) was able to identify two subtypes of estrogen receptor (ER)-positive tumors that were associated with statistically distinct clinical outcomes in both untreated and tamoxifen-treated patients. Here, we aim to investigate the ability of the GGI to predict relapses in postmenopausal women who were treated with tamoxifen (T) or letrozole (L) within the BIG 1-98 trial. Methods: We generated gene expression profiles (Affymetrix) and computed the GGI for a matched, case-control sample of patients enrolled in the BIG 1-98 trial from the two hospitals where frozen samples were available. All relapses (cases) were identified from patients randomized to receive monotherapy or from the switching treatment arms for whom relapse occurred before the switch. Each case was randomly matched with four controls based upon nodal status and treatment (T or L). The prognostic value of GGI was assessed as a continuous predictor and divided at the median. Predictive accuracy of GGI was estimated using time-dependent area under the curve (AUC) of the ROC curves. Results: Frozen samples were analyzable for 48 patients (10 cases and 38 controls). Seven of the 10 cases had been assigned to receive L. Cases and controls were comparable with respect to menopausal and nodal status, local and chemotherapy, and HER2 positivity. Cases were slightly older than controls and had a larger proportion of large, poorly differentiated ER+/PgR- tumors. The GGI was significantly and linearly related to risk of relapse: each 10-unit increase in GGI resulted in an increase of approximately 11% in the hazard rate (p = 0.02). Within the subgroups of patients with node-positive disease or who were treated with L, the hazard of relapse was significantly greater for patients with GGI at or above the median. AUC reached a maximum of 78% at 27 months. Conclusion: This analysis supports the GGI as a good predictor of relapse for ER-positive patients, even among patients who receive L. Validation of these results, in a larger series from BIG 1-98, is planned using the simplified GGI represented by a smaller set of genes and tested by qRT-PCR on paraffin-embedded tissues. C1 [Desmedt, Christine; Lallemand, Francoise; Haibe-Kains, Benjamin; Piccart, Martine; Sotiriou, Christos] Univ Libre Bruxelles, Inst Jules Bordet, Brussels, Belgium. [Neven, Patrick; Paridaens, Robert; Christiaens, Marie-Rose; Smeets, Ann] Katholieke Univ Leuven, UZ Gasthuisberg, Leuven, Belgium. [Viale, Giuseppe] European Inst Oncol, Milan, Italy. [Gelber, Richard D.] Harvard Univ, Sch Publ Hlth, Frontier Sci & Technol Res Fdn, IBCSG Stat Ctr,Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sotiriou, C (reprint author), Univ Libre Bruxelles, Inst Jules Bordet, Brussels, Belgium. EM christine.desmedt@bordet.be; agiohur@jimmy.harvard.edu; patrick.neven@uz.kuleuven.ac.be; robert.paridaens@uz.kuleuven.ac.be; marie-rose.christiaens@uz.kuleuven.ac.be; anne.smeets@uz.kuleuven.ac.be; francoise.lallemand@bordet.be; bhaibeka@ulb.ac.be; giuseppe.viale@ieo.it; gelber@jimmy.harvard.edu; martine.piccart@bordet.be; christos.sotiriou@bordet.be RI Haibe-Kains, Benjamin/D-3702-2011; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Desmedt, Christine/0000-0002-5223-5579 FU Breast Cancer Research Foundation; Belgian Federation Against Cancer; Belgian Foundation for Scientific Research FNRS; Novartis; National Cancer Institute [CA-75362] FX This work was supported, in part, by the Breast Cancer Research Foundation, by the Belgian Federation Against Cancer, by the Belgian Foundation for Scientific Research FNRS (C.D. and C.S.). The BIG 1-98 trial was sponsored by Novartis and coordinated by IBCSG. The IBCSG Statistical Center is partially supported by National Cancer Institute Grant CA-75362 (R.D.G. and A.G.-H.). We thank the BIG 1-98 Collaborative Group and International Breast Cancer Study Group (IBCSG), Bern, Switzerland, for their collaboration. NR 16 TC 41 Z9 41 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD JUL 2 PY 2009 VL 2 AR 40 DI 10.1186/1755-8794-2-40 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 533GY UT WOS:000272812900001 PM 19573224 ER PT J AU Geijsen, N Hochedlinger, K AF Geijsen, Niels Hochedlinger, Konrad TI gPS Navigates Germ Cells to Pluripotency SO CELL STEM CELL LA English DT Editorial Material ID STEM-CELLS; MOUSE TESTIS; GENERATION AB The establishment of pluripotent stem cell lines from explanted testes has been hampered by a poor understanding of their cellular origin. In this issue of Cell Stem Cell, Ko et al. (2009) reproducibly generate pluripotent cell lines from murine testes and unequivocally demonstrate their origin from spermatogonial stem cells. C1 [Geijsen, Niels; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Geijsen, Niels; Hochedlinger, Konrad] Harvard Stem Cell Inst, Ctr Canc, Boston, MA 02114 USA. [Geijsen, Niels] Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. [Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Geijsen, N (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St, Boston, MA 02114 USA. EM ngeijsen@mgh.harvard.edu; khochedlinger@helix.mgh.harvard.edu FU NICHD NIH HHS [R01 HD048769] NR 11 TC 10 Z9 11 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 2 PY 2009 VL 5 IS 1 BP 3 EP 4 DI 10.1016/j.stem.2009.06.012 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 469ET UT WOS:000267879200002 PM 19570505 ER PT J AU Schindler, JW Van Buren, D Foudi, A Krejci, O Qin, JZ Orkin, SH Hock, H AF Schindler, Jeffrey W. Van Buren, Denille Foudi, Adlen Krejci, Ondrej Qin, Jinzhong Orkin, Stuart H. Hock, Hanno TI TEL-AML1 Corrupts Hematopoietic Stem Cells to Persist in the Bone Marrow and Initiate Leukemia SO CELL STEM CELL LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; T(12/21) TRANSLOCATION; ADULT HEMATOPOIESIS; FUSION GENE; MICE; DIFFERENTIATION; TRANSFORMATION; TEL/AML1; RUNX1; FETAL AB The initial steps in the pathogenesis of acute leukemia remain incompletely understood. The TEL-AML1 gene fusion, the hallmark translocation in Childhood Acute Lymphoblastic Leukemia and the first hit, occurs years before the clinical disease, most often in utero. We have generated mice in which TEL-AML1 expression is driven from the endogenous promoter and can be targeted to specific populations. TEL-AML1 renders mice prone to malignancy after chemical mutagenesis when expressed in hematopoietic stem cells (HSCs), but not in early lymphoid progenitors. We reveal that TEL-AML1 markedly increases the number of HSCs and predominantly maintains them in the quiescent (Go) stage of the cell cycle. TEL-AML1(+) HSCs retain self-renewal properties and contribute to hematopoiesis, but fail to out-compete normal HSCs. Our work shows that stem cells are susceptible to subversion by weak oncogenes that can subtly alter their molecular program to provide a latent reservoir for the accumulation of further mutations. C1 [Schindler, Jeffrey W.; Van Buren, Denille; Foudi, Adlen; Krejci, Ondrej; Qin, Jinzhong; Hock, Hanno] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Schindler, Jeffrey W.; Van Buren, Denille; Foudi, Adlen; Krejci, Ondrej; Qin, Jinzhong; Hock, Hanno] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Orkin, Stuart H.; Hock, Hanno] Harvard Stem Cell Inst, Boston, MA 02111 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02111 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02111 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02111 USA. RP Hock, H (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM hock.hanno@mgh.harvard.edu FU NCI NIH HHS [P01 CA68486] NR 43 TC 49 Z9 49 U1 2 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 2 PY 2009 VL 5 IS 1 BP 43 EP 53 DI 10.1016/j.stem.2009.04.019 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 469ET UT WOS:000267879200009 PM 19570513 ER PT J AU Zou, JZ Maeder, ML Mali, P Pruett-Miller, SM Thibodeau-Beganny, S Chou, BK Chen, GB Ye, ZH Park, IH Daley, GQ Porteus, MH Joung, JK Cheng, L AF Zou, Jizhong Maeder, Morgan L. Mali, Prashant Pruett-Miller, Shondra M. Thibodeau-Beganny, Stacey Chou, Bin-Kuan Chen, Guibin Ye, Zhaohui Park, In-Hyun Daley, George Q. Porteus, Matthew H. Joung, J. Keith Cheng, Linzhao TI Gene Targeting of a Disease-Related Gene in Human Induced Pluripotent Stem and Embryonic Stem Cells SO CELL STEM CELL LA English DT Article ID ZINC-FINGER NUCLEASES; HUMAN SOMATIC-CELLS; HUMAN BLASTOCYSTS; MAMMALIAN-CELLS; DEFINED FACTORS; LINES; DIFFERENTIATION; FIBROBLASTS; EXPRESSION; LOCUS AB We report here homologous recombination (HR)-mediated gene targeting of two different genes in human PS cells (hiPSCs) and human ES cells (hESCs). HR-mediated correction of a chromosomally integrated mutant GFP reporter gene reaches efficiencies of 0.14%-0.24% in both cell types transfected by donor DNA with plasmids expressing zinc finger nucleases (ZFNs). Engineered ZFNs that induce a sequence-specific double-strand break in the GFP gene enhanced HR-mediated correction by > 1400-fold without detectable alterations in stem cell karyotypes or pluripotency. Efficient HR-mediated insertional mutagenesis was also achieved at the endogenous PIG-A locus, with a > 200-fold enhancement by ZFNs targeted to that gene. Clonal PIG-A null hESCs and iPSCs with normal karyotypes were readily obtained. The phenotypic and biological defects were rescued by PIG-A transgene expression. Our study provides the first demonstration of HR-mediated gene targeting in hiPSCs and shows the power of ZFNs for inducing specific genetic modifications in hiPSCs, as well as hESCs. C1 [Pruett-Miller, Shondra M.; Porteus, Matthew H.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Pruett-Miller, Shondra M.; Porteus, Matthew H.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Zou, Jizhong; Mali, Prashant; Chou, Bin-Kuan; Chen, Guibin; Ye, Zhaohui; Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA. [Mali, Prashant] Johns Hopkins Univ, Sch Med, Grad Program Biomed Engn, Baltimore, MD 21205 USA. [Chou, Bin-Kuan; Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Grad Program Cellular & Mol Med, Baltimore, MD 21205 USA. [Ye, Zhaohui; Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Grad Program Immunol, Baltimore, MD 21205 USA. [Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. [Maeder, Morgan L.; Thibodeau-Beganny, Stacey; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Mol Pathol Unit, Charlestown, MA 02129 USA. [Maeder, Morgan L.; Thibodeau-Beganny, Stacey; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Park, In-Hyun; Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Porteus, MH (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. EM matthew.porteus@utsouthwestern.edu; jjoung@partners.org; lcheng@welch.jhu.edu RI Zou, Jizhong/B-4902-2011; OI Ye, Zhaohui/0000-0001-5272-9168 FU Stem Cell Research Foundation [S2005-026]; Johns Hopkins Institute for Cell Engineering; NIH [R01 HL073781, R01GM069906, R21RR024189, R21HL091808, R01 HL079295]; Maryland Stem Cell Research Postdoctoral Fellowship Grant; Cystic Fibrosis Foundation; Burroughs-Wellcome Fund FX We thank Sarah Dowey and the Johns Hopkins Hospital Prenatal Cytogenetics Laboratory for professional karyotyping. We also thank three anonymous reviewers for suggestions that helped us in revision. This work is funded in part by the Stem Cell Research Foundation (S2005-026), Johns Hopkins Institute for Cell Engineering, and the NIH grant R01 HL073781 to L.C. J.Z. is supported by a Maryland Stem Cell Research Postdoctoral Fellowship Grant. J.K.J.'s group is supported by the NIH (R01GM069906, R21RR024189, and R21HL091808), the Cystic Fibrosis Foundation, and the MGH Pathology Service. M.H.P.'s lab is supported by the state of Texas, NIH R01 HL079295, and by a Career Development Award from the Burroughs-Wellcome Fund. G.Q.D. is an Investigator of Howard Hughes Medical Institute. NR 41 TC 311 Z9 323 U1 4 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 2 PY 2009 VL 5 IS 1 BP 97 EP 110 DI 10.1016/j.stem.2009.05.023 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 469ET UT WOS:000267879200014 PM 19540188 ER PT J AU Bu, L Jiang, X Martin-Puig, S Caron, L Zhu, SJ Shao, Y Roberts, DJ Huang, PL Domian, IJ Chien, KR AF Bu, Lei Jiang, Xin Martin-Puig, Silvia Caron, Leslie Zhu, Shenjun Shao, Ying Roberts, Drucilla J. Huang, Paul L. Domian, Ibrahim J. Chien, Kenneth R. TI Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages SO NATURE LA English DT Article ID EMBRYONIC STEM-CELLS; CARDIAC PROGENITORS; SMOOTH-MUSCLE; CARDIOMYOCYTE; DIFFERENTIATION; CARDIOGENESIS; POPULATION; PRECURSORS; CONTRIBUTE; ORIGINS AB The generation and expansion of diverse cardiovascular cell lineages is a critical step during human cardiogenesis, with major implications for congenital heart disease. Unravelling the mechanisms for the diversification of human heart cell lineages has been hampered by the lack of genetic tools to purify early cardiac progenitors and define their developmental potential(1-4). Recent studies in the mouse embryo have identified a multipotent cardiac progenitor that contributes to all of the major cell types in the murine heart(5-8). In contrast to murine development, human cardiogenesis has a much longer onset of heart cell lineage diversification and expansion, suggesting divergent pathways. Here we identify a diverse set of human fetal ISL1(+) cardiovascular progenitors that give rise to the cardiomyocyte, smooth muscle and endothelial cell lineages. Using two independent transgenic and gene-targeting approaches in human embryonic stem cell lines, we show that purified ISL1(+) primordial progenitors are capable of self-renewal and expansion before differentiation into the three major cell types in the heart. These results lay the foundation for the generation of human model systems for cardiovascular disease and novel approaches for human regenerative cardiovascular medicine. C1 [Bu, Lei; Jiang, Xin; Martin-Puig, Silvia; Caron, Leslie; Zhu, Shenjun; Shao, Ying; Huang, Paul L.; Domian, Ibrahim J.; Chien, Kenneth R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bu, Lei; Jiang, Xin; Martin-Puig, Silvia; Caron, Leslie; Domian, Ibrahim J.; Chien, Kenneth R.] Harvard Univ, Stem Cell Inst, Cambridge, MA 02138 USA. [Roberts, Drucilla J.] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Pediat Surg Res Labs,Med Sch, Boston, MA 02114 USA. RP Chien, KR (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charles River Plaza,CPZN 3208,185 Cambridge St, Boston, MA 02114 USA. EM krchien@partners.org OI Martin-Puig, Silvia/0000-0003-3048-6729 FU Foundation Alfonso Martin Escudero, Spain; Harvard Stem Cell Institute; Leducq Foundation FX We thank C. Cowan for advice on human ES cell culture and electroporation; A. Nagy for providing the DsRed-MST plasmid; Y. Qyang for discussion and comments; E. Hansson for a critical reading of this manuscript; M. Lindsay and M. Ortega-Molina for help on human fetal heart anatomy; L. B. Prickett-Rice and K. Folz-Donahue for flow cytometry support; and Advanced Bioscience Resources for providing the human fetal tissues. S. M. P. is funded by Foundation Alfonso Martin Escudero, Spain. This study is supported by Harvard Stem Cell Institute and the Leducq Foundation. NR 25 TC 285 Z9 304 U1 2 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 2 PY 2009 VL 460 IS 7251 BP 113 EP U130 DI 10.1038/nature08191 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464XW UT WOS:000267545200040 PM 19571884 ER PT J AU Donohoe, ME Silva, SS Pinter, SF Xu, N Lee, JT AF Donohoe, Mary E. Silva, Susana S. Pinter, Stefan F. Xu, Na Lee, Jeannie T. TI The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting SO NATURE LA English DT Article ID EMBRYONIC STEM-CELLS; DOSAGE COMPENSATION; INACTIVATION; TRANSCRIPTION; CHOICE; TSIX; IDENTIFICATION; INITIATION; ACTIVATOR; PROTEIN AB Pluripotency of embryonic stem (ES) cells is controlled by defined transcription factors(1,2). During differentiation, mouse ES cells undergo global epigenetic reprogramming, as exemplified by X-chromosome inactivation (XCI) in which one female X chromosome is silenced to achieve gene dosage parity between the sexes(3-5). Somatic XCI is regulated by homologous X-chromosome pairing(6,7) and counting(8-10), and by the random choice of future active and inactive X chromosomes. XCI and cell differentiation are tightly coupled(11), as blocking one process compromises the other(8,12) and dedifferentiation of somatic cells to induced pluripotent stem cells is accompanied by X chromosome reactivation(2). Recent evidence suggests coupling of Xist expression to pluripotency factors occurs(13), but how the two are interconnected remains unknown. Here we show that Oct4 (also known as Pou5f1)(14) lies at the top of the XCI hierarchy, and regulates XCI by triggering X-chromosome pairing and counting. Oct4 directly binds Tsix and Xite, two regulatory noncoding RNA genes of the X-inactivation centre(15,16), and also complexes with XCI trans-factors, Ctcf and Yy1 (ref. 17), through protein-protein interactions. Depletion of Oct4 blocks homologous X-chromosome pairing and results in the inactivation of both X chromosomes in female cells. Thus, we have identified the first trans-factor that regulates counting, and ascribed new functions to Oct4 during X-chromosome reprogramming. C1 [Donohoe, Mary E.; Silva, Susana S.; Pinter, Stefan F.; Xu, Na; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Donohoe, Mary E.; Silva, Susana S.; Pinter, Stefan F.; Xu, Na; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Donohoe, Mary E.; Silva, Susana S.; Pinter, Stefan F.; Xu, Na; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu OI Pinter, Stefan/0000-0003-4750-1403 FU National Institutes of Health [GM58839] FX We thank N. Stavropoulos and J. Lopilato for their contributions to the early phase of this work. We also thank J. Zhao, J. A. Erwin and J. Ahn for critical reading of the manuscript and all laboratory members for stimulating discussion. This work was funded by a National Institutes of Health grant to J. T. L. (GM58839). J. T. L. is an Investigator of the Howard Hughes Medical Institute. NR 30 TC 159 Z9 163 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 2 PY 2009 VL 460 IS 7251 BP 128 EP U147 DI 10.1038/nature08098 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464XW UT WOS:000267545200043 PM 19536159 ER PT J AU Perkins, BA Aiello, LP Krolewski, AS AF Perkins, Bruce A. Aiello, Lloyd Paul Krolewski, Andrzej S. TI Diabetes Complications and the Renin-Angiotensin System. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CONTROLLED-TRIAL; RENAL-FUNCTION; PROGRESSION; NEPHROPATHY; CANDESARTAN; RETINOPATHY; THERAPY; RISK C1 [Perkins, Bruce A.] Univ Toronto, Dept Med, Div Endocrinol, Toronto, ON, Canada. [Krolewski, Andrzej S.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Aiello, Lloyd Paul] Beetham Eye Inst, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Perkins, BA (reprint author), Univ Toronto, Dept Med, Div Endocrinol, Toronto, ON, Canada. NR 13 TC 11 Z9 15 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 JUL 2 PY 2009 VL 361 IS 1 BP 83 EP 85 DI 10.1056/NEJMe0904293 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 464UK UT WOS:000267533100015 PM 19571288 ER PT J AU Herring, A Wilper, A Himmelstein, DU Woolhandler, S Espinola, JA Brown, DFM Camargo, CA AF Herring, Andrew Wilper, Andrew Himmelstein, David U. Woolhandler, Steffie Espinola, Janice A. Brown, David F. M. Camargo, Carlos A., Jr. TI Increasing Length of Stay Among Adult Visits to US Emergency Departments, 2001-2005 SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Academic-Emergency-Medicine (SAEM) CY JUN 02, 2008 CL Washington, DC SP Soc Acad Emergency Med DE length of stay; crowding; emergency service; hospital/trends; emergency service; hospital/utilization; healthcare disparities/trends ID INTENSIVE-CARE-UNIT; AMBULANCE DIVERSION; CRITICALLY-ILL; IMPACT; ASSOCIATION; MORTALITY; CAPACITY; ACCESS; LONGER; LEAVE AB Background: Emergency departments (EDs) are traditionally designed to provide rapid evaluation and stabilization and are neither staffed nor equipped to provide prolonged care. Longer ED length of stay (LOS) may compromise quality of care and contribute to delays in the emergency evaluation of other patients. Objectives: The objective was to determine whether ED LOS increased between 2001 and 2005 and whether trends varied by patient and hospital factors. Methods: This was a retrospective analysis of a nationally representative sample of 138,569 adult ED visits from the National Hospital Ambulatory Medical Care Survey (NHAMCS), 2001 to 2005. ED LOS was measured from registration to discharge. Results: Median ED LOS increased 3.5% per year from 132 minutes in 2001 to 154 minutes in 2005 (p-value for trend < 0.001). There was a larger increase among critically ill patients for whom ED LOS increased 7.0% annually from 185 minutes in 2001 to 254 minutes in 2005 (p-value for trend < 0.01). ED LOS was persistently longer for black/African American, non-Hispanic patients (10.6% longer) and Hispanic patients (13.9% longer) than for non-Hispanic white patients, and these differences did not diminish over time. Among factors potentially associated with increasing ED LOS, a large increase was found (60.1%, p-value for trend < 0.001) in the use of advanced diagnostic imaging (computed tomography [CT], magnetic resonance imaging [MR], and ultrasound [US]) and in the proportion of ED visits at which five or more diagnostic or screening tests were ordered (17.6% increase, p-value for trend = 0.001). The proportion of uninsured patients was stable throughout the study period, and EDs with predominately privately insured patients experienced significant increases in ED LOS (4.0% per year from 2001 to 2005, p-value for trend < 0.01). Conclusions: Emergency department LOS in the United States is increasing, especially for critically ill patients for whom time-sensitive interventions are most important. The disparity of longer ED LOS for African Americans and Hispanics is not improving. ACADEMIC EMERGENCY MEDICINE 2009; 16:609-616 (c) 2009 by the Society for Academic Emergency Medicine C1 [Herring, Andrew] Highland Gen Hosp, Dept Emergency Med, Alameda Cty Med Ctr, Oakland, CA USA. [Wilper, Andrew; Himmelstein, David U.; Woolhandler, Steffie; Brown, David F. M.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Wilper, Andrew; Himmelstein, David U.; Woolhandler, Steffie] Cambridge Hlth Alliance, Dept Med, Cambridge, MA USA. [Espinola, Janice A.; Brown, David F. M.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Herring, A (reprint author), Highland Gen Hosp, Dept Emergency Med, Alameda Cty Med Ctr, Oakland, CA USA. EM andrew.a.herring@gmail.com NR 37 TC 60 Z9 62 U1 2 U2 4 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 JUL PY 2009 VL 16 IS 7 BP 609 EP 616 DI 10.1111/j.1553-2712.2009.00428.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 466JD UT WOS:000267656500007 PM 19538503 ER PT J AU Soremekun, OA Noble, VE Liteplo, AS Brown, DFM Zane, RD AF Soremekun, Olanrewaju A. Noble, Vicki E. Liteplo, Andrew S. Brown, David F. M. Zane, Richard D. TI Financial Impact of Emergency Department Ultrasound SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Research Forum of the American-College-of-Emergency-Physicians CY OCT 24-28, 2008 CL Chicago, IL SP Amer Coll Emergency Phys DE emergency department ultrasound; financial impact ID CONTROLLED CLINICAL-TRIAL; POINT-OF-CARE; LIMITED ULTRASONOGRAPHY; SONOGRAPHY; PROGRAM; TRAUMA AB Objectives: There is limited information on the financial implications of an emergency department ultrasound (ED US) program. The authors sought to perform a fiscal analysis of an integrated ED US program. Methods: A retrospective review of billing data was performed for fiscal year (FY) 2007 for an urban academic ED with an ED US program. The ED had an annual census of 80,000 visits and 1,101 ED trauma activations. The ED is a core teaching site for a 4-year emergency medicine (EM) residency, has 35 faculty members, and has 24-hour availability of all radiology services including formal US. ED US is utilized as part of evaluation of all trauma activations and for ED procedures. As actual billing charges and reimbursement rates are institution-specific and proprietary information, relative value units (RVUs) and reimbursement based on the Centers for Medicare & Medicaid Services (CMS) 2007 fee schedule (adjusted for fixed diagnosis-related group [DRG] payments and bad debt) was used to determine revenue generated from ED US. To estimate potential volume, assumptions were made on improvement in documentation rate for diagnostic scans (current documentation rates based on billed volume versus diagnostic studies in diagnostic image database), with no improvements assumed for procedural ED US. Expenses consist of three components-capital costs, training costs, and ongoing operational costs-and were determined by institutional experience. Training costs were considered sunken expenses by this institution and were thus not included in the original return on investment (ROI) calculation, although for this article a second ROI calculation was done with training cost estimates included. For the purposes of analysis, certain key assumptions were made. We utilized a collection rate of 45% and hospitalization rates (used to adjust for fixed DRG payments) of 33% for all diagnostic scans, 100% for vascular access, and 10% for needle placement. An optimal documentation rate of 95% was used to estimate potential revenue. Results: In FY 2007, 486 limited echo exams of abdomen (current procedural terminology [CPT] 76705) and 480 limited echo cardiac exams were performed (CPT 93308) while there were 78 exams for US-guided vascular access (CPT 76937) and 36 US-guided needle placements when performing paracentesis, thoracentesis, or location of abscess for drainage (CPT 76492). Applying the 2007 CMS fee schedule and above assumptions, the revenue generated was 578 RVUs and $35,541 ($12,934 in professional physician fees and $22,607 in facility fees). Assuming optimal documentation rates for diagnostic ED US scans, ED US could have generated 1,487 RVUs and $94,593 ($33,953 in professional physician fees and $60,640 in facility fees). Program expenses include an initial capital expense (estimated at $120,000 for two US machines) and ongoing operational costs ($68,640 per year to cover image quality assurance review, continuing education, and program maintenance). Based on current revenue, there would be an annual operating loss, and thus an ROI cannot be calculated. However, if potential revenue is achieved, the annual operating income will be $22,846 per year with an ROI of 4.9 years to break even with initial investment. Conclusions: Determining an ROI is a required procedure for any business plan for establishing an ED US program. Our analysis demonstrates that an ED US program that captures charges for trauma and procedural US and achieves the potential billing volume breaks even in less than 5 years, at which point it would generate a positive margin. ACADEMIC EMERGENCY MEDICINE 2009; 16:674-680 (c) 2009 by the Society for Academic Emergency Medicine C1 [Soremekun, Olanrewaju A.] Brigham & Womens Hosp, Harvard Affiliated EM Residency Program, Boston, MA 02115 USA. [Noble, Vicki E.; Liteplo, Andrew S.; Brown, David F. M.] Massachusetts Gen Hosp, Dept Emergency Serv, Boston, MA 02114 USA. [Noble, Vicki E.; Liteplo, Andrew S.; Brown, David F. M.; Zane, Richard D.] Harvard Univ, Sch Med, Boston, MA USA. [Zane, Richard D.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. RP Soremekun, OA (reprint author), Brigham & Womens Hosp, Harvard Affiliated EM Residency Program, 75 Francis St, Boston, MA 02115 USA. EM osoremekun1@partners.org RI Siry, Bonnie/D-7189-2017 NR 18 TC 3 Z9 3 U1 1 U2 2 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 JUL PY 2009 VL 16 IS 7 BP 674 EP 680 DI 10.1111/j.1553-2712.2009.00447.x PG 7 WC Emergency Medicine SC Emergency Medicine GA 466JD UT WOS:000267656500018 PM 19549014 ER PT J AU Lyss-Lerman, P Teherani, A Aagaard, E Loeser, H Cooke, M Harper, GM AF Lyss-Lerman, Pamela Teherani, Arianne Aagaard, Eva Loeser, Helen Cooke, Molly Harper, G. Michael TI What Training Is Needed in the Fourth Year of Medical School? Views of Residency Program Directors SO ACADEMIC MEDICINE LA English DT Article ID 4TH-YEAR CURRICULUM; CLINICAL EDUCATION; FAMILY MEDICINE; STUDENTS; SKILLS; SUBINTERNSHIP; PERCEPTIONS; OUTCOMES; PROJECT AB Purpose To identify common struggles of interns, determine residency program directors' (PDs') views of the competencies to be gained in the fourth year of medical school, and apply this information to formulate goals of curricular reform and student advising. Method In 2007, semistructured interviews were conducted with 30 PDs in the 10 most common specialty choices of students the University of California, San Francisco, School of Medicine to assess the PDs' priorities for knowledge, skills, and attitudes to be acquired in the fourth year. Interviews were coded to identify major themes. Results Common struggles of interns were lack of self-reflection and improvement, poor organizational skills, underdeveloped professionalism, and lack of medical knowledge. The Accreditation Council for Graduate Medical Education competencies of patient care, practice-based learning and improvement, interpersonal and communication skills, and professionalism were deemed fundamental to fourth-year students' development. Rotations recommended across specialties were a subinternship in a student's future field and in internal medicine (IM), rotations in an IM subspecialty, critical care, and emergency and ambulatory medicine. PDs encouraged minimizing additional time spent in the student's future field. Suggested coursework included an intensively coached transitional subinternship and courses to improve students' medical knowledge. Conclusions PDs deemed the fourth year to have a critical role in the curriculum. There was consensus about expected fourth-year competencies and the common clinical experiences that best prepare students for residency training. These findings support using the fourth year to transition students to graduate medical training and highlight areas for curricular innovation. C1 [Harper, G. Michael] Univ Calif San Francisco, Sch Med, Dept Med, Div Geriatr, San Francisco, CA 94143 USA. [Harper, G. Michael] San Francisco VA Med Ctr, San Francisco, CA USA. [Aagaard, Eva] Univ Colorado, Dept Med, Denver Sch Med, Denver, CO USA. [Teherani, Arianne] Univ Calif San Francisco, Sch Med, Off Med Educ, San Francisco, CA USA. RP Harper, GM (reprint author), 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. EM Michael.harper3@med.va.gov NR 33 TC 84 Z9 84 U1 2 U2 10 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 JUL PY 2009 VL 84 IS 7 BP 823 EP 829 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 466IT UT WOS:000267655500007 PM 19550170 ER PT J AU Hacker, KA Williams, S Myagmarjav, E Cabral, H Murphy, M AF Hacker, Karen A. Williams, Sandra Myagmarjav, Enkhbolor Cabral, Howard Murphy, Michael TI Persistence and Change in Pediatric Symptom Checklist Scores Over 10 to 18 Months SO ACADEMIC PEDIATRICS LA English DT Article DE mental health; parental concern; Pediatric Symptom Checklist; referral; screening ID MENTAL-HEALTH PROBLEMS; PSYCHIATRIC-DISORDERS; PSYCHOSOCIAL DYSFUNCTION; CARE VISITS; CHILD; MANAGEMENT; SETTINGS; SCHOOL; IDENTIFICATION; ADOLESCENTS AB Objective.-There are many studies of the Pediatric Symptom Checklist (PSC), but none has followed a naturalistic sample longitudinally. We aimed to examine persistence and change in PSC scores over time in children seen in an ambulatory pediatric setting. Methods.-The sample of 1033 patients was PSC screened at 2 consecutive preventive care visits (10 to 18 months apart) in 2 pediatric clinics. Longitudinal analyses were conducted to assess predictors of change in PSC category and score. Results.-Approximately 30% of the initially screened population did not return for preventive pediatric care. Those who did not return were significantly more likely to have positive PSC scores than those who returned (8% compared with 4.3%, P < .01). PSC scores were highly stable at visit 2 for those who initially scored negative, but they fluctuated more for those who initially scored positive. After controlling for sociodemographic variables and counseling at either visit, referral at visit 1 (P < .0001) predicted changes in mean PSC scores at visit 2. On average, PSC score decreased 3.2 points among those referred at visit 1 but increased 1.6 points in nonreferred children. Conclusions.-This is the first study to document the stability and change in PSC scores in a sample of ambulatory pediatric patients. The statistically significant association between pediatrician referral and improved PSC scores provides evidence for the value of referral in primary care, although the study did not examine the relationship between PSC screening and referral. The high rate of positive scores in children who did not return for follow-up suggests the need for alternative strategies for this population. C1 [Hacker, Karen A.; Williams, Sandra] Cambridge Hlth Alliance, Inst Community Hlth, Cambridge, MA 02141 USA. [Myagmarjav, Enkhbolor] Cambridge Hlth Alliance, Dept Qual Management, Cambridge, MA 02141 USA. [Cabral, Howard] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murphy, Michael] Massachusetts Gen Hosp, Dept Child Psychiat, Boston, MA 02114 USA. RP Hacker, KA (reprint author), Cambridge Hlth Alliance, Inst Community Hlth, 163 Gore St, Cambridge, MA 02141 USA. EM khacker@challiance.org FU Healthy Tomorrows Partnership for Children Program; Maternal and Child Health Bureau; Health Resources and Services Administration; American Academy of Pediatrics [H57MC07372] FX Supported in part by a grant through the Healthy Tomorrows Partnership for Children Program, a public private partnership between the Maternal and Child Health Bureau, the Health Resources and Services Administration, and the American Academy of Pediatrics (grant H57MC07372; PI, Karen A. Hacker, MD).; None of the authors has any financial interests in the subject contained in this article. Dr Murphy is one of the developers of the Pediatric Symptom Checklist, which is free to users.; We thank the primary care providers, office staff, and patients of Cambridge and Somerville Pediatrics for their efforts in collecting study information and for their ongoing commitment to the mental health needs of their population. NR 33 TC 15 Z9 15 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 J9 ACAD PEDIATR JI Acad. Pediatr. PD JUL-AUG PY 2009 VL 9 IS 4 BP 270 EP 277 PG 8 WC Pediatrics SC Pediatrics GA 573KV UT WOS:000275913200012 PM 19487170 ER PT J AU Nagata, K Okawa, T Honma, A Endo, S Kudo, S Yoshida, H AF Nagata, Koichi Okawa, Tomohiko Honma, Akihiro Endo, Shungo Kudo, Shin-ei Yoshida, Hiroyuki TI Full-laxative Versus Minimum-laxative Fecal-tagging CT Colonography Using 64-detector Row CT: Prospective Blinded Comparison of Diagnostic Performance, Tagging Quality, and Patient Acceptance SO ACADEMIC RADIOLOGY LA English DT Article DE Colorectal neoplasms; bowel preparation; fecal tagging; computed tomography; colonography ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; COLORECTAL-CANCER; BOWEL PREPARATION; SODIUM-PHOSPHATE; CONVENTIONAL COLONOSCOPY; CATHARTIC PREPARATION; VIRTUAL COLONOSCOPY; CONTRAST-MEDIUM; TRIAL; FEASIBILITY AB Rationale and Objectives. To compare prospectively 64-detector-row computed tomographic colonography (CTC) after a full-laxative tagging-based preparation (full preparation) with a minimum-laxative tagging-based preparation (minimum preparation) with respect to diagnostic performance in the detection of polyps, tagging quality, and patient acceptance. Materials and Methods. Consecutive 10 1 patients at high risk for developing colorectal cancer were alternately assigned to either a full preparation group (n = 51) or a minimum preparation group (n = 50) for fecal-tagging CTC. The full preparation consisted of administration of 2-L polyethylene glycol solution with 20 mL of sodium diatrizoate for fecal tagging. The minimum preparation consisted of ingestion of a total of 45 mL of sodium diatrizoate during the 3 days before and 1 0 mL of sodium picosulfate solution the night before CT. Colonoscopy was used as the reference standard. We assessed the accuracy of polyp detection and the tagging quality for each preparation. All patients were given questionnaires related to their acceptance. Results. Per-patient sensitivity, specificity, and positive and negative predictive values for polyps >= 6 mm were as follows: full preparation group, 97%, 92%, 88%, and 98%, respectively; minimum preparation group, 88%, 68%, 56%, and 92%, respectively. Average visual subjective tagging scores for the full and minimum preparation groups were 94.6% and 76.1%, respectively (P < .0001). Minimum preparation was better tolerated than full preparation. Conclusion. Although full-laxative and minimum-laxative fecal-tagging CTC yielded an equally high sensitivity in the detection of polyps >= 6 min, the full-laxative fecal-tagging CTC yielded a better specificity than did the minimum-laxative fecal-tagging CTC. Thus, it is desirable to offer patients an option of either full-laxative fecal-tagging CTC for highest diagnostic accuracy and ability to perforin a same-day therapeutic colonoscopy without additional bowel preparation, or minimum-laxative fecal-tagging CTC for those unwilling to undergo full preparation but willing to accept moderate decrease in specificity. C1 [Nagata, Koichi; Yoshida, Hiroyuki] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nagata, Koichi; Yoshida, Hiroyuki] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Okawa, Tomohiko; Honma, Akihiro] Tokyo W Tokushukai Hosp, Dept Radiol, Tokyo, Japan. [Endo, Shungo; Kudo, Shin-ei] Showa Univ, No Yokohama Hosp, Ctr Digest Dis, Yokohama, Kanagawa, Japan. RP Nagata, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA. EM Nagata7@aol.com NR 41 TC 17 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2009 VL 16 IS 7 BP 780 EP 789 DI 10.1016/j.acra.2008.12.027 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 462WN UT WOS:000267388900002 PM 19375954 ER PT J AU Caravan, P AF Caravan, Peter TI Protein-Targeted Gadolinium-Based Magnetic Resonance Imaging (MRI) Contrast Agents: Design and Mechanism of Action SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID ELECTRON-SPIN RELAXATION; HUMAN SERUM-ALBUMIN; WATER EXCHANGE-RATE; HYDRATION NUMBER; ENDOR SPECTROSCOPY; HIGH RELAXIVITY; GD3+ COMPLEXES; MS-325; BINDING; ANGIOGRAPHY AB Magnetic resonance imaging (MRI) is a powerful medical diagnostic technique: it can penetrate deep into tissue, provide excellent soft tissue contrast with sub-millimeter resolution, and does not employ ionizing radiation. Targeted contrast agents provide an additional layer of molecular specificity to the wealth of anatomical and functional information already attainable by MRI. However, the major challenge for molecular MR imaging is sensitivity: micromolar concentrations of Gd-III are required to cause a detectable signal change, which makes detecting proteins by MR[ a challenge. Protein-targeted MRI contrast agents are bifunctional molecules comprising a protein-targeting moiety and typically one or more gadolinium chelates for detection by MRI. The ability of the contrast agent to enhance the MR image is termed relaxivity, and it depends upon many molecular factors, including protein binding itself. As in other imaging modalities, protein binding provides the pharmacokinetic effect of concentrating the agent at the region of interest. Unique to MRI, protein binding provides the pharmacodynamic effect of increasing the relaxivity of the contrast agent, thereby increasing the MR signal. In designing new agents, optimization of both the targeting function and the relaxivity is critical. In this Account, we focus on optimization of the relaxivity of targeted agents. Relaxivity depends upon speciation, chemical structure, and dynamic processes, such as water exchange kinetics and rotational tumbling rates. We describe mechanistic studies that relate these factors to the observed relaxivities and use these findings as the basis of rational design of improved agents. In addition to traditional biochemical methods to characterize ligand-protein interactions, the presence of the metal ion enables more obscure biophysical techniques, such as relaxometry and electron nuclear double resonance, to be used to elucidate the mechanism of relaxivity differences. As a case study, we explore the mechanism of action of the serum-albumin-targeted angiography agent MS-325 and closely related compounds and show how small changes in the metal chelate can impact relaxivity. We found that, while protein binding generally improves relaxivity by slowing the tumbling rate of the complex, in some cases, the protein itself can also negatively affect hydration of the metal complex and/or inner-sphere water exchange. Drawing on these findings, we designed next-generation agents targeting albumin, fibrin, or collagen and incorporating up to four gadolinium chelates. Through judicious molecular design, we show that high-relaxivity complexes with high target affinity can be realized. C1 [Caravan, Peter] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Caravan, Peter] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Caravan, P (reprint author), Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu NR 45 TC 218 Z9 221 U1 12 U2 108 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 EI 1520-4898 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD JUL PY 2009 VL 42 IS 7 BP 851 EP 862 DI 10.1021/ar800220p PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 479NA UT WOS:000268665100005 PM 19222207 ER PT J AU Moy, TI Conery, AL Larkins-Ford, J Wu, G Mazitschek, R Casadei, G Lewis, K Carpenter, AE Ausubel, FM AF Moy, Terence I. Conery, Annie L. Larkins-Ford, Jonah Wu, Gang Mazitschek, Ralph Casadei, Gabriele Lewis, Kim Carpenter, Anne E. Ausubel, Frederick M. TI High-Throughput Screen for Novel Antimicrobials using a Whole Animal Infection Model SO ACS CHEMICAL BIOLOGY LA English DT Article ID ANTIBACTERIAL DRUG DISCOVERY; CAENORHABDITIS-ELEGANS; C-ELEGANS; INHIBITORS; BACTERIAL; ASSAY AB The nematode Coenorhabditis elegons is a unique whole animal model system for identifying small molecules with in vivo anti-infective properties. C elegons can be infected with a broad range of human pathogens, including Enterococcus faecalis, an important human nosocomial pathogen. Here, we describe an automated, high-throughput screen of 37,200 compounds and natural product extracts for those that enhance survival of C elegans infected with E faecalis. Using a robot to dispense live, infected animals into 384-well plates and automated microscopy and image analysis, we identified 28 compounds and extracts not previously reported to have antimicrobial properties, including six structural classes that cure infected C elegons animals but do not affect the growth of the pathogen in vitro, thus acting by a mechanism of action distinct from antibiotics currently in clinical use. C1 [Moy, Terence I.; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Moy, Terence I.; Conery, Annie L.; Larkins-Ford, Jonah; Wu, Gang; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Moy, Terence I.; Conery, Annie L.; Larkins-Ford, Jonah; Wu, Gang; Ausubel, Frederick M.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Casadei, Gabriele; Lewis, Kim] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Carpenter, Anne E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Ausubel, FM (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM ausubel@molbio.mgh.harvard.edu RI Carpenter, Anne/C-4982-2008; Mazitschek, Ralph/E-3741-2013 OI Carpenter, Anne/0000-0003-1555-8261; Mazitschek, Ralph/0000-0002-1105-689X FU NCI NIH HHS [N01-CO-12400, N01 CO012400, N01CO12400]; NIAID NIH HHS [R01 AI072508, R01 AI072508-01, R01 AI072508-02]; NIDDK NIH HHS [P30 DK040561, P30 DK040561-14] NR 23 TC 104 Z9 113 U1 1 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUL PY 2009 VL 4 IS 7 BP 527 EP 533 DI 10.1021/cb900084v PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473TS UT WOS:000268233000005 PM 19572548 ER PT J AU Raw, M Regan, S Rigotti, NA McNeill, A AF Raw, Martin Regan, Susan Rigotti, Nancy A. McNeill, Ann TI A survey of tobacco dependence treatment guidelines in 31 countries SO ADDICTION LA English DT Article DE Tobacco dependence treatment; national treatment guidelines; survey ID TREATMENT SERVICES AB The Framework Convention on Tobacco Control (FCTC) asks countries to develop and disseminate comprehensive evidence-based guidelines and promote adequate treatment for tobacco dependence, yet to date no summary of the content of existing guidelines exists. This paper describes the national tobacco dependence treatment guidelines of 31 countries. A questionnaire on tobacco dependence treatment guidelines was sent by e-mail to a convenience sample of contacts working in tobacco control in 31 countries in 2007. Completed questionnaires were received from respondents in all 31 countries. During the course of these enquiries we also made contact with people in 14 countries that did not have treatment guidelines and sent them a short questionnaire asking about their plans to produce guidelines. The survey instrument was a 17-item questionnaire asking the following key questions: do the guidelines recommend brief interventions, intensive behavioural support, medications; which medications; do the guidelines apply to the whole health-care system and all professionals; do they refer explicitly to the Cochrane database; are they based on another country's guidelines; are they national or more local; are they endorsed formally by government; did they undergo peer review; who funded them; where were they published; do they include evidence on cost effectiveness of treatment? According to respondents, all their countries' guidelines recommended brief advice, intensive behavioural support and nicotine replacement therapy (NRT); 84% recommended bupropion; 19% recommended varenicline; and 35% recommended telephone quitlines. Nearly half (48%) included cost-effectiveness evidence. Seventy-one per cent were supported formally by their government and 65% were supported financially by the government. Most (84%) used the Cochrane reviews as a source of evidence, 84% underwent a peer review process and 55% were based on the guidelines of other countries, most often the United States and England. Overall, the guidelines reviewed followed the evidence base closely, recommending brief interventions, intensive behavioural support and NRT, and most recommended bupropion. Varenicline was not on the market in most of the countries in this survey when their guidelines were written, illustrating the need for guidelines to be updated periodically. None recommended interventions not proven to be effective, and some recommended explicitly against specific interventions (for lack of evidence). Most were peer-reviewed, many through lengthy and rigorous procedures, and most were endorsed or supported formally by their governments. Some countries that did not have guidelines expressed a need for technical support, emphasizing the need for countries to share experience, something the FCTC process is well placed to support. C1 [Raw, Martin; McNeill, Ann] Univ Nottingham, UK Ctr Tobacco Control Studies, Div Epidemiol & Publ Hlth, Nottingham NGS 1PB, England. [Regan, Susan; Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. [Regan, Susan; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Div Gen Med, Boston, MA 02114 USA. RP Raw, M (reprint author), Univ Nottingham, UK Ctr Tobacco Control Studies, Div Epidemiol & Publ Hlth, City Hosp Nottingham, Clin Sci Bldg, Nottingham NGS 1PB, England. EM martin@martinraw.com OI Regan, Susan/0000-0003-0940-2017 FU Society for the Study of Addiction; Doreen McIntyre; Global Treatment Partnership; Pfizer; International Non-Governmental Coalition Against Tobacco (INGCAT) FX We gratefully acknowledge the Society for the Study of Addiction for financial support for the data analysis and writing-up of this report, Doreen McIntyre and the Global Treatment Partnership for financial support of the survey and Catherine Slevin for research assistance with the survey. We thank the following for advice on various aspects of the project, including development of the questionnaire: Mira Aghi, Peter Anderson, Linda Bailey, Rick Botelho, David Graham, Joe Gitchell, Paul Hooper, John Hughes, Natasha Jategaonkar, Luk Joossens, Hayden McRobbie, Yumiko Mochizukiy, Hana Ross, Peter Selby, Karen Slama, Fran Stillman, Ken Wassum, Robert West and Heather Wipfli. Finally, we thank sincerely the many country contacts who completed the questionnaire and without whom this survey could not have happened. The Society for the Study of Addiction is a learned society based in Britain. The Global Treatment Partnership was a project funded by Pfizer and other organizations, hosted by the International Non-Governmental Coalition Against Tobacco (INGCAT), whose director was, at the time of the project, Doreen McIntyre. NR 16 TC 17 Z9 17 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD JUL PY 2009 VL 104 IS 7 BP 1243 EP 1250 DI 10.1111/j.1360-0443.2009.02584.x PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 454MK UT WOS:000266686000025 PM 19563566 ER PT J AU Yaremchuk, MJ Chen, YC AF Yaremchuk, Michael J. Chen, Yi-Chieh TI Bridge of Bone Canthopexy SO AESTHETIC SURGERY JOURNAL LA English DT Article AB Bridge of bone canthopexy has utility when significant movements of canthal position are required. It is a technique whereby the lateral canthal structures are purchased with a figure-of-eight suture of titanium wire. Drill holes are placed in the lateral orbital rim using the zygomaticofrontal sutures as reference landmarks. A canthal fixation point (the inferior drill hole) creates a measured distance from a fixed anatomic point (the zygomaticofrontal suture) assuring accurate and symmetric canthus positioning. Wire suture fixation over the bridge of bone created by the two drill holes provides maximum stability to counter soft tissue deforming forces. Fine adjustments can be made to the canthal position by twisting or untwisting the wire ends. (Aesthetic Surg J 2009;29:323-329.) C1 [Yaremchuk, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yaremchuk, Michael J.] Harvard Univ, Sch Med, Div Plast & Reconstruct Surg, Boston, MA USA. [Chen, Yi-Chieh] Chang Gung Mem Hosp, Taipei 10591, Taiwan. RP Yaremchuk, MJ (reprint author), Massachusetts Gen Hosp, 15 Parkman St, Boston, MA 02114 USA. EM dr.y@dryaremchuk.com NR 12 TC 4 Z9 4 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-820X J9 AESTHET SURG J JI Aesthet. Surg. J. PD JUL PY 2009 VL 29 IS 4 BP 323 EP 329 DI 10.1016/j.asj.2009.07.001 PG 7 WC Surgery SC Surgery GA V20KV UT WOS:000208139800014 PM 19717067 ER PT J AU Ghebremichael, M Paintsil, E Ickovics, JR Vlahov, D Schuman, P Boland, R Schoenbaum, E Moore, J Zhang, HP AF Ghebremichael, Musie Paintsil, Elijah Ickovics, Jeannette R. Vlahov, David Schuman, Paula Boland, Robert Schoenbaum, Ellie Moore, Janet Zhang, Heping TI Longitudinal association of alcohol use with HIV disease progression and psychological health of women with HIV SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE alcohol use; HIV/AIDS; multilevel longitudinal models; CD4+T-cells; depression ID NATIONAL COMORBIDITY SURVEY; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; INJECTION-DRUG USERS; CD4 CELL COUNT; DEPRESSIVE SYMPTOMS; COMMUNITY SAMPLE; PSYCHIATRIC-DISORDERS; EPIDEMIOLOGY RESEARCH; MAJOR DEPRESSION AB We evaluated the association of alcohol consumption and depression, and their effects on HIV disease progression among women with HIV. The study included 871 women with HIV who were recruited from 19931995 in four US cities. The participants had physical examination, medical record extraction, and venipuncture, CD4+ T-cell Counts determination, measurement of depression symptoms (using the self-report Center for Epidemiological Studies-Depression Scale), and alcohol use assessment at enrollment, and semiannually until March 2000. Multilevel random coefficient ordinal models as well as multilevel models with joint responses were used in the analysis. There was no significant association between level of alcohol use and CD4+ T-cell counts. When participants were stratified by antiretroviral therapy (ART) Use. the association between alcohol and CD4+ T-cell did not reach statistical significance. The association between alcohol consumption and depression was significant (p < 0.001). Depression had a significant negative effect on CD4+ T-cell counts over time regardless of ART use. Our findings Suggest that alcohol consumption has a direct association with depression, Moreover, depression is associated with HIV disease progression. Our findings have implications for the provision of alcohol use interventions and psychological resources to improve the health of women with HIV. C1 [Ghebremichael, Musie] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Ghebremichael, Musie] Dana Farber Canc Inst, Boston, MA 02115 USA. [Paintsil, Elijah] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Paintsil, Elijah] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. [Ickovics, Jeannette R.; Zhang, Heping] Yale Univ, Sch Publ Hlth, Dept Epidemiol, New Haven, CT USA. [Ickovics, Jeannette R.; Zhang, Heping] Yale Univ, Sch Publ Hlth, Dept Publ Hlth, New Haven, CT USA. [Vlahov, David] New York Acad Med, Ctr Urban Epidemiol Studies, New York, NY USA. [Schuman, Paula] Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA. [Boland, Robert] Brown Univ, Dept Psychiat, Providence, RI 02912 USA. [Schoenbaum, Ellie] Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. [Moore, Janet] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Ghebremichael, M (reprint author), Harvard Univ, Dept Biostat, Boston, MA 02115 USA. EM musie@jimmy.harvard.edu FU CSP VA [U64/CU106795, U64/CU200714, U64/CU306802, U64/CU506831]; NIDA NIH HHS [5 U01-DA017387-03S1, K02 DA017713, K02 DA017713-05, K02-DA017713, R01-DA076750-02, U01 DA017387, U01 DA017387-03S1]; NIMH NIH HHS [T32-MH014235, T32 MH014235, T32 MH014235-31] NR 47 TC 18 Z9 20 U1 5 U2 9 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD JUL PY 2009 VL 21 IS 7 BP 834 EP 841 DI 10.1080/09540120802537864 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 478DZ UT WOS:000268569300004 PM 20024739 ER PT J AU Reisner, SL Mimiaga, MJ Skeer, M Mayer, KH AF Reisner, Sari L. Mimiaga, Matthew J. Skeer, Margie Mayer, Kenneth H. TI Beyond Anal Sex: Sexual Practices Associated with HIV Risk Reduction among Men Who Have Sex with Men in Boston, Massachusetts SO AIDS PATIENT CARE AND STDS LA English DT Article ID PSYCHOSOCIAL HEALTH-PROBLEMS; SUBSTANCE USE; ALCOHOL-USE; BEHAVIORS AB Men who have sex with men (MSM) continue to bear a disproportionate HIV and sexually transmitted disease (STD) burden. The current study examined the frequency and associations of sexual risk reduction behaviors among a sample of MSM in the greater Boston, Massachusetts area. One hundred eighty-nine MSM completed a one-time behavioral and psychosocial assessment between March 2006 and May 2007. Logistic regression procedures examined the association of demographic, psychosocial, and behavioral factors with risk reduction practices. Twenty percent of the sample reported rimming, mutual masturbation, digital penetration, using sex toys, or 100% condom use as a means to reduce their risk of acquiring or transmitting HIV in the prior 12 months. In bivariate analyses, risk reducers were more likely to disclose their MSM status (i.e., be "out''; odds ratio [OR] = 3.64; p < 0.05), and report oral sex with a condom in the prior 12 months (OR = 4.85; p < 0.01). They were less likely to report: depression (Center for Epidemiologic Studies Depression Scale [CES-D] score 16+; OR = 0.48; p < 0.05), a history of one or more sexually transmitted diseases (STDs; OR = 0.40; p < 0.05), and meeting sexual partners at public cruising areas (OR = 0.32; p < 0.01). In a multivariable model, risk reducers were less likely to report: alcohol use during sex (adjusted odds ratio [AOR] = 0.33; p < 0.05), depression (CESD score 16+; AOR = 0.32; p < 0.05), or meeting sexual partners at public cruising areas (AOR = 0.30; p < 0.05), or via the Internet (AOR = 0.12; p < 0.05) in the previous 12 months. Identifying and understanding such factors associated with risk reduction behaviors may be important to consider in designing effective prevention interventions to promote sexual health for MSM. C1 [Reisner, Sari L.; Mimiaga, Matthew J.; Skeer, Margie; Mayer, Kenneth H.] Fenway Community Hlth, Fenway Inst, Boston, MA 02119 USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Skeer, Margie] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mayer, Kenneth H.] Miriam Hosp, Brown Med Sch, Providence, RI 02906 USA. RP Mimiaga, MJ (reprint author), Fenway Community Hlth, Fenway Inst, Prudential Tower,4th Floor,800 Boylston St, Boston, MA 02119 USA. EM mmimiaga@fenwayhealth.org FU National Institutes of Health [P30 AI42853] FX Funding for some investigator and staff time was from the Lifespan/ Tufts/ Brown University Center for AIDS Research grant (National Institutes of Health # P30 AI42853). NR 33 TC 19 Z9 19 U1 0 U2 1 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 JUL PY 2009 VL 23 IS 7 BP 545 EP 550 DI 10.1089/apc.2008.0249 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 472UD UT WOS:000268156800008 PM 19534602 ER PT J AU Leo-Lieber, MA AF Leo-Lieber, Maria Anna TI Beyond Science: My Memories of Charles S. Lieber SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Biographical-Item C1 [Leo-Lieber, Maria Anna] Mt Sinai Sch Med MALL, New York, NY USA. [Leo-Lieber, Maria Anna] James J Peters VA Med Ctr, Sp Bronx, NY USA. RP Leo-Lieber, MA (reprint author), Mt Sinai Sch Med MALL, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2009 VL 33 IS 7 BP 1123 EP 1124 DI 10.1111/j.1530-0277.2009.00999.x PG 2 WC Substance Abuse SC Substance Abuse GA 461PR UT WOS:000267281200004 ER PT J AU Barnes, DE Yaffe, K Belfor, N Jagust, WJ DeCarli, C Reed, BR Kramer, JH AF Barnes, Deborah E. Yaffe, Kristine Belfor, Nataliya Jagust, William J. DeCarli, Charles Reed, Bruce R. Kramer, Joel H. TI Computer-based Cognitive Training for Mild Cognitive Impairment Results from a Pilot Randomized, Controlled Trial SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article; Proceedings Paper CT 10th International Conference on Alzheimers Disease and Related Disorders CY JUL 16-18, 2006 CL Madrid, SPAIN DE human; aged; cognition; cognitive rehabilitation; memory; neuropsychologic tests; randomized controlled trial; mild cognitive impairment ID ALZHEIMERS-DISEASE PATIENTS; HEALTHY OLDER-ADULTS; CHOLINESTERASE-INHIBITORS; MEMORY ENHANCEMENT; REHABILITATION; DEMENTIA; STIMULATION; PROGRAM; PEOPLE; INTERVENTION AB We performed a pilot randomized, controlled trial of intensive, computer-based cognitive training in 47 subjects with mild cognitive impairment. The intervention group performed exercises specifically designed to improve auditory processing speed and accuracy for 100 min/d, 5 d/wk for 6 weeks; the control group performed more passive computer activities (reading, listening, visuospatial game) for similar amounts of time. Subjects had a mean age of 74 years and 60% were men; 77% successfully completed training. On our primary outcome, Repeatable Battery for Assessment of Neuropsychological Status total scores improved 0.36 standard deviations (SD) in the intervention group (P = 0.097) compared with 0.03 SD in the control group (P = 0.88) for a nonsignificant difference between the groups of 0.33 SD (P = 0.26). On 12 secondary outcome measures, most differences between the groups were not statistically significant. However, we observed a pattern in which effect sizes for verbal learning and memory measures tended to favor the intervention group whereas effect sizes for language and visuospatial function measures tended to favor the control group, which raises the possibility that these training programs may have domain-specific effects. We conclude that intensive, computer-based mental activity is feasible in subjects with mild cognitive impairment and that larger trials are warranted. C1 [Barnes, Deborah E.; Yaffe, Kristine; Belfor, Nataliya] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine; Kramer, Joel H.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94121 USA. [Barnes, Deborah E.; Yaffe, Kristine] San Francisco VA Med Ctr, Mental Hlth Res Serv, San Francisco, CA USA. [DeCarli, Charles; Reed, Bruce R.] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [Jagust, William J.] Univ Calif Berkeley, Dept Neurosci, Berkeley, CA 94720 USA. [Jagust, William J.] Univ Calif Berkeley, Dept Publ Hlth, Berkeley, CA 94720 USA. RP Barnes, DE (reprint author), Univ Calif San Francisco, Dept Psychiat, 4150 Clement St 151R, San Francisco, CA 94121 USA. EM Deborah.Barnes@ucsf.edu FU NIA NIH HHS [P30 AG010129, K01 AG 024069, K01 AG024069, K01 AG024069-04, P30 AG010129-17, P30 AG010129-18] NR 37 TC 93 Z9 97 U1 5 U2 54 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2009 VL 23 IS 3 BP 205 EP 210 PG 6 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 495QO UT WOS:000269909300005 PM 19812460 ER PT J AU Chao, LL Pa, J Duarte, A Schuff, N Weiner, MW Kramer, JH Miller, BL Freeman, KM Johnson, JK AF Chao, Linda L. Pa, Judy Duarte, Audrey Schuff, Norbert Weiner, Michael W. Kramer, Joel H. Miller, Bruce L. Freeman, Katie M. Johnson, Julene K. TI Patterns of Cerebral Hypoperfusion in Amnestic and Dysexecutive MCI SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE mild cognitive impairment (MCI); memory; executive function; perfusion; MRI ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; BRAIN; PRECUNEUS; DEMENTIA; MATTER; MRI AB Although early studies on mild cognitive impairment (MCI) focused on memory dysfunction; more recent Studies suggest that MCI is clinically heterogeneous. The objective of this study is to examine patterns of cerebral perfusion in anmestic (N = 12) and nonamnestic (N = 12) single-domain MCI patients from 4 a priori regions of interest: middle and superior frontal cortex, posterior cingulate, and precuneus, to compare them relative to healthy controls (N = 12), and to correlate perfusion with neuropsychologic measures. Relative to controls, all MCI patients had hypoperfusion in the posterior cingulate, bilaterally. MCI patients with executive dysfunctions also showed hypoperfusion in bilateral middle frontal cortex and the left precuneus relative to controls and in the left middle frontal cortex, left posterior cingulate, and left precuneus relative to amnestic MCI patients. Perfusion in the posterior cingulate correlated positively with memory performance whereas perfusion in all 4 a priori regions of interest, predominately on the left side, correlated with executive function performance. The finding that single-domain MCI patients with prominent deficits in different cognitive domains exhibited different patterns of hypoperfusion relative to controls supports the existence of distinct subgroups of MCI. These data further Suggest that cognitive impairment in MCI is related to cerebral hypoperfusion. C1 [Chao, Linda L.; Duarte, Audrey; Schuff, Norbert; Weiner, Michael W.] Univ Calif San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Chao, Linda L.; Schuff, Norbert; Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94121 USA. [Pa, Judy; Kramer, Joel H.; Miller, Bruce L.; Freeman, Katie M.; Johnson, Julene K.] Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, San Francisco, CA 94121 USA. [Duarte, Audrey] Georgia Inst Technol, Dept Psychol, Atlanta, GA 30332 USA. RP Chao, LL (reprint author), Univ Calif San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco VA Med Ctr, 4150 Clement St,114M, San Francisco, CA 94121 USA. EM linda.chao@ucsf.edu FU NIH NIA [R01 AG022538, R01 AG010897, P50 AG0300601] FX Supported by NIH NIA R01 AG022538, R01 AG010897, P50 AG0300601. NR 41 TC 41 Z9 43 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2009 VL 23 IS 3 BP 245 EP 252 PG 8 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 495QO UT WOS:000269909300012 PM 19812467 ER PT J AU Appelbaum, E Abraham, JM Pride, YB Harrigan, CJ Peters, DC Biller, LH Manning, WJ Gibson, CM AF Appelbaum, Evan Abraham, JoEllyn M. Pride, Yuri B. Harrigan, Caitlin J. Peters, Dana C. Biller, Leah H. Manning, Warren J. Gibson, C. Michael TI Association of Thrombolysis in Myocardial Infarction Myocardial Perfusion Grade with cardiovascular magnetic resonance measures of infarct architecture after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID MICROVASCULAR OBSTRUCTION; VENTRICULAR-TACHYCARDIA; HETEROGENEITY; DYSFUNCTION; MORPHOLOGY; MORTALITY AB Background Primary percutaneous coronary intervention (pPCI) routinely restores normal epicardial flow among patients with ST-segment elevation myocardial infarction (STEMI). However, impairment of myocardial perfusion frequently persists. The goal of this analysis was to determine whether impaired myocardial perfusion was associated with cardiovascular magnetic resonance-defined abnormalities in infarct architecture, including infarct size (IS), infarct surface area (ISA), infarct border zone (IBZ), and infarct complexity (IC). Methods Thirty-one patients with STEMI treated with pPCI were included in the analysis. Cardiovascular magnetic resonance was performed within 7 days of presentation and repeated at 3 months. Infarct complexity was defined as the ratio of actual ISA to an idealized smooth ISA and normalized to IS. Results Impaired Thrombolysis in Myocardial Infarction Myocardial Perfusion Grade (TMPG) (<3) was associated with larger ISA at baseline (78.2 +/- 25.3 cm(2) vs 40.3 +/- 30.3 cm(2), P = .02) and follow-up (58.8 +/- 27.5 cm(2) vs 26.3 +/- 20.2 cm(2), P = .03) and larger IBZ at follow-up (7.8% +/- 2.7% vs 4.1% +/- 3.3%, P = .02). At follow-up, ISA, when normalized to 15, was significantly higher among patients with impaired myocardial perfusion (TMPG <3) (6.9 +/- 2.5 vs 5.9 +/- 2.4 cm(2)/%, P = .03). Thrombolysis in MI myocardial perfusion grade <3 was also associated with increased IC at follow-up (52% +/- 12% vs 33% +/- 16%, P = .01). Conclusions Impaired TMPG is associated with larger ISA, IBZ, and increased IC. At 3 months, TMPG remained associated with ISA and IC after adjusting for IS, suggesting that impaired TMPG after pPCI is associated with infarct architecture after healing, independent of IS. (Am Heart J 2009; 158:84-91.) C1 [Appelbaum, Evan; Manning, Warren J.; Gibson, C. Michael] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Cardiovasc Med, Boston, MA USA. [Appelbaum, Evan; Harrigan, Caitlin J.; Biller, Leah H.; Manning, Warren J.; Gibson, C. Michael] PERFUSE Core Labs, Boston, MA USA. [Appelbaum, Evan; Harrigan, Caitlin J.; Biller, Leah H.; Manning, Warren J.; Gibson, C. Michael] Data Coordinating Ctr, Boston, MA USA. [Peters, Dana C.; Manning, Warren J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA USA. RP Gibson, CM (reprint author), 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM mgibson@perfuse.org FU American College of Cardiology Foundation; Merck Adult Cardiology Research Fellowship Award; Harvard/Massachusetts Institute of Technology/Pfizer; Merck Clinical Investigator Training Program FX This study was supported in part by grants from the American College of Cardiology Foundation, Merck Adult Cardiology Research Fellowship Award, Harvard/Massachusetts Institute of Technology/Pfizer, Merck Clinical Investigator Training Program. NR 22 TC 13 Z9 14 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUL PY 2009 VL 158 IS 1 BP 84 EP 91 DI 10.1016/j.ahj.2009.04.012 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465ZU UT WOS:000267630600013 PM 19540396 ER PT J AU Dumaine, RL Montalescot, G Steg, PG Ohman, EM Eagle, K Bhatt, DL AF Dumaine, Raphaelle L. Montalescot, Gilles Steg, Ph. Gabriel Ohman, E. Magnus Eagle, Kim Bhatt, Deepak L. CA REACH Registry Investigators TI Renal function, atherothrombosis extent, and outcomes in high-risk patients SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CORONARY SYNDROME; CHRONIC KIDNEY-DISEASE; CARDIOVASCULAR EVENTS; CREATININE CLEARANCE; CONTROLLED-TRIAL; HEMODIALYSIS; INSUFFICIENCY; ATORVASTATIN; ASSOCIATION; PREVENTION AB Background Although prior data showed an association between chronic kidney disease (CKD) and atherothrombotic events, little is known about the risk profile and specific outcomes of atherothrombotic outpatients with CKD. Methods More than 69,000 outpatients at risk of atherothrombotic events were enrolled in the REACH Registry. Creatinine clearance (CrCl) was available for 51,208 patients divided into A groups: normal (CrCl >= 90 mL/min, n = 13,949), mild (60-89 mL/min, n = 19,474), moderate (30-59 mL/min, n = 15,883), and severe CKD (CrCl <30 mL/min, n = 1902). Baseline characteristics, number of arterial beds overtly affected, medications, overall mortality, cardiovascular death, myocardial infarction, stroke, congestive heart failure, peripheral arterial events, and bleeding events were assessed according to renal function. Results The number of arterial beds affected increased with severity of CKD. However, patients with severe CKD were less likely to receive medications of proven benefit. Severe CKD was an independent correlate of all-cause mortality, cardiovascular mortality, myocardial infarction, congestive heart failure, peripheral arterial revascularization, or amputation. Conclusion One third of outpatients at risk for atherothrombotic events have moderate to severe CKD. They are less likely to receive beneficial therapies despite a higher atherothrombotic burden and worse outcomes. (Am Heart J 2009; 158:141-8.) C1 [Dumaine, Raphaelle L.; Montalescot, Gilles] Pitie Salpetriere Univ Hosp, Paris, France. [Steg, Ph. Gabriel] Bichat Claude Bernard Univ Hosp, Paris, France. [Ohman, E. Magnus] Duke Univ, Durham, NC USA. [Eagle, Kim] Univ Michigan, Ctr Cardiovasc, Ann Arbor, MI 48109 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. RP Montalescot, G (reprint author), CHU Pitie Salpetriere, Inst Cardiol, 47 Boul Hop, F-75013 Paris, France. EM gilles.montalescot@psl.aphp.fr NR 19 TC 19 Z9 19 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 JUL PY 2009 VL 158 IS 1 BP 141 EP U11 DI 10.1016/j.ahj.2009.05.011 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465ZU UT WOS:000267630600021 PM 19540404 ER PT J AU Gibson, CM Pride, YB Buros, JL Ciaglo, LN Morrow, DA Scirica, BM Stone, PH AF Gibson, C. Michael Pride, Yuri B. Buros, Jacqueline L. Ciaglo, Lauren N. Morrow, David A. Scirica, Benjamin M. Stone, Peter H. CA TIMI Study Grp TI Timing and Duration of Myocardial Ischemia on Holter Monitoring Following Percutaneous Coronary Intervention and Their Association With Clinical Outcomes (a PROTECT-TIMI 30 Substudy Analysis) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LONG-TERM PROGNOSIS; UNSTABLE ANGINA; SILENT ISCHEMIA; RISK SCORE; INFARCTION; REPERFUSION; DEATH AB In patients with unstable angina, evidence of myocardial ischemia on Holter monitoring is associated with an adverse prognosis. However, the association of duration and timing of ischemia on Holter monitoring with outcomes after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTEACSs) has not been systematically evaluated. PROTECT-TIMI 30 randomized 857 patients with NSTEACSs undergoing PCI to eptifibatide plus a heparin product or bivalirudin monotherapy. Patients underwent continuous Holter monitoring following PCI, and the association between ischemia and clinical outcomes was evaluated retrospectively. Forty-three patients (5.0%) had ischemia on Holter after PCI. Any ischemia was associated with a significant increase in the incidence of death or myocardial infarction (MI) within 48 hours (32.6% vs 6.1%, odds ratio 7.S, 95% confidence interval 3.70 to 15.10, p <0.001). In patients who developed ischemia, there was a 1.44-fold increase in the odds for death or MI for every 30 minutes of ischemia (95% confidence interval 1.12 to 1.84, p = 0.004). Duration of ischemic events was related to their timing, such that ischemic events that occurred within the first 4 hours after PCI (median duration 141 minutes, interquartile range 36 to 227.5) were significantly longer than events occurring 4 to 24 hours after PCI (median duration 32.8 minutes, interquartile range 17.5 to 118, p = 0.041). In conclusion, early ischemia after PCI for NSTEACS is of longer duration, and longer duration of ischemia recognized by Holter monitoring is associated with an increased incidence of death or MI. Holter monitoring may be a useful surrogate end point in clinical trials. (c) 2009 Elsevier Inc. (Am J Cardiol 2009;104:36-40) C1 [Gibson, C. Michael; Buros, Jacqueline L.; Ciaglo, Lauren N.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, TIMI Study Grp,Div Cardiovasc Med, Boston, MA 02115 USA. [Pride, Yuri B.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. [Morrow, David A.; Scirica, Benjamin M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp, Boston, MA USA. [Stone, Peter H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA USA. RP Gibson, CM (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, TIMI Study Grp,Div Cardiovasc Med, Boston, MA 02115 USA. EM mgibson@timi.org OI Buros, Jacqueline/0000-0001-9588-4889 FU Millennium Pharmaceuticals, Cambridge, Massachusetts; Schering-Plough Research Institute, Kermilworth, New Jersey FX This word was supported in part by grants from Millennium Pharmaceuticals, Cambridge, Massachusetts, and Schering-Plough Research Institute, Kermilworth, New Jersey. NR 19 TC 2 Z9 2 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2009 VL 104 IS 1 BP 36 EP 40 DI 10.1016/j.amjcard.2009.02.044 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 469JX UT WOS:000267895100008 PM 19576318 ER PT J AU Friedewald, VE Kornman, KS Beck, JD Genco, R Goldfine, A Libby, P Offenbacher, S Ridker, PM Van Dyke, TE Roberts, WC AF Friedewald, Vincent E. Kornman, Kenneth S. Beck, James D. Genco, Robert Goldfine, Allison Libby, Peter Offenbacher, Steven Ridker, Paul M. Van Dyke, Thomas E. Roberts, William C. TI The American Journal of Cardiology and Journal of Periodontology Editors' Consensus: Periodontitis and Atherosclerotic Cardiovascular Disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Editorial Material ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; ALVEOLAR BONE LOSS; DENSITY-LIPOPROTEIN CHOLESTEROL; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INDUCED GINGIVAL HYPERPLASIA; NUTRITION EXAMINATION SURVEY; PERIPHERAL ARTERIAL-DISEASE; DEPENDENT DIABETES-MELLITUS; CALCIUM-CHANNEL BLOCKERS C1 [Friedewald, Vincent E.] Univ Notre Dame, Notre Dame, IN 46556 USA. [Friedewald, Vincent E.] Univ Texas Med Sch Houston, Dept Internal Med, Houston, TX USA. [Kornman, Kenneth S.] Interleukin Genet, Waltham, MA USA. [Beck, James D.] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Genco, Robert] SUNY Buffalo, Dept Oral Biol, Amherst, NY USA. [Genco, Robert] SUNY Buffalo, Dept Microbiol, Amherst, NY USA. [Goldfine, Allison; Libby, Peter] Harvard Univ, Sch Med, Boston, MA USA. [Goldfine, Allison] Joslin Diabet Ctr, Boston, MA 02215 USA. [Libby, Peter] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ridker, Paul M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Van Dyke, Thomas E.] Boston Univ, Clin Res Ctr, Goldman Sch Dent Med, Boston, MA 02215 USA. [Roberts, William C.] Baylor Univ, Med Ctr Proceedings, Dallas, TX USA. [Roberts, William C.] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. [Roberts, William C.] Baylor Hlth Care Syst, A Webb Roberts Ctr Continuing Med Educ, Dallas, TX USA. RP Friedewald, VE (reprint author), Univ Notre Dame, Notre Dame, IN 46556 USA. EM vfriedew@nd.edu NR 122 TC 105 Z9 110 U1 0 U2 9 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 JUL 1 PY 2009 VL 104 IS 1 BP 59 EP 68 DI 10.1016/j.amjcard.2009.05.002 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 469JX UT WOS:000267895100012 PM 19576322 ER PT J AU Schnabel, RB Larson, MG Yamamoto, JF Kathiresan, S Rong, J Levy, D Keaney, JF Wang, TJ Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Larson, Martin G. Yamamoto, Jennifer F. Kathiresan, Sekar Rong, Jian Levy, Daniel Keaney, John F., Jr. Wang, Thomas J. Vasan, Ramachandran S. Benjamin, Emelia J. TI Relation of Multiple Inflammatory Biomarkers to Incident Atrial Fibrillation SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID C-REACTIVE PROTEIN; OSTEOPROTEGERIN LEVELS; PLASMA OSTEOPROTEGERIN; DIABETIC-PATIENTS; INTERLEUKIN-6; METAANALYSIS; HEART; RISK; THROMBOGENESIS; POPULATION AB Basic and clinical studies have suggested that inflammation predisposes to atrial fibrillation (AF). We assessed the association of 12 circulating inflammatory biomarkers (i.e., C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase A2 [mass and activity], monocyte chemoattractant protein-1, myelo-peroxidase, CD40 ligand, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II) with incident AF in 2863 Framingham Offspring Study participants (mean age 60.7 years, SD = 9.4, 55% women). During follow-up (median 6 years), 148 participants (43% women) developed incident AF. In the multivariable proportional hazards models, the inflammatory biomarker panel was associated with incident AF (p = 0.03). With stepwise selection (p <0.01 for entry and retention), log-transformed osteoprotegerin was associated with incident AF (hazard ratio per SD 1.30, 95% confidence interval 1.08 to 1.56, p = 0.006). Adjusting for interim myocardial infarction or heart failure attenuated the association between osteoprotegerin and incident AF (hazard ratio 1.18, 95% confidence interval 0.98 to 1.43, p = 0.09). In conclusion, circulating osteoprotegerin concentration was significantly associated with incident AF in our community-based sample, possibly mediated by interim cardiovascular events. (c) 2009 Published by Elsevier Inc. (Am J Cardiol 2009;104:92-96) C1 [Schnabel, Renate B.; Larson, Martin G.; Yamamoto, Jennifer F.; Rong, Jian; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Natl Heart Lung Blood Inst, Framingham Study, Framingham, MA USA. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Dept Med 2, Mainz, Germany. [Yamamoto, Jennifer F.] Boston Univ, Sch Publ Hlth, Dept Math & Stat, Boston, MA USA. [Yamamoto, Jennifer F.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Kathiresan, Sekar; Wang, Thomas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Kathiresan, Sekar] Broad Inst Harvard, Cambridge, MA USA. [Kathiresan, Sekar] MIT, Cambridge, MA 02139 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Boston, MA 02125 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Mem Med Dept, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Prevent Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. RP Benjamin, EJ (reprint author), Natl Heart Lung Blood Inst, Framingham Study, Framingham, MA USA. EM melia@bu.edu OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health/National Heart, Lung, Blood Institute [N01-HC-25195, 6R01-NS 17950]; National Institutes of Health [HL064753, HL076784, AG028321, R01HL71039]; National Institutes of Health Research Career Award [K24 HL04334]; Deutsche Forschungsgemeinschaft (German Research Foundation) Research Fellowship [SCHN 1149/1-1]; Doris Duke Charitable Foundation Clinical Scientist Development Award [1K231-11-083102] FX This study was supported by National Institutes of Health/National Heart, Lung, Blood Institute Grants N01-HC-25195 and 6R01-NS 17950, and National Institutes of Health Grants HL064753. HL076784, and AG028321 (E. J. Benjamin), 1 R01HL71039 (R. S. Vasan), Bethesda, Maryland; National Institutes of Health Research Career Award K24 HL04334 (R. S. Vasan), Bethesda, Maryland Deutsche Forschungsgemeinschaft (German Research Foundation) Research Fellowship SCHN 1149/1-1 (R. B. Schnabel), Bonn, Germany; and Grant 1K231-11-083102, Doris Duke Charitable Foundation Clinical Scientist Development Award (S. Kathiresan), New York, New York. NR 28 TC 68 Z9 71 U1 0 U2 6 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 JUL 1 PY 2009 VL 104 IS 1 BP 92 EP 96 DI 10.1016/j.amjcard.2009.02.053 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 469JX UT WOS:000267895100016 PM 19576326 ER PT J AU Baggish, AL Weiner, RB Yared, K Wang, F Kupperman, E Hutter, AM Picard, MH Wood, MJ AF Baggish, Aaron L. Weiner, Rory B. Yared, Kibar Wang, Francis Kupperman, Eli Hutter, Adolph M., Jr. Picard, Michael H. Wood, Malissa J. TI Impact of Family Hypertension History on Exercise-Induced Cardiac Remodeling SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR STRUCTURE; CONVERTING ENZYME GENE; SYSTEMIC HYPERTENSION; POLYMORPHISM; MASS; ASSOCIATION; COMMITTEE; YOUNG AB Left ventricular (LV) hypertrophy is a well-established, but highly variable, finding among exercise-trained persons. The causes for the variability in LV remodeling in response to exercise training remain incompletely understood. The present study sought to determine whether a family history of hypertension is a determinant of the cardiac response to exercise training. The cardiac parameters in 60 collegiate rowers (30 men/30 women; age 19.8 +/- 1.1 years) with (family history positive [FH+], n = 22) and without (family history negative [FH-], n = 38) a FH of hypertension were studied with echocardiography before and after 90 days of rowing training. The LV mass increased significantly in both groups. However, the LV mass increased significantly more in FH- persons (Delta 17 +/- 5 g/m(2)) than in FH+ persons (Delta 9 +/- 6 g/m(2), p <0.001) with distinctly differently patterns of LV hypertrophy between the 2 groups. FH- athletes experienced eccentric LV hypertrophy (relative wall thickness index 0.39 +/- 0.4) characterized by LV dilation. In contrast, FH+ athletes developed concentric LV hypertrophy (relative wall thickness index 0.44 +/- 0.3; p <0.001) characterized by LV wall thickening. Furthermore, the eccentric LV remodeling in FH- athletes was associated with a more robust enhancement of LV diastolic function than the concentric LV remodeling that occurred in FH+ athletes. In conclusion, these findings suggest that patterns of exercise-induced LV remodeling are strongly associated with FH history status. (c) 2009 Elsevier Inc. (Am J Cardiol 2009;104:101-106) C1 [Baggish, Aaron L.; Weiner, Rory B.; Yared, Kibar; Hutter, Adolph M., Jr.; Picard, Michael H.; Wood, Malissa J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Wang, Francis; Kupperman, Eli] Harvard Univ, Univ Hlth Serv, Cambridge, MA 02138 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM abaggish@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 20 TC 10 Z9 12 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2009 VL 104 IS 1 BP 101 EP 106 DI 10.1016/j.amjcard.2009.02.052 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 469JX UT WOS:000267895100018 PM 19576328 ER PT J AU Noseworthy, PA Rosenberg, MA Fifer, MA Palacios, IF Lowry, PA Ruskin, JN Sanborn, DM Picard, MH Vlahakes, GJ Mela, T Das, S AF Noseworthy, Peter A. Rosenberg, Michael A. Fifer, Michael A. Palacios, Igor F. Lowry, Patricia A. Ruskin, Jeremy N. Sanborn, Danita M. Picard, Michael H. Vlahakes, Gus J. Mela, Theofanie Das, Saumya TI Ventricular Arrhythmia Following Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID OUTFLOW TRACT OBSTRUCTION; SUDDEN CARDIAC DEATH; TRANSCORONARY ABLATION; TACHYCARDIA; RISK; PREVENTION; SURVIVAL AB We sought to assess the risk of sudden cardiac death (SCD) and ventricular arrhythmia after alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy. ASA is a nonsurgical alternative to septal myectomy for treatment of symptomatic, drug-refractory, obstructive hypertrophic cardiomyopathy. The effect of ASA on ventricular arrhythmia risk is not well established. We examined the rates of SCD among 89 patients treated with ASA. The secondary end point was ventricular tachycardia/ventricular fibrillation (VT/VF), appropriate implantable cardioverter defibrillator (ICD) therapy, or cardiac arrest after ASA among those with implanted ICDs or permanent pacemakers (n = 42). Patients were classified as either high-risk or low-risk on the basis of established clinical indications for ICD implantation. No mortality was attributable to SCD at a mean follow-up of 5.0 +/- 2.3 years in the entire cohort. Among the 42 patients with an ICD or permanent pacemaker, 9 had documented VT/VF, cardiac arrest, or appropriate ICD therapy, resulting in an annual event rate of 4.9%/year. The annual event rate for VT/VF, cardiac arrest, or appropriate ICD therapy was 2.8%/year (4 of 29 patients) in low-risk patients and 13.4% in high-risk patients (5 of 13 patients). A 10-mm Hg increase in the immediate post-ASA gradient was associated with a hazard ratio of 2.66 for arrhythmic events (95% confidence interval 1.55 to 4.56, p <0.001). In conclusion, ASA was performed in patients with highly symptomatic, drug-refractory hypertrophic cardiomyopathy with no mortality attributable to SCD and an annual rate of VT/VF, cardiac arrest, or appropriate ICD therapy of 4.9%/year. (c) 2009 Elsevier Inc. (Am J Cardiol 2009;104:128-132) C1 [Ruskin, Jeremy N.; Mela, Theofanie; Das, Saumya] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Noseworthy, Peter A.; Fifer, Michael A.; Palacios, Igor F.; Lowry, Patricia A.; Sanborn, Danita M.; Picard, Michael H.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Vlahakes, Gus J.] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [Rosenberg, Michael A.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. RP Das, S (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. EM sdas@partners.org OI Picard, Michael/0000-0002-9264-3243 FU American College of Cardiology- Pfizer, Bethesda, Maryland; Merck, Whitehouse Station FX Dr. Das was funded by a career development grant from American College of Cardiology- Pfizer, Bethesda, Maryland. Dr. Fifer has received a research grant from Merck, Whitehouse Station, NJ (2 >=$10,000) and private donations (2 >=$10,000) for research in hypertrophic cardionlyopathy, as well as honoraria for speaking on hypertrophic cardiomyopathy. NR 16 TC 35 Z9 38 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2009 VL 104 IS 1 BP 128 EP 132 DI 10.1016/j.amjcard.2009.02.056 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 469JX UT WOS:000267895100023 PM 19576333 ER PT J AU Imamura, F Lichtenstein, AH Dallal, GE Meigs, JB Jacques, PF AF Imamura, Fumiaki Lichtenstein, Alice H. Dallal, Gerard E. Meigs, James B. Jacques, Paul F. TI Confounding by Dietary Patterns of the Inverse Association Between Alcohol Consumption and Type 2 Diabetes Risk SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; bias (epidemiology); confounding factors (epidemiology); diabetes mellitus; type 2; diet; factor analysis; statistical; least-squares analysis; proportional hazards models ID FOOD-FREQUENCY QUESTIONNAIRE; PROPENSITY SCORE; NUTRITIONAL EPIDEMIOLOGY; DRINKING PATTERNS; HEART-DISEASE; VALIDITY; REPRODUCIBILITY; FRAMINGHAM; MELLITUS; BIAS AB The ability to interpret epidemiologic observations is limited because of potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as standard risk factors and selected nutrients, the authors modeled the longitudinal association between alcohol consumption and 7-year risk of type 2 diabetes mellitus in 2,879 healthy adults enrolled in the Framingham Offspring Study (1991-2001) by Cox proportional hazard models. After adjustment for standard risk factors, consumers of >= 9.0 drinks/week had a significantly lower risk of type 2 diabetes mellitus compared with abstainers (hazard ratio = 0.47, 95% confidence interval (CI): 0.27, 0.81). Adjustment for selected nutrients had little effect on the hazard ratio, whereas adjustment for dietary pattern variables by factor analysis significantly shifted the hazard ratio away from null (hazard ratio = 0.33, 95% CI: 0.17, 0.64) by 40.0% (95% CI: 16.8, 57.0; P = 0.002). Dietary pattern variables by partial least squares showed similar results. Therefore, the observed inverse association, consistent with past studies, was confounded by dietary patterns, and this confounding was not captured by individual nutrient adjustment. The data suggest that alcohol intake, not dietary patterns associated with alcohol intake, is responsible for the observed inverse association with type 2 diabetes mellitus risk. C1 [Imamura, Fumiaki; Lichtenstein, Alice H.; Dallal, Gerard E.; Jacques, Paul F.] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Imamura, Fumiaki; Lichtenstein, Alice H.; Dallal, Gerard E.; Jacques, Paul F.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. RP Jacques, PF (reprint author), Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM paul.jacques@tufts.edu OI Imamura, Fumiaki/0000-0002-6841-8396 FU NHLBI NIH HHS [N01HC25195, N01-HC-25195]; NIDDK NIH HHS [K24-DK090140] NR 34 TC 26 Z9 26 U1 0 U2 3 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 JUL 1 PY 2009 VL 170 IS 1 BP 37 EP 45 DI 10.1093/aje/kwp096 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 463NZ UT WOS:000267440200005 PM 19429876 ER PT J AU Cavusoglu, E Chopra, V Gupta, A Choksi, PU Ruwende, C Yanamadala, S Frishman, WH Pinsky, DJ Marmur, JD AF Cavusoglu, Erdal Chopra, Vineet Gupta, Amit Choksi, Palak U. Ruwende, Cyril Yanamadala, Sunitha Frishman, William H. Pinsky, David J. Marmur, Jonathan D. TI Relation of Baseline Serum Potassium Levels to Angiographic Findings in Patients With Known or Suspected Coronary Artery Disease SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article ID SPONTANEOUSLY HYPERTENSIVE RATS; ACUTE MYOCARDIAL-INFARCTION; BLOOD-CELL COUNT; CARDIAC MORTALITY; PREDICTOR AB BACKGROUND In experimental animal studies, potassium has been demonstrated to protect against the development of atherosclerosis through a variety of mechanisms. Data regarding the role of potassium in the development of human atherosclerosis are sparse. The objective of this study was to determine the association between plasma potassium levels and angiographically defined coronary artery disease (CAD). METHODS In a cohort of 389 male patients undergoing coronary angiography for a variety of clinical indications, the association between baseline serum potassium levels and the extent of angiographically defined atherosclerosis was analyzed. Adjustments were made for clinical and laboratory variables (including inflammatory markers) known to be associated with atherosclerosis. RESULTS By multivariate logistic regression analysis, baseline serum potassium levels were an independent predictor of the presence of multivessel disease (odds ratio (OR) 1.31, 95% confidence interval (CI) 1.01-1.69; P<0.05). In addition, in the non-myocardial infarction subpopulation of patients, serum potassium was also an independent predictor of the presence of multivessel disease by multivariate logistic regression analysis (OR 1.34, 95% Cl, 1.02-1.76; P<0.05). In the myocardial infarction (MI) subpopulation, serum potassium was not a predictor of multivessel disease, possibly due to the confounding effect of hypokalemia known-to be present during MI. CONCLUSIONS These data demonstrate that a simple baseline serum potassium level is independently associated with the presence of multivessel disease, even in the context of clinical CAD risk factors and other established inflammatory markers. C1 [Cavusoglu, Erdal; Gupta, Amit; Marmur, Jonathan D.] Suny Downstate Med Ctr, Dept Med, Div Cardiol, Brooklyn, NY 11203 USA. [Cavusoglu, Erdal; Chopra, Vineet; Choksi, Palak U.] Bronx Vet Affairs Med Ctr, Dept Med, Bronx, NY USA. [Ruwende, Cyril; Yanamadala, Sunitha; Pinsky, David J.] Univ Michigan, Dept Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Frishman, William H.] New York Med Coll, Dept Med, Westchester Med Ctr, Valhalla, NY 10595 USA. RP Cavusoglu, E (reprint author), Suny Downstate Med Ctr, Dept Med, Div Cardiol, Brooklyn, NY 11203 USA. EM ECavusoglu@aol.com NR 12 TC 2 Z9 2 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUL PY 2009 VL 22 IS 7 BP 754 EP 762 DI 10.1038/ajh.2009.65 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 462IX UT WOS:000267346100012 PM 19373212 ER PT J AU Egan, BM Basile, JN Rehman, SU Davis, PB Grob, CH Riehle, JF Walters, CA Lackland, DT Merali, C Sealey, JE Laragh, JH AF Egan, Brent M. Basile, Jan N. Rehman, Shakaib U. Davis, Phillip B. Grob, Curt H., III Riehle, Jessica Flynn Walters, Christine A. Lackland, Daniel T. Merali, Carmen Sealey, Jean E. Laragh, John H. TI Plasma Renin Test-Guided Drug Treatment Algorithm for Correcting Patients With Treated but Uncontrolled Hypertension: A Randomized Controlled Trial SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article ID CONVERTING-ENZYME-INHIBITOR; BLOOD-PRESSURE RESPONSE; RESISTANT HYPERTENSION; LARAGHS LESSONS; CLINICAL PEARLS; ANTIHYPERTENSIVE ACTION; RENAL-FUNCTION; THERAPY; PATHOPHYSIOLOGY; DIAGNOSIS AB BACKGROUND Undefined pathophysiologic mechanisms likely contribute to unsuccessful anti hypertensive drug therapy. The renin test-guided therapeutic (RTGT) algorithm is based on the concept that, irrespective of current drug treatments, subnormal plasma renin activity (PRA) (<0.65 ng/ml/h) indicates sodium-volume excess "V" hypertension, whereas values >= 0.65 indicate renin-angiotensin vasoconstriction excess "R" hypertension. METHODS The RTGT algorithm was applied to treated, uncontrolled hypertensives and compared to clinical hypertension specialists' care (CHSC) without access to PRA. RTGT protocol: "V" patients received natriuretic anti-"V"drugs (diuretics, spironolactone, calcium antagonists, or alpha(1)-blockers) while withdrawing antirenin "R" drugs (converting enzyme inhibitors, angiotensin receptor antagonists, or beta-blockers). Converse strategies were applied to "R" patients. Eighty-four ambulatory hypertensives were randomized and 77 qualified for the intention-to-treat analysis including 38 in RTGT (63.9 +/- 1.8 years; baseline blood pressure (BP) 157.0 +/- 2.6/87.1 +/- 2.0 mm Hg; PRA 5.8 +/- 1.6; 3.1 +/- 0.3 antihypertensive drugs) and 39 in CHSC (58.0 +/- 2.0 years; BD 153.6 +/- 2.3/91.9 +/- 2.0; PRA 4.6 +/- 1.1; 2.7 +/- 0.2 drugs). RESULTS BP was controlled in 28/38 (74% (RTGT)) vs. 23/39 (59% (CHSC)), P=0.17, falling to 127.9 +/- 2.3/73.1 +/- 1.8 vs. 134.0 +/- 2.8/79.8 +/- 1.9 mm Hg, respectively. Systolic BP (SBP) fell more with RTGT (-29.1 +/- 3.2 vs. -19.2 +/- 3.2 mm Hg, P=0.03), whereas diastolic BP (DBP) declined similarly (P=0.32). Although final anti hypertensive drug numbers were similar (3.1 +/- 0.2 (RTGT) vs. 3.0 +/- 0.3 (CHSC), P=0.73) in "V" patients, 60% (RTGT) vs. 11% (CHSC) of "R" drugs were withdrawn and BP medications were reduced (-0.5 +/- 03 vs. +0.7 +/- 0.3, P=0.01). CONCLUSIONS In treated but uncontrolled hypertension, RTGT improves control and lowers BP equally well or better than CHSC, indicating that RTGT provides a reasonable strategy for correcting treated but uncontrolled hypertension. C1 [Egan, Brent M.; Basile, Jan N.; Rehman, Shakaib U.; Davis, Phillip B.; Grob, Curt H., III; Lackland, Daniel T.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Basile, Jan N.; Rehman, Shakaib U.] Ralph H Johnson VA Med Ctr, Dept Med, Charleston, SC USA. [Riehle, Jessica Flynn; Walters, Christine A.; Lackland, Daniel T.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Merali, Carmen; Laragh, John H.] Weill Cornell Med Coll, Dept Cardiothorac Surg, New York, NY USA. [Sealey, Jean E.] Weill Cornell Med Coll, Dept Med, New York, NY USA. RP Egan, BM (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. EM eganbm@musc.edu RI Sealey, Jean/A-9562-2009 FU New York Presbyterian Hospital; National Institutes of Health [HL04290]; Ralph H. Johnson Veterans Affairs Hospital FX This research was supported by grants from the New York Presbyterian Hospital, National Institutes of Health HL04290, and the Ralph H. Johnson Veterans Affairs Hospital. NR 49 TC 59 Z9 59 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUL PY 2009 VL 22 IS 7 BP 792 EP 801 DI 10.1038/ajh.2009.63 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 462IX UT WOS:000267346100017 PM 19373213 ER PT J AU Pfeffer, MA Burdmann, EA Chen, CY Cooper, ME de Zeeuw, D Eckardt, KU Ivanovich, P Kewalramani, R Levey, AS Lewis, EF McGill, J McMurray, JJV Parfrey, P Parving, HH Remuzzi, G Singh, AK Solomon, SD Toto, R Uno, H AF Pfeffer, Marc A. Burdmann, Emmanuel A. Chen, Chao-Yin Cooper, Mark E. de Zeeuw, Dick Eckardt, Kai-Uwe Ivanovich, Peter Kewalramani, Reshma Levey, Andrew S. Lewis, Eldrin F. McGill, Janet McMurray, John J. V. Parfrey, Patrick Parving, Hans-Henrik Remuzzi, Giuseppe Singh, Ajay K. Solomon, Scott D. Toto, Robert Uno, Hajime CA TREAT Investigators TI Baseline Characteristics in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Erythropoiesis-stimulating agents; anemia; diabetes; chronic kidney disease ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; RECOMBINANT-HUMAN-ERYTHROPOIETIN; HEMODIALYSIS-PATIENTS; RANDOMIZED-TRIALS; DIABETES-MELLITUS; ANEMIA CORRECTION; MORTALITY; OUTCOMES; RISK AB Background: Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes. Study Design: Randomized trial. Setting & Participants: 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin <= 11 g/dL) from 24 countries. Intervention: Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo. Outcomes: TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point. Conclusions: With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia. Am J Kidney Dis 54:59-69. (c) 2009 by the National Kidney Foundation, Inc. C1 [Pfeffer, Marc A.; Lewis, Eldrin F.; Singh, Ajay K.; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc, Dept Med, Boston, MA 02115 USA. [Pfeffer, Marc A.; Lewis, Eldrin F.; Singh, Ajay K.; Solomon, Scott D.] Brigham & Womens Hosp, Div Renal, Dept Med, Boston, MA 02115 USA. [Pfeffer, Marc A.; Lewis, Eldrin F.; Singh, Ajay K.; Solomon, Scott D.] Harvard Univ, Sch Med, Boston, MA USA. [Burdmann, Emmanuel A.] Fac Med Sao Jose Rio Pret, Sao Jose Do Rio Preto, Brazil. [Chen, Chao-Yin; Kewalramani, Reshma] Amgen Inc, Global Biostat & Epidemiol, Thousand Oaks, CA USA. [Chen, Chao-Yin; Kewalramani, Reshma] Amgen Inc, Global Clin Dev, Thousand Oaks, CA USA. [Cooper, Mark E.] Baker Heart Res Inst, Melbourne, Vic, Australia. [de Zeeuw, Dick] Univ Groningen, Univ Med Ctr Groningen, Div Clin Pharmacol, NL-9713 AV Groningen, Netherlands. [Eckardt, Kai-Uwe] Univ Erlangen Nurnberg, Dept Hypertens & Nephrol, Erlangen, Germany. [Ivanovich, Peter] NW Univ Feinberg, Div Nephrol, Dept Med, Chicago, IL USA. [Levey, Andrew S.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [McGill, Janet] Washington Univ, Sch Med, Med Ctr, St Louis, MO USA. [McMurray, John J. V.] Univ Glasgow, Dept Cardiol, Glasgow G12 8QQ, Lanark, Scotland. [Parfrey, Patrick] Hlth Sci Ctr, Div Nephrol, St John, NF, Canada. [Parving, Hans-Henrik] Univ Copenhagen, Dept Med Endocrinol, Rigshosp, DK-1168 Copenhagen, Denmark. [Remuzzi, Giuseppe] Mario Negri Inst Pharmacol Res, I-24100 Bergamo, Italy. [Toto, Robert] Univ Texas SW, Dept Med, Dallas, TX USA. [Uno, Hajime] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Pfeffer, MA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM mpfeffer@rics.bwh.harvard.edu RI Cooper, Mark/E-8680-2010; Burdmann, Emmanuel/B-7023-2009; Solomon, Scott/I-5789-2013; de Zeeuw, Dick/E-9080-2014; OI Cooper, Mark/0000-0002-5953-642X; Burdmann, Emmanuel/0000-0002-7644-8579; de Zeeuw, Dick/0000-0003-3434-7777; mcmurray, john/0000-0002-6317-3975 FU Amgen FX Amgen. which markets darbepoetin alfa, funded this study. Dr Pfeffer has received support (research grant to Brigham and Women's Hospital) for the conduct of TREAT and has served as a consultant to Amgen. Dr de Zeeuw is a member of the TREAT Steering Committee (financial compensation to the University Medical Center Groningen). Dr Burdniann has received Support (research grant to Hospital de Base, Sao Jose do Rio Preto Medical School) and has served as a consultant to Amgen. Dr Parving has received lecture and consultant fees from Amgen. Dr Eckardt has received lecture and Consulting fees from companies producing ESAs, including Amgen. Johnson & Johnson, Roche. Affymax. Stada. Sandoz, and Hexal. Drs Cooper and Ivanovich have received financial support from Amgen for work related to the Study. Dr Solomon has received research Support from Amgen. Dr Levey is a member of the TREAT Steering Committee (financial compensation to Tufts Medical Center). Dr Lewis has received Support (research grant to Brigham and Women's Hospital) from Amgen and has served as a consultant( to Amgen. Dr McGill has received consulting fees from Amgen (for the Executive Committee). Dr McMurray is a member of the TREAT Steering Committee (financial compensation to Glasgow University). Dr Parfrey has received research support from Amgen and Ortho Biotech to pefform RCT,; of anemia therapy. Dr Remuzzi has received lecture support from Merckm Amgen, and AstraZeneca. Drs Chen and Kewalrainani are employees of Amgen. NR 36 TC 32 Z9 34 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2009 VL 54 IS 1 BP 59 EP 69 DI 10.1053/j.ajkd.2009.04.008 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 499JC UT WOS:000270214400012 PM 19501439 ER PT J AU Flythe, JE Rueda, JF Riscoe, MK Watnick, S AF Flythe, Jennifer E. Rueda, Jose F. Riscoe, Michael K. Watnick, Suzanne TI Silicate Nephrolithiasis After Ingestion of Supplements Containing Silica Dioxide SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Silicate; silica; nephrolithiasis; over-the-counter supplements ID MAGNESIUM TRISILICATE; URINARY CALCULI; UROLITHIASIS AB Silicate calculi are common in some mammals, such as dogs and sheep, but extremely rare in humans. We report a case of silicate calculi in a woman using oral over-the-counter Uncaria tomentosa, Digestive Advantage and FlexProtex supplements. All 3 contained the excipient silica dioxide. Stone analysis showed composition of 100% silicate. The nephrolithiasis promptly abated after discontinuation of the products containing silica, then returned when the patient restarted her supplements. This case emphasizes the importance of stone analysis when obvious causes of nephrolithiasis are unclear and highlights the concerns of using over-the-counter supplements without substantial oversight. Am J Kidney Dis 54:127-130. (c) 2009 by the National Kidney Foundation, Inc. C1 [Watnick, Suzanne] Portland VA Med Ctr, P3NEPH, Div Hosp & Specialty Med, Portland, OR 97239 USA. [Rueda, Jose F.; Watnick, Suzanne] Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97201 USA. [Riscoe, Michael K.] Portland VA Med Ctr, Res & Dev Serv, Portland, OR USA. RP Watnick, S (reprint author), Portland VA Med Ctr, P3NEPH, Div Hosp & Specialty Med, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM suzanne.watnick@va.gov NR 27 TC 4 Z9 5 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2009 VL 54 IS 1 BP 127 EP 130 DI 10.1053/j.ajkd.2008.10.042 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 499JC UT WOS:000270214400020 PM 19100669 ER PT J AU Patel, TV Rennke, HG Sloan, JM DeAngelo, DJ Charytan, DM AF Patel, Tejas V. Rennke, Helmut G. Sloan, J. Mark DeAngelo, Daniel J. Charytan, David M. TI A Forgotten Cause of Kidney Injury in Chronic Myelomonocytic Leukemia SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Leukemia; renal failure; lysozyme; proteinuria; cation ID NEPHROTIC SYNDROME; LYSOZYME MURAMIDASE; PROGNOSTIC-FACTORS; RENAL-FAILURE; PATIENT; SERUM; PROTEINURIA; DYSFUNCTION; DAUNOMYCIN; AGENT C1 [Charytan, David M.] Brigham & Womens Hosp, Div Renal, Ctr Clin Biometr, Boston, MA 02120 USA. [Rennke, Helmut G.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02120 USA. [Sloan, J. Mark; DeAngelo, Daniel J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Charytan, DM (reprint author), Brigham & Womens Hosp, Div Renal, Ctr Clin Biometr, 1620 Tremont St, Boston, MA 02120 USA. EM dcharytan@partners.org OI Sloan, John/0000-0001-7069-4528 FU National Institutes of Health [T32-DK07527-23] FX This, work was Supported by National Institutes of Health Grant T32-DK07527-23 to Dr Patel. NR 28 TC 9 Z9 9 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2009 VL 54 IS 1 BP 159 EP 164 DI 10.1053/j.ajkd.2008.11.013 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 499JC UT WOS:000270214400024 PM 19185401 ER PT J AU Hendricks, AE Latourelle, JC Lunetta, KL Cupples, LA Wheeler, V MacDonald, ME Gusella, JF Myers, RH AF Hendricks, Audrey E. Latourelle, Jeanne C. Lunetta, Kathryn L. Cupples, L. Adrienne Wheeler, Vanessa MacDonald, Marcy E. Gusella, James F. Myers, Richard H. TI Estimating the Probability of de novo HD Cases From Transmissions of Expanded Penetrant CAG Alleles in the Huntington Disease Gene From Male Carriers of High Normal Alleles (27-35 CAG) SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Huntington disease; high normal alleles; intermediate alleles; mutable normal alleles; genetic counseling; de novo ID 29 TRINUCLEOTIDE REPEATS; INTERMEDIATE ALLELES; PARKINSONS-DISEASE; INSTABILITY; ONSET; AGE; CHROMOSOMES; MECHANISMS; MUTATION; SIZE AB Huntington disease (HD) is a dominantly transmitted neurodegenerative disorder that arises from expansion of a CAG trinucleotide repeat on chromosome4p16.3. CAG repeat allele lengths are defined as fully penetrant at >= 40, reduced penetrance at 36-39, high normal at 27-35, and normal at <= 26. Fathers, but not mothers, with high normal alleles are at risk of transmitting potentially penetrant HD alleles (>= 36) to offspring. We estimated the conditional probability of an offspring inheriting an expanded penetrant allele given a father with a high normal allele by applying probability definitions and rules to estimates of HD incidence, paternal birth rate, frequency of de novo HD, and frequency of high normal alleles in the general population. The estimated probability that a male high normal allele carrier will have an offspring with an expanded penetrant allele ranges from 1/6,241 to 1/951. These estimates may be useful in genetic counseling for male high normal allele carriers. (C) 2009 Wiley-Liss, Inc. C1 [Hendricks, Audrey E.; Lunetta, Kathryn L.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Latourelle, Jeanne C.; Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Wheeler, Vanessa; MacDonald, Marcy E.; Gusella, James F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. RP Hendricks, AE (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA. EM baera@bu.edu RI Hendricks, Audrey/I-4127-2016; OI Hendricks, Audrey/0000-0002-7152-0287; Latourelle, Jeanne/0000-0002-4218-9572; Lunetta, Kathryn/0000-0002-9268-810X; Cupples, L. Adrienne/0000-0003-0273-7965; Myers, Richard/0000-0002-8365-2674 FU Huntington's Disease Center Without walls [P50 NS 16367]; Jerry MacDonald HD research fund; Huntington's Disease Society of America; Massachusetts Huntington's Disease Society of America; HDSA; HDSA [NS049206]; NIH NCRR [ISIORR163736-OIAI] FX This study was supported by P50 NS 16367 "Huntington's Disease Center Without walls," the Jerry MacDonald HD research fund, the Huntington's Disease Society of America, the Massachusetts Huntington's Disease Society of America, the HDSA Coalition for the Cure, and by NINDS NS049206. This research was conducted using the Boston University Linux Cluster for Genetic Analysis (LinGA) funded by the NIH NCRR (National Center for Research Resources) Shared Instrurrientation grant (ISIORR163736-OIAI). NR 27 TC 20 Z9 20 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2009 VL 149A IS 7 BP 1375 EP 1381 DI 10.1002/ajmg.a.32901 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 467VA UT WOS:000267770000002 PM 19507258 ER PT J AU Wilhelm-Leen, ER Hall, YN Tamura, MK Chertow, GM AF Wilhelm-Leen, Emilee R. Hall, Yoshio N. Tamura, Manjula K. Chertow, Glenn M. TI Frailty and Chronic Kidney Disease: The Third National Health and Nutrition Evaluation Survey SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Body composition; Chronic kidney disease; Frailty ID GLOMERULAR-FILTRATION-RATE; FUNCTIONAL DECLINE; DIALYSIS PATIENTS; SERUM CREATININE; OLDER-ADULTS; PREDICTION; WOMEN AB BACKGROUND: Frailty is common in the elderly and in persons with chronic diseases. Few studies have examined the association of frailty with chronic kidney disease. METHODS: We used data from the Third National Health and Nutrition Examination Survey to estimate the prevalence of frailty among persons with chronic kidney disease. We created a definition of frailty based on established validated criteria, modified to accommodate available data. We used logistic regression to determine whether and to what degree stages of chronic kidney disease were associated with frailty. We also examined factors that might mediate the association between frailty and chronic kidney disease. RESULTS: The overall prevalence of frailty was 2.8%. However, among persons with moderate to severe chronic kidney disease (estimated glomerular filtration rate < 45 mL/min/1.73 m(2)), 20.9% were frail. The odds of frailty were significantly increased among all stages of chronic kidney disease, even after adjustment for the residual effects of age, sex, race, and prevalent chronic diseases. The odds of frailty associated with chronic kidney disease were only marginally attenuated with additional adjustment for sarcopenia, anemia, acidosis, inflammation, vitamin D deficiency, hypertension, and cardiovascular disease. Frailty and chronic kidney disease were independently associated with mortality. CONCLUSION: Frailty is significantly associated with all stages of chronic kidney disease and particularly with moderate to severe chronic kidney disease. Potential mechanisms underlying the chronic kidney disease and frailty connection remain elusive. (C) 2009 Elsevier Inc. All rights reserved. The American Journal of Medicine (2009) 122, 664-671 C1 [Wilhelm-Leen, Emilee R.; Tamura, Manjula K.; Chertow, Glenn M.] Stanford Univ, Sch Med, Div Nephrol, Dept Med, Palo Alto, CA 94304 USA. [Hall, Yoshio N.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Hall, Yoshio N.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Wilhelm-Leen, ER (reprint author), Stanford Univ, Sch Med, Div Nephrol, Dept Med, 780 Welch Rd,Suite 106, Palo Alto, CA 94304 USA. EM ewilhelm@stanford.edu RI Kurella Tamura, Manjula/C-8284-2014 OI Kurella Tamura, Manjula/0000-0001-5227-2479 FU Stanford University School of Medicine Medical Scholars Program FX This research was funded by a grant from the Stanford University School of Medicine Medical Scholars Program. NR 23 TC 104 Z9 107 U1 2 U2 7 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 JUL PY 2009 VL 122 IS 7 BP 664 EP U86 DI 10.1016/j.amjmed.2009.01.026 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 462HF UT WOS:000267341000014 PM 19559169 ER PT J AU Choi, AI Rodriguez, RA Bacchetti, P Bertenthal, D Hernandez, GT O'Hare, AM AF Choi, Andy I. Rodriguez, Rudolph A. Bacchetti, Peter Bertenthal, Daniel Hernandez, German T. O'Hare, Ann M. TI White/Black Racial Differences in Risk of End-stage Renal Disease and Death SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Kidney disease; Mortality; Racial disparities ID CHRONIC KIDNEY-DISEASE; OF-VETERANS-AFFAIRS; UNITED-STATES; ETHNIC-DIFFERENCES; AFRICAN-AMERICAN; MORTALITY; PREVALENCE; STRATIFICATION; BENEFICIARIES; ASCERTAINMENT AB BACKGROUND: End-stage renal disease disproportionately affects black persons, but it is unknown when in the course of chronic kidney disease racial differences arise. Understanding the natural history of racial differences in kidney disease may help guide efforts to reduce disparities. METHODS: We compared white/black differences in the risk of end-stage renal disease and death by level of estimated glomerular filtration rate (eGFR) at baseline in a national sample of 2,015,891 veterans between 2001 and 2005. RESULTS: Rates of end-stage renal disease among black patients exceeded those among white patients at all levels of baseline eGFR. The adjusted hazard ratios for end-stage renal disease associated with black versus white race for patients with an eGFR >= 90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73m(2), respectively, were 2.14 (95% confidence interval [CI], 1.72-2.65), 2.30 (95% CI, 2.02-2.61), 3.08 (95% CI, 2.74-3.46), 2.47 (95% CI, 2.26-2.70), 1.86 (95% CI, 1.75-1.98), and 1.23 (95% CI, 1.12-1.34). We observed a similar pattern for mortality, with equal or higher rates of death among black persons at all levels of eGFR. The highest risk of mortality associated with black race also was observed among those with an eGFR 45-59 mL/min/1.73m(2) (hazard ratio 1.32, 95% CI, 1.27-1.36). CONCLUSION: Racial differences in the risk of end-stage renal disease appear early in the course of kidney disease and are not explained by a survival advantage among blacks. Efforts to identify and slow progression of chronic kidney disease at earlier stages may be needed to reduce racial disparities. Published by Elsevier Inc. The American Journal of Medicine (2009) 122, 672-678 C1 [Choi, Andy I.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Rodriguez, Rudolph A.; O'Hare, Ann M.] Univ Washington, Seattle, WA 98195 USA. [Rodriguez, Rudolph A.; O'Hare, Ann M.] VA Puget Sound Healthcare Syst, Dept Med, Seattle, WA USA. [Choi, Andy I.; Bacchetti, Peter] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bertenthal, Daniel] San Francisco VA Med Ctr, VA Res Enhancement Award Program, San Francisco, CA USA. [Hernandez, German T.] Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, Dept Med, El Paso, TX USA. RP Choi, AI (reprint author), San Francisco VA Med Ctr, Dept Med, Box 111J,4150 Clement St, San Francisco, CA 94121 USA. EM andy.choi@ucsf.edu FU National Kidney Foundation; National Institutes of Health [K23DK080645-01A1, K23AG028980-03, R01AI069952-03]; W. K. Kellogg Scholars in Health Disparities Program; Paso del Norte Health Foundation's Center for Border Health Research; San Francisco VA Research Enhancement Award Program FX This study was supported by a fellowship grant from the National Kidney Foundation, grants from the National Institutes of Health (K23DK080645-01A1, K23AG028980-03, R01AI069952-03), W. K. Kellogg Scholars in Health Disparities Program, Paso del Norte Health Foundation's Center for Border Health Research, and the San Francisco VA Research Enhancement Award Program to Improve Care for Older Veterans. These funding sources had no involvement in the design or execution of this study. NR 38 TC 52 Z9 52 U1 0 U2 5 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 JUL PY 2009 VL 122 IS 7 BP 672 EP 678 DI 10.1016/j.amjmed.2008.11.021 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 462HF UT WOS:000267341000015 PM 19559170 ER PT J AU Stefancyk, AL AF Stefancyk, Amanda L. TI Safe and Reliable Care SO AMERICAN JOURNAL OF NURSING LA English DT Editorial Material C1 Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. RP Stefancyk, AL (reprint author), Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. EM astefancyk@partners.org NR 1 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-936X J9 AM J NURS JI Am. J. Nurs. PD JUL PY 2009 VL 109 IS 7 BP 70 EP 71 PG 2 WC Nursing SC Nursing GA 465SO UT WOS:000267607700020 ER PT J AU Minkoff, H Ecker, J AF Minkoff, Howard Ecker, Jeffrey TI The California octuplets and the duties of reproductive endocrinologists SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material DE assisted reproductive technology; ethics; octuplets; reproductive endocrinology AB The recent birth of octuplets unleashed a firestorm of publicity, casting a harsh light on the mother and her presumed inadequacies as a parent. It also raised questions about the role of reproductive endocrinologists. Herein we consider 3 aspects of this question: should reproductive endocrinologists consider the economic interests of society, should they consider parenting abilities, and should the number of embryos transferred be limited? We conclude that the ethical obligation of reproductive endocrinologists does not extend to protection of society's economic interests; that reproductive endocrinologists, although poorly trained and situated to gauge an individual's ability to parent, can in extreme circumstances refuse to provide assisted reproductive technology; and that a firm limit on the number of transferred embryos is ethically and medically appropriate. C1 [Minkoff, Howard] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Minkoff, Howard] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Ecker, Jeffrey] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. RP Minkoff, H (reprint author), Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. NR 6 TC 2 Z9 2 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 JUL PY 2009 VL 201 IS 1 AR 15.e1 DI 10.1016/j.ajog.2009.04.053 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 465PM UT WOS:000267599300006 PM 19576370 ER PT J AU Masoud, MI Masoud, I Kent, RL Gowharji, N Hassan, AH Cohen, LE AF Masoud, Mohamed I. Masoud, Ibrahim Kent, Ralph L., Jr. Gowharji, Nour Hassan, Ali H. Cohen, Laurie E. TI Relationship between blood-spot insulin-like growth factor 1 levels and hand-wrist assessment of skeletal maturity SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Article ID FILTER-PAPER; FACTOR-I; IGF-I; HEALTHY-CHILDREN; FACIAL GROWTH; BODY HEIGHT; BONE-GROWTH; HORMONE; SOMATOMEDIN; MATURATION AB Introduction: Accurate prediction of the timing of the pubertal growth spurt and the amount of remaining growth are factors that affect treatment decisions in orthodontics, orthognathic surgery, and dental implantology. For many years, medical and dental professionals have considered hand-wrist radiographs the method of choice for the assessment of skeletal maturity. Insulin-like growth factor 1 (IGF-1) mirrors growth hormone levels and is used by endocrinologists to diagnose growth hormone disturbances. Methods: The objective of this study was to establish a relationship between IGF-1 levels collected from blood-spot samples and hand-wrist radiographs at various skeletal stages. Eighty-four subjects (45 female, 39 male) between the ages of 5 and 25 were included in the study. Each subject had personal information, a hand-wrist radiograph, and a blood-spot sample collected on the same day. Results: The IGF-1 levels were highest at the hand-wrist skeletal stages that were previously associated with the greatest amount of mandibular growth. These levels were significantly higher than at prepuburtal and postpubertal stages. In the postpubertal group, the IGF-1 levels were lower as the subjects' ages increased and they moved away from the onset of puberty. Conclusions: Longitudinal data are necessary to confirm the usefulness of this technique in predicting the timing, the intensity, and the end of the growth spurt. (Am J Orthod Dentofacial Orthop 2009; 136: 59-64) C1 [Hassan, Ali H.] King Abdulaziz Univ, Div Orthodont, Jeddah 21413, Saudi Arabia. [Masoud, Mohamed I.] Dent Specialty Clin, Jeddah, Saudi Arabia. [Kent, Ralph L., Jr.] Forsyth Inst, Boston, MA USA. [Masoud, Mohamed I.; Kent, Ralph L., Jr.] Harvard Univ, Sch Dent Med, Dept Oral Epidemiol & Hlth Policy, Boston, MA 02115 USA. [Cohen, Laurie E.] Childrens Hosp, Neuroendocrinol Program, Boston, MA 02115 USA. RP Masoud, MI (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Epidemiol & Hlth Policy, 188 Longwood Ave,REB 402, Boston, MA 02115 USA. EM masoudortho@gmail.com RI Hassan, Ali/A-3007-2013 OI Hassan, Ali/0000-0002-6132-862X NR 45 TC 7 Z9 7 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0889-5406 EI 1097-6752 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD JUL PY 2009 VL 136 IS 1 BP 59 EP 64 DI 10.1016/j.ajodo.2007.07.023 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 466WR UT WOS:000267695500019 PM 19577149 ER PT J AU Au, P Tam, J Duda, DG Lin, PC Munn, LL Fukumura, D Jain, RK AF Au, Patrick Tam, Joshua Duda, Dan G. Lin, Pei-Chun Munn, Lance L. Fukumura, Dai Jain, Rakesh K. TI Paradoxical Effects of PDGF-BB Overexpression in Endothelial Cells on Engineered Blood Vessels In Vivo SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR; VASCULAR-PERMEABILITY; MOLECULAR REGULATION; ANGIOGENESIS; VEGF; PERICYTES; DIFFERENTIATION; EXPRESSION; MATURATION; MONOCYTES AB Therapeutic revascularization with either exogenous angiogenic growth factors or vascular cells has yet to demonstrate efficacy in the clinic. Injection of angiogenic growth factors often produces unstable and abnormal blood vessels. Blood vascular networks derived from implanted endothelial cells persist only transiently due to the insufficient recruitment of perivascular cells. We hypothesize that a combination of the two approaches may act synergistically to yield a better result. To enhance the recruitment of perivascular cells, human umbilical vein endothelial cells were genetically modified to overexpress platelet-derived growth factor (PDGF)-BB. PDGF-BB overexpression promoted both proliferation and migration of perivascular precursor cells (10T1/2 cells) in vitro. When mock-infected endothelial cells were implanted alone in vivo, they formed transient blood vascular networks that regressed by day 30. PDGF-BB overexpression enhanced the survival of endothelial cells in vivo. However, the PDGF-BB-expressing vessel network failed to establish patent blood flow. Co-implantation of PDGF-BB-overexpressing endothelial cells with 10T1/2 cells paradoxically resulted in the rapid regression of the vascular networks in vivo. PDGF-BB stimulated the expression of both chemokine (C-C motif) ligand 2 (CCL2) and CCL7 in 10T1/2 cells and led to the increased accumulation of macrophages in vivo. These results suggest a potential negative interaction between angiogenic growth factors and vascular cells; their use in combination should be carefully tested in vivo for such opposing effects. (Am J Pathol 2009, 175:294-302; DOI: 10.2353/ajpath.2009.080887) C1 [Au, Patrick; Tam, Joshua; Duda, Dan G.; Lin, Pei-Chun; Munn, Lance L.; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA. [Au, Patrick; Tam, Joshua] MIT, Div Hlth Sci & Technol, Harvard Massachusetts Inst Technol, Cambridge, MA 02139 USA. RP Jain, RK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,Edwin L Steele Lab, 100 Blossom St,Cox 7, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu RI Lin, Pei-Chun/A-3200-2013; Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU American Heart Association Predoctoral Fellowship; National Institutes of Health [P01-CA80124, R01-CA96915, R01-CA115767, R01-CA126642, R01CA85140]; Federal Share/NCI Proton Beam Program Income Grants FX Supported in part by American Heart Association Predoctoral Fellowship (PA) and National Institutes of Health grants P01-CA80124 (RKJ, DF), R01-CA96915 (DIF), R01-CA115767 (RKJ), R01-CA126642 (RKJ), R01CA85140 (RKJ), and Federal Share/NCI Proton Beam Program Income Grants (RKJ, DGD). NR 33 TC 21 Z9 23 U1 1 U2 3 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 JUL PY 2009 VL 175 IS 1 BP 294 EP 302 DI 10.2353/ajpath.2009.080887 PG 9 WC Pathology SC Pathology GA 464MG UT WOS:000267508600027 PM 19477947 ER PT J AU Dicianno, BE Gaines, A Collins, DM Lee, S AF Dicianno, Brad E. Gaines, Anna Collins, Diane M. Lee, Shannon TI Mobility, Assistive Technology Use, and Social Integration Among Adults with Spina Bifida SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Depression; Rehabilitation; Socialization; Spinal Dysraphism; Self-Help Devices; Walking; Wheelchairs ID QUALITY-OF-LIFE; YOUNG-ADULTS; FUNCTIONAL INDEPENDENCE; CORD-INJURY; ADOLESCENTS; MENINGOMYELOCELE; HYDROCEPHALUS; DETERMINANTS; CHILDREN; MYELOMENINGOCELE AB Objective: Many individuals with spina bifida have impairments that limit mobility and functional independence. Sedentary lifestyles and social isolation are very prevalent. This study evaluated the association between the use of mobility devices and degree of socialization. Design: A retrospective chart review was performed on 208 adults with spina bifida attending a university-based clinic. Data collected included the Craig Handicap Assessment Reporting Technique-Short Form, Beck Depression Inventory, and data on wheelchair and other assistive technology use. We hypothesized that community and home mobility and social Integration, as measured by the Craig Handicap Assessment Reporting Technique-Short Form, would be lower for manual and power wheelchair users than for ambulators, regardless of depression scores or shunt history. Results: We found that individuals with spina bifida who used both manual and power wheelchairs do have lower daily home and community activity levels compared with ambulators, but that most individuals with spina bifida have low social integration and economic self-sufficiency scores, regardless of whether they can ambulate or use wheelchairs. These findings were not explained by wheelchair quality because most were prescribed high-quality devices. A high prevalence of depression was also found. Conclusions: Special considerations for wheelchair provision are discussed. Additional research is needed to identify other barriers to social integration. C1 [Dicianno, Brad E.; Gaines, Anna; Collins, Diane M.; Lee, Shannon] Univ Pittsburgh, Human Engn Res Labs, Pittsburgh, PA 15260 USA. [Dicianno, Brad E.; Collins, Diane M.] Univ Pittsburgh, Adult Spina Bifida Clin, Pittsburgh, PA 15260 USA. [Dicianno, Brad E.; Collins, Diane M.; Lee, Shannon] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15260 USA. [Dicianno, Brad E.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA. [Dicianno, Brad E.; Gaines, Anna] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Dicianno, Brad E.; Collins, Diane M.] Ctr Excellence Wheelchairs & Associated Rehabil E, VA Pittsburgh HealthCare Syst, Pittsburgh, PA USA. RP Dicianno, BE (reprint author), Suite 202 Kaufmann Bldg,3471 5th Ave, Pittsburgh, PA 15213 USA. OI Dicianno, Brad/0000-0003-0738-0192 NR 37 TC 20 Z9 20 U1 1 U2 8 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 JUL PY 2009 VL 88 IS 7 BP 533 EP 541 DI 10.1097/PHM.0b013e3181aa41d4 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 463CO UT WOS:000267406400002 PM 19542778 ER PT J AU Larauche, M Gourcerol, G Wang, LX Pambukchian, K Brunnhuber, S Adelson, DW Rivier, J Million, M Tache, Y AF Larauche, Muriel Gourcerol, Guillaume Wang, Lixin Pambukchian, Karina Brunnhuber, Stefan Adelson, David W. Rivier, Jean Million, Mulugeta Tache, Yvette TI Cortagine, a CRF1 agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE CRF1 agonist; colonic motility; visceral pain; rat; mice; colonic permeability; astressin; CP-154,526 ID CORTICOTROPIN-RELEASING-FACTOR; IRRITABLE-BOWEL-SYNDROME; FACTOR SIGNALING PATHWAYS; FACTOR-RELATED PEPTIDES; ENTERIC NERVOUS-SYSTEM; COLORECTAL DISTENSION; RECEPTOR ANTAGONIST; MOTOR FUNCTION; MAST-CELLS; RAT COLON AB Larauche M, Gourcerol G, Wang L, Pambukchian K, Brunnhuber S, Adelson DW, Rivier J, Million M, Tache Y. Cortagine, a CRF1 agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways. Am J Physiol Gastrointest Liver Physiol 297: G215-G227, 2009. First published April 30, 2009; doi:10.1152/ajpgi.00072.2009.-Corticotropin-releasing factor (CRF) 1 receptor (CRF1) activation in the brain is a core pathway orchestrating the stress response. Anatomical data also support the existence of CRF signaling components within the colon. We investigated the colonic response to intraperitoneal (ip) injection of cortagine, a newly developed selective CRF1 peptide agonist. Colonic motor function and visceral motor response (VMR) were monitored by using a modified miniaturized pressure transducer catheter in adult conscious male Sprague-Dawley rats and C57Bl/6 mice. Colonic permeability was monitored by the Evans blue method and myenteric neurons activation by Fos immunohistochemistry. Compared with vehicle, cortagine (10 mu g/kg ip) significantly decreased the distal colonic transit time by 45% without affecting gastric transit, increased distal and transverse colonic contractility by 35.6 and 66.2%, respectively, and induced a 7.1-fold increase in defecation and watery diarrhea in 50% of rats during the first hour postinjection whereas intracerebroventricular (icv) cortagine (3 mu g/rat) had lesser effects. Intraperitoneal (ip) cortagine also increased colonic permeability, activated proximal and distal colonic myenteric neurons, and induced visceral hypersensitivity to a second set of phasic colorectal distention (CRD). The CRF antagonist astressin (10 mu g/kg ip) abolished ip cortagine-induced hyperalgesia whereas injected icv it had no effect. In mice, cortagine (30 mu g/kg ip) stimulated defecation by 7.8-fold, induced 60% incidence of diarrhea, and increased VMR to CRD. Stresslike colonic alterations induced by ip cortagine in rats and mice through restricted activation of peripheral CRF1 receptors support a role for peripheral CRF1 signaling as the local arm of the colonic response to stress. C1 [Larauche, Muriel; Gourcerol, Guillaume; Wang, Lixin; Pambukchian, Karina; Brunnhuber, Stefan; Adelson, David W.; Million, Mulugeta; Tache, Yvette] Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Los Angeles, CA USA. [Larauche, Muriel; Gourcerol, Guillaume; Wang, Lixin; Pambukchian, Karina; Brunnhuber, Stefan; Adelson, David W.; Million, Mulugeta; Tache, Yvette] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Ctr Neurobiol Stress,Dept Med, Los Angeles, CA 90095 USA. [Tache, Yvette] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Rivier, Jean] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, La Jolla, CA USA. RP Larauche, M (reprint author), W Los Angeles VA Med Ctr, CURE Digest Dis Res Ctr, 11301 Wilshire Blvd,Bldg 115,Rm 111, Los Angeles, CA 90073 USA. EM mlarauche@mednet.ucla.edu OI Larauche, Muriel/0000-0003-3320-3675; Adelson, David/0000-0002-4623-6030 FU VA Career Scientist Award; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK-57238, DK-33061, P50 DK-64539, DK AM 41301, DK PO1-26741, DK-068155, T32 DK07180-3255]; French Society of Gastroenterology (SNFGE) FX The research was supported by a VA Career Scientist Award (Y. Tache), National Institute of Diabetes and Digestive and Kidney Diseases Grants R01 DK-57238 and DK-33061 (Y. Tache), P50 DK-64539 (Emeran Mayer), DK AM 41301 (Animal Model Core, Y. Tache), DK PO1-26741 (J. Rivier), DK-068155 (M. Million), T32 DK07180-32 (M. Larauche), and the French Society of Gastroenterology (SNFGE; G. Gourcerol). NR 67 TC 58 Z9 58 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JUL PY 2009 VL 297 IS 1 BP G215 EP G227 DI 10.1152/ajpgi.00072.2009 PG 13 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 472RU UT WOS:000268150500025 PM 19407218 ER PT J AU Nakano, T Inoue, I Alpers, DH Akiba, Y Katayama, S Shinozaki, R Kaunitz, JD Ohshima, S Akita, M Takahashi, S Koyama, I Matsushita, M Komoda, T AF Nakano, Takanari Inoue, Ikuo Alpers, David H. Akiba, Yasutada Katayama, Shigehiro Shinozaki, Rina Kaunitz, Jonathan D. Ohshima, Susumu Akita, Masumi Takahashi, Seiichiro Koyama, Iwao Matsushita, Makoto Komoda, Tsugikazu TI Role of lysophosphatidylcholine in brush-border intestinal alkaline phosphatase release and restoration SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE Caco-2 cells; lipid absorption; small intestine; enzyme-labeled fluorescence-97 ID SURFACTANT-LIKE PARTICLES; FAT; SECRETION; ABSORPTION; PROTEINS; INHIBITION; PROTEASES; FISSION; SERUM; RATS AB Nakano T, Inoue I, Alpers DH, Akiba Y, Katayama S, Shinozaki R, Kaunitz JD, Ohshima S, Akita M, Takahashi S, Koyama I, Matsushita M, Komoda T. Role of lysophosphatidylcholine in brush-border intestinal alkaline phosphatase release and restoration. Am J Physiol Gastrointest Liver Physiol 297: G207-G214, 2009. First published April 30, 2009; doi:10.1152/ajpgi.90590.2008.-Intestinal alkaline phosphatase (IAP) is a brush-border membrane ectoenzyme (BBM-IAP) that is released into the lumen (L-IAP) after a high-fat diet. We examined the effects of oil feeding and the addition of mixed-lipid micelles on the formation of L-IAP in oil-fed rat intestine, Caco-2 cell monolayers, and mouse intestinal loops. We localized IAP in the duodenum of rats fed corn oil using fluorescence microscopy with enzyme-labeled fluorescence-97 as substrate. Four hours after oil feeding, L-IAP increased similar to 10-fold accompanied by the loss of BBM-IAP, consistent with BBM-IAP release. Rat IAP isozyme mRNAs progressively increased 4-6 h after oil feeding, followed by the increase of IAP activity in the subapical location at 6 h, consistent with the restoration of IAP protein. Postprandial lipid-micelle components, sodium taurocholate with or without oleic acid, mono-oleylglycerol, cholesterol, or lysophosphatidylcholine (lysoPC) were applied singly or as mixed-lipid micelles to the apical surface of polarized Caco-2 cell monolayers. LysoPC increased L-IAP > 10-fold over basal release. LysoPC released IAP into the apical medium more than other intestinal brush-border enzymes, 5'-nucleotidase, sucrase, aminopeptidase N, and lactase, without comparable lactate dehydrogenase release or cell injury. LysoPC increased human IAP mRNA levels by 1.5-fold in Caco-2 cells. Luminally applied lysoPC also increased release of IAP preferentially in mouse intestinal loops. These data show that lysoPC accelerates the formation of L-IAP from BBM-IAP, followed by enhanced IAP synthesis, suggesting the role that lysoPC might play in the turnover of brush-border proteins. C1 [Nakano, Takanari; Shinozaki, Rina; Takahashi, Seiichiro; Koyama, Iwao; Matsushita, Makoto; Komoda, Tsugikazu] Saitama Med Univ, Dept Biochem, Saitama, Japan. [Inoue, Ikuo; Katayama, Shigehiro] Saitama Med Univ, Dept Endocrinol & Diabet, Saitama, Japan. [Ohshima, Susumu; Akita, Masumi] Saitama Med Univ, Dept Morphol Sci, Biomed Res Ctr, Fac Med, Saitama, Japan. [Alpers, David H.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Akiba, Yasutada; Kaunitz, Jonathan D.] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. [Nakano, Takanari; Kaunitz, Jonathan D.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Akiba, Yasutada] Brentwood Biomed Res Inst, Los Angeles, CA USA. RP Nakano, T (reprint author), W Angeles VA Med Ctr, Bldg 114,Suite 217,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM nk.takanari@gmail.com FU Japan Foundation of Applied Enzymology; NIH [DK56341, R01 DK54221]; Department of Veterans Affairs Merit Review Award FX This work was supported in part by a grant from the Japan Foundation of Applied Enzymology for T. Nakano, the CNRU grant from NIH, DK56341, for partial support for D. H. Alpers, and a Department of Veterans Affairs Merit Review Award and NIH-NIDDK R01 DK54221 for J. D. Kaunitz. NR 34 TC 23 Z9 24 U1 1 U2 5 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 JUL PY 2009 VL 297 IS 1 BP G207 EP G214 DI 10.1152/ajpgi.90590.2008 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 472RU UT WOS:000268150500024 PM 19407215 ER PT J AU Mu, H Wang, XW Wang, H Lin, P Yao, QH Chen, CY AF Mu, Hong Wang, Xinwen Wang, Hao Lin, Peter Yao, Qizhi Chen, Changyi TI Lactosylceramide promotes cell migration and proliferation through activation of ERK1/2 in human aortic smooth muscle cells SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE vascular smooth muscle cell; cell proliferation; oxidative stress; extracellular signal-regulated kinase 1/2; antioxidant; vascular disease ID ENDOTHELIAL-CELLS; PROTEIN-KINASES; ATHEROSCLEROSIS; GROWTH; GLYCOSPHINGOLIPIDS; EXPRESSION; SELENIUM; DISEASE; ACCUMULATION; ADHESION AB Mu H, Wang X, Wang H, Lin P, Yao Q, Chen C. Lactosylceramide promotes cell migration and proliferation through activation of ERK1/2 in human aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 297: H400-H408, 2009. First published May 22, 2009; doi: 10.1152/ajpheart.01254.2008.-Increased plasma levels of lactosylceramide (LacCer) have been associated with cardiovascular disease. However, it is largely unknown whether LacCer directly contributes to dysfunction of smooth muscle cells (SMCs), a key event in vascular lesion formation. In the present study, we determined the effects and potential mechanisms of LacCer on cell migration and proliferation in human aortic SMCs (AoSMCs). Cell migration and proliferation were determined by a modified Boyden chamber assay and nonradioactive colorimetric (MTS) assay, respectively. We found that LacCer significantly induced AoSMC migration and proliferation in a concentration- and time-dependent manner. In addition, LacCer significantly upregulated the expression of PDGFR-B, integrins (alpha(v) and beta(3)), and matrix metalloproteinases (matrix metalloproteinase-1 and -2) at both mRNA and protein levels, as determined by real-time PCR and Western blot analyses, respectively. Furthermore, LacCer increased superoxide anion production and the transient phosphorylation of ERK1/2 in AoSMCs, as determined by dihydroethidium staining and immunoassay, respectively. Accordingly, LacCer-induced cell migration and proliferation were effectively blocked by antioxidants (seleno-L-methionine and Mn tetrakis porphyrin) and by a specific ERK1/2 inhibitor. Thus, LacCer promotes cell migration and proliferation through oxidative stress and activation of ERK1/2 in AoSMCs. These findings demonstrate the functional role of LacCer in the vascular disease pathogenesis. C1 [Mu, Hong; Wang, Xinwen; Wang, Hao; Lin, Peter; Yao, Qizhi; Chen, Changyi] Baylor Coll Med, Michael E DeBakey Dept Surg, Div Vasc Surg & Endovasc Therapy, Mol Surg Res Ctr, Houston, TX 77030 USA. [Lin, Peter; Yao, Qizhi; Chen, Changyi] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. RP Chen, CY (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg MARB413, 1 Baylor Plaza,Mail Stop BCM390, Houston, TX 77030 USA. EM jchen@bcm.tmc.edu FU Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center FX This work was partially supported by the Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center (Houston, TX). NR 34 TC 16 Z9 16 U1 0 U2 0 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 JUL PY 2009 VL 297 IS 1 BP H400 EP H408 DI 10.1152/ajpheart.01254.2008 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 464GI UT WOS:000267492900047 PM 19465542 ER PT J AU Kolliputi, N Waxman, AB AF Kolliputi, Narasaiah Waxman, Aaron B. TI IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE apoptosis; mitochondria; endothelial cells; JNK; cytokine; Bcl-2 ID DRUG-INDUCED APOPTOSIS; TUMOR-NECROSIS-FACTOR; ENDOTHELIAL-CELLS; MITOCHONDRIAL TRANSLOCATION; SIGNAL-TRANSDUCTION; INDUCED ACTIVATION; MULTIPLE-MYELOMA; INTERLEUKIN-6; DEATH; PROTECTS AB Kolliputi N, Waxman AB. IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation. Am J Physiol Lung Cell Mol Physiol 297: L6-L16, 2009. First published April 17, 2009; doi: 10.1152/ajplung. 90381.2008.-IL-6 overexpression protects mice from hyperoxic acute lung injury in vivo, and treatment with IL-6 protects cells from oxidant-mediated death in vitro. The mechanisms of protection, however, are not clear. We characterized the expression, localization, and regulation of Bax, a proapoptotic member of the Bcl-2 family, in wild-type (WT) and IL-6 lung-specific transgenic (Tg(+)) mice exposed to 100% O(2) and in human umbilical vein endothelial cells (HUVEC) treated with H(2)O(2) and IL-6. In control HUVEC treated with H(2)O(2) or in WT mice exposed to 100% O(2), a marked induction of Bax translocation and dimerization was associated with increased JNK and p38 kinase activity. In contrast, specific JNK or p38 kinase inhibitors or treatment with IL-6 inhibited Bax mitochondrial translocation and apoptosis of HUVEC. IL-6 Tg(+) mice exposed to 100% O(2) exhibited enhanced phosphatidylinositol 3-kinase (PI3K)/Akt kinase and increased serine phosphorylation of Bax at Ser184 compared with WT mice. The PI3K-specific inhibitor LY-2940002 blocked this IL-6-induced Bax phosphorylation and promoted cell death. Furthermore, IL-6 potently blocked hyperoxia-or oxidant-induced Bax insertion into mitochondrial membranes. Thus IL-6 functions in a cytoprotective manner, in part, by suppressing Bax translocation and dimerization through PI3K/Akt-mediated Bax phosphorylation. C1 [Kolliputi, Narasaiah; Waxman, Aaron B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA USA. RP Waxman, AB (reprint author), 55 Fruit St,Bulfinch 148, Boston, MA 02114 USA. EM ABWaxman@Partners.org RI Kolliputi, Narasaiah/I-6050-2012 OI Kolliputi, Narasaiah/0000-0002-2654-1900 FU National Heart, Lung, and Blood Institute [RO1 HL-074859] FX This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-074859 (to A. B. Waxman). NR 44 TC 34 Z9 35 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JUL PY 2009 VL 297 IS 1 BP L6 EP L16 DI 10.1152/ajplung.90381.2008 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 474ID UT WOS:000268276100002 PM 19376889 ER PT J AU Bhargava, P AF Bhargava, Pankaj TI VEGF kinase inhibitors: how do they cause hypertension? SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE neoangiogenesis; side effects; cancer ID ENDOTHELIAL GROWTH-FACTOR; ADVANCED SOLID TUMORS; RENAL-CELL CARCINOMA; PHASE-I; BLOOD-PRESSURE; ANGIOGENESIS INHIBITION; CAPILLARY RAREFACTION; TYROSINE KINASE; FACTOR RECEPTOR; NITRIC-OXIDE AB Bhargava P. VEGF kinase inhibitors: how do they cause hypertension?. Am J Physiol Regul Integr Comp Physiol 297: R1-R5, 2009. First published May 13, 2009; doi:10.1152/ajpregu.90502.2008.-Neoangiogenesis is a critical phenomenon enabling the growth and metastasis of tumors, and inhibitors of neoangiogenesis have been recently added to the armamentarium of anticancer therapies available for clinical use. Dysregulated signaling through the vascular endothelial growth factor ( VEGF) pathway has been implicated as a key mediator of neoangiogenesis in tumors. Agents that block signaling through the VEGF pathway demonstrated tumor shrinkage in preclinical models and were therefore developed as anticancer therapies for use in humans. VEGF kinase inhibitors are being used in the treatment of a wide variety of cancers, and recent studies have shown that patients will likely require long-term treatment with these agents. Hypertension has emerged as a frequent side effect associated with agents that block signaling through the VEGF pathway. A thorough understanding of the mechanisms underlying hypertension is crucial to developing appropriate therapeutic strategies for treating hypertension associated with VEGF kinase inhibitors. Several recent studies have advanced our understanding of the pathophysiology of hypertension associated with VEGF kinase inhibitors and will be the subject of this review. C1 [Bhargava, Pankaj] AVEO Pharmaceut, Clin Res, Cambridge, MA 02139 USA. [Bhargava, Pankaj] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. RP Bhargava, P (reprint author), AVEO Pharmaceut, Clin Res, 75 Sidney St,4th Fl, Cambridge, MA 02139 USA. EM pbhargava@aveopharma.com NR 52 TC 39 Z9 40 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JUL PY 2009 VL 297 IS 1 BP R1 EP R5 DI 10.1152/ajpregu.90502.2008 PG 5 WC Physiology SC Physiology GA 467CO UT WOS:000267714300001 PM 19439616 ER PT J AU Ehrenkranz, PD Pagan, JA Begier, EM Linas, BP Madison, K Armstrong, K AF Ehrenkranz, Peter D. Pagan, Jose A. Begier, Elizabeth M. Linas, Benjamin P. Madison, Kristin Armstrong, Katrina TI Written Informed-Consent Statutes and HIV Testing SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH-CARE SETTINGS; UNITED-STATES; PUBLIC-HEALTH; COST-EFFECTIVENESS; EPIDEMIC; RISK; EXCEPTIONALISM; PHYSICIANS; EMERGENCY; END AB Background: Almost 1 million Americans are infected with HIV, yet it is estimated that as many as 250,000 of them do not know their serostatus. This study examined whether people residing in states with statutes requiring written informed consent prior to HIV testing were less likely to report a recent HIV test. Methods: The study is based on survey data from the 2004 Behavioral Risk Factor Surveillance System. Logistic regression was used to assess the association between residence in a state with a pre-test written informed-consent requirement and individual self-report of recent HIV testing. The regression analyses controlled for potential state- and individual-level confounders. Results: Almost 17% of respondents reported that they had been tested for HIV in the prior 12 months. Ten states had statutes requiring written informed consent prior to routine HIV testing; nine of those were analyzed in this study. After adjusting for other state- and individual-level factors, people who resided in these nine states were less likely to report a recent history of HIV testing (OR=0.85; 95% CI=0.80, 0.90). The average marginal effect was -0.02 (p<0.001, 95% CI=-0.03, -0.01); thus, written informed-consent statutes are associated with a 12% reduction in HIV testing from the baseline testing level of 17%. The association between a consent requirement and lack of testing was greatest among respondents who denied HIV risk factors, were non-Hispanic whites, or who had higher levels of education. Conclusions: This study's findings suggest that the removal of written informed-consent requirements might promote the non-risk-based routine-testing approach that the Centers for Disease Control and Prevention (CDC) advocates in its new testing guidelines. (Am J Prev Med 2009;37(1):57-63) (C) 2009 American journal of Preventive Medicine C1 [Pagan, Jose A.] Univ Texas Pan Amer, Dept Econ & Finance, Edinburg, TX 78539 USA. [Ehrenkranz, Peter D.; Armstrong, Katrina] Univ Penn, Dept Gen Med, Philadelphia, PA 19104 USA. [Ehrenkranz, Peter D.; Pagan, Jose A.; Madison, Kristin; Armstrong, Katrina] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Madison, Kristin] Univ Penn, Sch Law, Philadelphia, PA 19104 USA. [Begier, Elizabeth M.] New York City Dept Hlth & Mental Hyg, New York, NY USA. [Linas, Benjamin P.] Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. RP Pagan, JA (reprint author), Univ Texas Pan Amer, Dept Econ & Finance, 1201 W Univ Dr, Edinburg, TX 78539 USA. EM jpagan@utpa.edu OI Linas, Benjamin/0000-0001-9574-7075 FU Robert Wood Johnson Foundation; National Institute of Allergy and Infectious Diseases [K01A1073193] FX The principal investigator, Peter Ehrenkranz, MD, MPH, had full access to all the data in the study and takes responsibility for its integrity and the accuracy of the data analysis. None of the authors has financial interests, relationships, or affiliations relevant to the subject of the manuscript. The work was funded by the Robert Wood Johnson Foundation and its support of the Clinical Scholars Program. Dr. Linas acknowledges tile financial support of the National Institute of Allergy and Infectious Diseases (grant number K01A1073193). NR 40 TC 15 Z9 15 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUL PY 2009 VL 37 IS 1 BP 57 EP 63 DI 10.1016/j.amepre.2009.03.011 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 462IE UT WOS:000267343800009 PM 19423271 ER PT J AU Tuerk, PW Grubaugh, AL Hamner, MB Foa, EB AF Tuerk, Peter W. Grubaugh, Anouk L. Hamner, Mark B. Foa, Edna B. TI Diagnosis and Treatment of PTSD-Related Compulsive Checking Behaviors in Veterans of the Iraq War: The Influence of Military Context on the Expression of PTSD Symptoms SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID EXPOSURE; DISORDER AB This case study presents an overview of the conceptualization and treatment of two veterans of the Iraq War who presented for combat-related treatment at a Veterans Administration Medical Center. In addition to posttraumatic stress disorder (PTSD) symptoms of reexperiencing, arousal, and avoidance, the veterans exhibited compulsive checking behaviors that appear to be influenced by theater-specific combat duties and traumatic events. These cases represent what the authors believe to be an increasingly common expression of PTSD in veterans of the Iraq and Afghanistan wars. Both veterans were treated with prolonged exposure therapy, which includes imaginal and in vivo exposure to anxiety-provoking stimuli, processing of traumatic events, and self-assessment of anxiety. Treatment also included in vivo exposure with response prevention techniques borrowed from the literature on obsessive-compulsive disorder to address compulsive checking behaviors within the ecological context of each patient's symptom presentation. Measures related to PTSD and depression were obtained before, during, and after treatment. Treatment was associated with significant declines in symptom severity and improved functioning for both veterans. The unique nature of the conflict in the Middle East represents role challenges for soldiers that affect symptom presentation. Variations in symptom presentation can in turn complicate efforts to identify and appropriately address PTSD-related health concerns in this population. Thus, clinicians and researchers must remain cognizant of how theater-specific duties influence the manifestation and treatment of PTSD in order to provide optimal care to a new generation of veterans. C1 Ralph H Johnson Vet Affairs Med Ctr, Post Traumat Stress Clin Team, Charleston, SC USA. Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. Univ Penn, Dept Psychiat, Ctr Treatment & Study Anxiety, Philadelphia, PA 19104 USA. RP Tuerk, PW (reprint author), Charleston VAMC, Mental Hlth 116,109 Bee St, Charleston, SC 29401 USA. EM Tuerk@musc.edu NR 24 TC 15 Z9 16 U1 1 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2009 VL 166 IS 7 BP 762 EP 767 DI 10.1176/appi.ajp.2009.08091315 PG 6 WC Psychiatry SC Psychiatry GA 465RF UT WOS:000267603800007 PM 19570938 ER PT J AU Torriani, M Souto, SCL Thomas, BJ Ouellette, H Bredella, MA AF Torriani, Martin Souto, Silvio C. L. Thomas, Bijoy J. Ouellette, Hugue Bredella, Miriam A. TI Ischiofemoral Impingement Syndrome: An Entity With Hip Pain and Abnormalities of the Quadratus Femoris Muscle SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE femur; impingement; ischium; lesser trochanter; quadratus femoris muscle ID LESSER TROCHANTER; TEAR AB OBJECTIVE. The purpose of this study was to describe the MRI findings of an entity in which patients present with hip pain, abnormal MR signal intensity of the quadratus femoris muscle, and narrowing of the ischiofemoral space. MATERIALS AND METHODS. We reviewed MR images of 12 hips in nine patients with hip pain and abnormal MR signal intensity of the quadratus femoris muscle. Using axial MR images, two musculoskeletal radiologists measured the ischiofemoral and quadratus femoris spaces. We also examined changes to muscles and tendons for the presence of edema and tears. Data were compared with 11 hips in 10 control subjects. Statistical analyses determined interobserver variability and differences between groups. RESULTS. Subjects with an abnormal quadratus femoris muscle were all women 30-71 years old ( mean age, 53 years) and had significantly narrower ischiofemoral spaces when compared with control subjects (13 +/- 5 vs 23 +/- 8 mm, respectively; p = 0.002). The quadratus femoris space was significantly narrower in affected subjects (7 +/- 3 vs 12 +/- 4 mm; p = 0.002). Abnormalities of the quadratus femoris muscle included edema (100%), partial tear (33%), and fatty infiltration (8%). The hamstring tendons of affected subjects showed evidence of edema (50%) and partial tears (25%). CONCLUSION. Ischiofemoral impingement may represent a cause of hip pain and should be considered in cases with MR signal abnormality of quadratus femoris muscle. C1 [Torriani, Martin; Thomas, Bijoy J.; Ouellette, Hugue; Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Radiol, Boston, MA 02114 USA. [Torriani, Martin; Thomas, Bijoy J.; Ouellette, Hugue; Bredella, Miriam A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Souto, Silvio C. L.] Tesla Med Diagnost, Pelotas, Rio Grande Sul, Brazil. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Radiol, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM mtorriani@hms.harvard.edu NR 7 TC 71 Z9 77 U1 1 U2 5 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 JUL PY 2009 VL 193 IS 1 BP 186 EP 190 DI 10.2214/AJR.08.2090 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 460XS UT WOS:000267226600025 PM 19542413 ER PT J AU Hariri, S Savidge, ET Reinold, MM Zachazewski, J Gill, TJ AF Hariri, Sanaz Savidge, Edgar T. Reinold, Michael M. Zachazewski, James Gill, Thomas J. TI Treatment of Recalcitrant Iliotibial Band Friction Syndrome With Open Iliotibial Band Bursectomy Indications, Technique, and Clinical Outcomes SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE iliotibial band friction syndrome; iliotibial band bursectomy; arthroscopy; lateral knee pain ID MR-IMAGING FINDINGS; SURGICAL-TREATMENT; RUNNERS; KNEE; MANAGEMENT AB Background: Iliotibial band friction syndrome (ITBFS) is an overuse injury causing lateral knee pain. There is evidence that the pathological lesion is in fact an inflamed bursa underlying the iliotibial band (ITB) rather than an inflamed ITB itself. Hypothesis: Resection of the bursa underlying the ITB in ITBFS patients will relieve their pain and allow them to return to their preinjury activity level. Study Design: Case series; Level of evidence, 4. Methods: We describe the technique of ITB bursectomy and report a minimal 20-month follow-up of patients who had ITB bursectomies performed by a single surgeon. The patients completed a survey detailing their preoperative and postoperative symptoms and activities. Results: The senior author performed 12 consecutive cases of ITB bursectomies (12 patients). One was excluded from the study (previous microfracture). The average age at surgery was 32 years (standard deviation, 5; range, 24-41). There were 7 men and 4 women. Postoperatively, patients were able to return to their preinjury Tegner activity levels, and the visual analog pain scores decreased by an average of 6 points (P < .001). Six patients were completely satisfied with the surgical outcome, 3 were mostly satisfied, 2 were somewhat satisfied, and none were dissatisfied. Nine of 11 patients said that knowing what they know now, they would have the surgery performed again for the same problem. Conclusion: Iliotibial band bursectomy successfully reduces knee pain in patients with ITBFS and allows them to return to their preinjury level of activity. The great majority of patients were satisfied with the results of the procedure. C1 [Hariri, Sanaz] Massachusetts Gen Hosp, Dept Orthopaed Surg, Div Sports Med, YCOC, Boston, MA 02114 USA. [Savidge, Edgar T.] MGH Sports Phys Therapy, Boston, MA USA. [Zachazewski, James] Mass Gen Rehab Serv Foxborough, Dept Phys & Occupat Therapy, Foxboro, MA USA. RP Hariri, S (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Div Sports Med, YCOC, 55 Fruit St,Suite 3700, Boston, MA 02114 USA. EM sanaz@post.harvard.edu NR 28 TC 5 Z9 6 U1 0 U2 5 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 JUL PY 2009 VL 37 IS 7 BP 1417 EP 1424 DI 10.1177/0363546509332039 PG 8 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 464OI UT WOS:000267514400020 PM 19286912 ER PT J AU Wilks, JA Liebig, C Tasleem, SH Haderxhanaj, K Lee, L Farrow, B Awad, S Berger, D Albo, D AF Wilks, Jonathan A. Liebig, Catherine Tasleem, Syed H. Haderxhanaj, Kujtim Lee, Liz Farrow, Buckminster Awad, Samir Berger, David Albo, Daniel TI Rectal cancer patients benefit from implementation of a dedicated colorectal cancer center in a Veterans affairs medical center SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Cancer center; Colorectal cancer; Clinical outcomes; Rectal cancer; Veterans ID RANDOMIZED-TRIAL; VOLUME; OUTCOMES; SURGERY; SPECIALIZATION; RADIOTHERAPY; QUALITY; THERAPY AB BACKGROUND: A dedicated colorectal cancer (CRC) center was created in a Veterans Affairs Medical Center with the intent of improving quality of patient care and multidisciplinary cooperation. METHODS: Retrospective and prospective databases before and after creation of the CRC center, respectively, were created. Patients entered in each database included those requiring surgical intervention for CRC treatment. Statistical analyses included Fisher's exact, chi-square, and unpaired Student t tests as well as analysis of variance. RESULTS: The overall quality of care of CRC patients has improved as evidenced by a larger percentage of complete, margin-negative resections (P <.05) as well as an increase in the number of lymph nodes excised at surgery (P <.0001). Furthermore, a multidisciplinary approach is clearly beneficial as evidenced by the increased number of CRC patients receiving appropriate multidisciplinary therapy (P <.0001). CONCLUSIONS: A dedicated CRC center has significantly improved quality of care for CRC patients. (C) 2009 Published by Elsevier Inc. C1 [Wilks, Jonathan A.; Liebig, Catherine; Tasleem, Syed H.; Haderxhanaj, Kujtim; Lee, Liz; Farrow, Buckminster; Awad, Samir; Berger, David; Albo, Daniel] Michael E DeBakey Vet Affairs Med Ctr, Dept Surg, Houston, TX 77030 USA. [Wilks, Jonathan A.; Liebig, Catherine; Lee, Liz; Farrow, Buckminster; Awad, Samir; Berger, David; Albo, Daniel] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA. RP Albo, D (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Dept Surg, Houston, TX 77030 USA. EM dalbo@bcm.edu NR 15 TC 9 Z9 10 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2009 VL 198 IS 1 BP 100 EP 104 DI 10.1016/j.amjsurg.2008.09.020 PG 5 WC Surgery SC Surgery GA 467WK UT WOS:000267773600017 PM 19268899 ER PT J AU Sano, Y Hermsen, JL Kang, W Gomez, FE Lan, J Maeshima, Y Kudsk, KA AF Sano, Yoshifumi Hermsen, Joshua L. Kang, Woodae Gomez, F. Enrique Lan, Jinggang Maeshima, Yoshinori Kudsk, Kenneth A. TI Parenteral nutrition maintains pulmonary IgA antibody transport capacity, but not active transport, following injury SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Mucosal immunology; Injury; Enteral nutrition; Parenteral nutrition; Polymeric immunoglobulin receptor ID POLYMERIC IMMUNOGLOBULIN RECEPTOR; MAJOR ABDOMINAL-TRAUMA; SECRETORY COMPONENT; SEPTIC MORBIDITY; MUCOSAL IMMUNITY; ROUTE; EXPRESSION; RESPONSES; BINDING; INTESTINE AB BACKGROUND: Parenteral nutrition (PN) increases post-trauma pneumonia versus enteral feeding. PN impairs murine immunoglobulin A (IgA) airway defenses and abrogates a normal IgA increase following injury. This work investigates the effect of type/route of nutrition on lung IgA and its transport protein, polymeric immunoglobulin receptor (pIgR), after injury. METHODS: Catheterized mice were randomized to Chow or PN for 5 days and sacrificed without injury (Chow: n = 12; PN n = 11), or 8 hours after laparotomy + neck incisions (Chow-injury: n = 11, PN-injury: n = 13). Bronchoalveolar lavage (BAL) and lung IgA levels were analyzed by enzyme-linked immunosorbent assay (ELISA) and lung pIgR by Western blot. RESULTS: BAL IgA levels increased in Chow-injury versus PN-injury (P <.01) with no differences in pIgR. PN-injury tissue IgA levels decreased versus Chow (P <.01), Chow-injury (P <.01), and PN (P <.05). CONCLUSIONS: PN impairs the airway IgA response to injury but not due to impaired IgA transport capacity/pIgR level. (C) 2009 Elsevier Inc. All rights reserved. C1 [Sano, Yoshifumi; Hermsen, Joshua L.; Kang, Woodae; Gomez, F. Enrique; Lan, Jinggang; Maeshima, Yoshinori; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Coll Med, Madison, WI 53706 USA. [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Kudsk, KA (reprint author), Univ Wisconsin, Dept Surg, Coll Med, Madison, WI 53706 USA. EM kudsk@surgery.wisc.edu RI Lan, Jinggang/F-1776-2011 FU National Institutes of Health [R01 GM53439]; Office of Research and Development, Biomedical Laboratory R&D Service, Department of Veterans Affairs FX Supported by Grant No. R01 GM53439 from the National Institutes of Health and based on work supported in part by the Office of Research and Development, Biomedical Laboratory R&D Service, Department of Veterans Affairs. NR 32 TC 13 Z9 13 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 0002-9610 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2009 VL 198 IS 1 BP 105 EP 109 DI 10.1016/j.amjsurg.2008.08.018 PG 5 WC Surgery SC Surgery GA 467WK UT WOS:000267773600018 PM 19249732 ER PT J AU Collins, LC Martyniak, A Kandel, MJ Stadler, ZK Masciari, S Miron, A Richardson, AL Schnitt, SJ Garber, JE AF Collins, Laura C. Martyniak, Anthony Kandel, Michaela J. Stadler, Zsofia K. Masciari, Serena Miron, Alexander Richardson, Andrea L. Schnitt, Stuart J. Garber, Judy E. TI Basal Cytokeratin and Epidermal Growth Factor Receptor Expression Are Not Predictive of BRCA1 Mutation Status in Women With Triple-negative Breast Cancers SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE breast cancer; basal; BRCA1 mutation; basal cytokeratins ID IMMUNOHISTOCHEMICAL MARKERS; EPITHELIAL PHENOTYPE; ESTROGEN-RECEPTOR; TUMORS; CARCINOMA AB Background: Over 80% of breast cancers in women with germline BRCA1 mutations are estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative ("triple negative") and most of these have a basal-like phenotype by expression profiling and immunophenotypic analysis. However, whether or not expression of biomarkers characteristic of basal-like breast cancers helps to define a subset of women with triple-negative breast cancers who are likely to harbor BRCA1 mutations is an Unresolved issue. Methods: We randomly identified 165 women from the Dana-Farber/Harvard Cancer Center SPORE annotated specimen bank with primary invasive, triple-negative breast cancers. Tissue microarrays were constructed by obtaining triplicate 0.6 mm cores from available paraffin blocks from 130 cases: only unstained slides were available for immunostaining from 35 cases. Slides cut from the tissue microarrays and the unstained slides were immunostained for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (to confirm triple-negative status) and for several markers that have been reported to be useful in defining the basal-like phenotype, including basal cytokeratins CK5/6, CK14, and CK17 and epidermal growth factor receptor (EGFR). Full sequencing analysis for BRCA1 germline mutations was performed on blood specimens from all cases. The final Study population consisted of 144 cases in which (1) triple-negative status was confirmed; (2) there was sufficient material for analysis of basal cytokeratins and EGFR; and (3) germline BRCA1 mutation status was known. Results: Among these triple-negative breast cancer cases, 97 (67%) expressed one or more basal cytokeratins and 102 (71%) showed EGFR expression. Basal cytokeratin expression was detected in 65% of the tumor from the 20 BRCA1 mutation carriers and in 68% of the cancers from women without mutations (P = NS). EGFR expression was identified in a similar proportion of tumors from women with and without BRCA1 Mutations (75% vs. 72%, P = NS). Conclusions: Basal cytokeratin and EGFR expression are both highly prevalent among triple-negative breast cancers. The frequency of expression of basal cytokeratins and EGFR was similar in women with and without BRCA1 mutations. Therefore, although the expression of basal cytokeratins and/or EGFR can be used to identify triple-negative breast cancers that have a basal-like phenotype, expression of these markers alone is not sufficient to distinguish which women with triple-negative breast cancers are likely to harbor BRCA1 germline mutations. C1 [Collins, Laura C.; Schnitt, Stuart J.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Martyniak, Anthony; Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Martyniak, Anthony; Richardson, Andrea L.] Harvard Univ, Sch Med, Boston, MA USA. [Masciari, Serena; Miron, Alexander; Garber, Judy E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Masciari, Serena; Miron, Alexander; Garber, Judy E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Kandel, Michaela J.] Dr Horst Schmidt Klin, Klin Gynakol & Gynakol Onkol, Wiesbaden, Germany. [Stadler, Zsofia K.] Mem Sloan Kettering Canc Ctr, Div Med Oncol, New York, NY 10021 USA. RP Collins, LC (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM lcollins@bidmc.harvard.edu FU Breast Cancer Research Foundation; Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence in Breast Cancer FX Supported by a grant from the Breast Cancer Research Foundation and the Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence in Breast Cancer. NR 17 TC 40 Z9 41 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JUL PY 2009 VL 33 IS 7 BP 1093 EP 1097 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 471GG UT WOS:000268043400016 PM 19390427 ER PT J AU Samah, B Porcheray, F Horellou, P Mabondzo, A Clayette, P Gras, G AF Samah, Boubekeur Porcheray, Fabrice Horellou, Philippe Mabondzo, Aloise Clayette, Pascal Gras, Gabriel TI Neurotrophins differently regulate glutamate transport in macrophages and astrocytes SO AMINO ACIDS LA English DT Meeting Abstract C1 [Samah, Boubekeur; Gras, Gabriel] CEA, Div Immunovirol, UMR E01, Fontenay Aux Roses, France. [Samah, Boubekeur; Gras, Gabriel] Univ Paris Sud, DSV, iMETI, SIV, Fontenay Aux Roses, France. [Porcheray, Fabrice] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Horellou, Philippe] Univ Paris Sud, INSERM, U802, Le Kremlin Bicetre, France. [Mabondzo, Aloise] CEA, Div Pharmacol & Immunoanal, DSV IBITEC S SPI, Saclay, France. [Clayette, Pascal] CEA, SPI BIO, Fontenay Aux Roses, France. RI porcheray, fabrice/B-9505-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD JUL PY 2009 VL 37 IS 1 SU S BP 20 EP 20 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 468MN UT WOS:000267823800063 ER PT J AU Rathmell, JP AF Rathmell, James P. TI Toward Improving the Safety of Transforaminal Injection SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID EPIDURAL STEROID INJECTIONS; INTRAVASCULAR PENETRATION; VERTEBRAL ARTERY C1 [Rathmell, James P.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care & Pain Med, Div Pain Med, Boston, MA 02114 USA. [Rathmell, James P.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. RP Rathmell, JP (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St,GRB 444, Boston, MA 02114 USA. EM jrathmell@partners.org NR 13 TC 11 Z9 11 U1 1 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 JUL PY 2009 VL 109 IS 1 BP 8 EP 10 DI 10.1213/ane.0b013e3181a81ee1 PG 3 WC Anesthesiology SC Anesthesiology GA 461NT UT WOS:000267275100004 PM 19535690 ER PT J AU Binshtok, AM Gerner, P Oh, SB Puopolo, M Suzuki, S Roberson, DP Herbert, T Wang, CF Kim, D Chung, G Mitani, AA Wang, GK Bean, BP Woolf, CJ AF Binshtok, Alexander M. Gerner, Peter Oh, Seog Bae Puopolo, Michelino Suzuki, Suzuko Roberson, David P. Herbert, Teri Wang, Chi-Fei Kim, Donghoon Chung, Gehoon Mitani, Aya A. Wang, Ging Kuo Bean, Bruce P. Woolf, Clifford J. TI Coapplication of Lidocaine and the Permanently Charged Sodium Channel Blocker QX-314 Produces a Long-lasting Nociceptive Blockade in Rodents SO ANESTHESIOLOGY LA English DT Article ID VANILLOID RECEPTOR TRPV1; IN-VIVO; CAPSAICIN RECEPTOR; LOCAL-ANESTHETICS; SENSORY NEURONS; PAIN; RAT; HYPERALGESIA; NERVE; SITE AB Background: Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314-mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia. Methods: Lidocaine (0.5% [17.5 mM], 1% [35 mM], and 2% [70 mM]) alone, QX-314 (0.2% [5-8 mM]) alone, and a combination of the two were injected subcutaneously and adjacent to the sciatic nerve in rats and mice. Mechanical and thermal responsiveness were measured, as was motor block. Results: Coapplication of 0.2% QX-314 with lidocaine prolonged the nociceptive block relative to lidocaine alone, an effect attenuated in TRPV1 knockout mice. The 0.2% QX-314 alone had no effect when injected intraplantary or perineurally, and it produced only weak short-lasting inhibition of the cutaneous trunci muscle reflex. Perisciatic nerve injection of lidocaine with QX-314 produced a differential nociceptive block much longer than the transient motor block, lasting 2 h (for 1% lidocaine) to 9 h (2% lidocaine). Triple application of lidocaine, QX-314, and capsaicin further increased the duration of the differential block. Conclusions: Coapplication of lidocaine and its quaternary derivative QX-314 produces a long-lasting, predominantly nociceptor-selective block, likely by facilitating QX-314 entry through TRPV1 channels. Delivery of QX-314 into nociceptors by using lidocaine instead of capsaicin produces sustained regional analgesia without nocifensive behavior. C1 Brigham & Womens Hosp, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 149 13th St, Charlestown, MA 02129 USA. EM cwoolf@partners.org RI Chung, Gehoon/C-5714-2008 OI Chung, Gehoon/0000-0002-8036-0879 FU Harvard Medical School, Boston, Massachusetts; Ministry of Science and Technology, Seoul, Republic of Korea [M103KV010015-08K2201-01510] FX Received from the Department of Anesthesia and Critical Care, Massachusetts General Hospital, the Department of Anesthesiology, Perioperative, Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Submitted for publication August 24, 2008. Accepted for publication March 7, 2009. This research was supported by Alice and Joseph Brooks Fund from Harvard Medical School, Boston, Massachusetts, (to Dr. Oh) and by grant M103KV010015-08K2201-01510 front Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Seoul, Republic of Korea (to Dr. Oh). Endo Pharmaceuticals (Chadds Ford, Pennsylvania) has obtained a license to develop this strategy with Harvard Medical School and the Massachusetts General Hospital. This agreement was concluded after completion of this body of work. Drs. Binshtok and Gerner authors contributed equally to this work. NR 36 TC 49 Z9 50 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2009 VL 111 IS 1 BP 127 EP 137 PG 11 WC Anesthesiology SC Anesthesiology GA 462IY UT WOS:000267346200022 PM 19512868 ER PT J AU Smith, AK Fisher, J Schonberg, MA Pallin, DJ Block, SD Forrow, L Phillips, RS McCarthy, EP AF Smith, Alexander K. Fisher, Jonathan Schonberg, Mara A. Pallin, Daniel J. Block, Susan D. Forrow, Lachlan Phillips, Russell S. McCarthy, Ellen P. TI Am I Doing the Right Thing? Provider Perspectives on Improving Palliative Care in the Emergency Department SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID ILLNESS; TRENDS; LIFE; END AB Study objective: Although the focus of emergency care is on the diagnosis and treatment of acute illnesses and injuries or the stabilization of patients for ongoing treatment, some patients may benefit from a palliative approach. Little is known about delivering palliative care in the emergency department (ED). We explore the attitudes, experiences, and beliefs of emergency providers about palliative care in the ED, using structured qualitative methods. Methods: We studied 3 focus groups with 26 providers, including 14 physicians (10 residents, 4 attending physicians), 6 nurses, 2 social workers, and 4 technicians, working in 2 academic EDs in Boston. We used a grounded theory approach to code responses, resolving discrepancies by consensus. Results: Six distinct themes emerged: (1) participants equated palliative care with end-of-life care; (2) participants disagreed about the feasibility and desirability of providing palliative care in the ED; (3) patients for whom a palliative approach has been established often visit the ED because family members are distressed by end-of-life symptoms; (4) lack of communication between outpatient and ED providers leads to undesirable outcomes leg, resuscitation of patients with a do-not-resuscitate order); (5) conflict around withholding life-prolonging treatment is common leg, between patient's family and written advance directives); and (6) training in pain management is inadequate. Conclusion: Providers ranked improved communication and documentation from outpatient providers as their highest priority for improvement. Attitudinal and structural barriers may need to be overcome to improve palliative care in the ED. Despite targeted recruitment, attending physician participation was low. [Ann Emerg Med. 2009;54:86-93.] C1 [Smith, Alexander K.; Schonberg, Mara A.; Forrow, Lachlan; Phillips, Russell S.; McCarthy, Ellen P.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Fisher, Jonathan] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA. [Smith, Alexander K.; Block, Susan D.] Dana Farber Canc Inst, Div Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Pallin, Daniel J.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Pallin, Daniel J.] Childrens Hosp Boston, Div Emergency Med, Boston, MA USA. RP Smith, AK (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St 181G, San Francisco, CA 94121 USA. EM aksmith@ucsf.edu RI Pallin, Daniel/H-6382-2013 OI Pallin, Daniel/0000-0002-8517-9702 FU The Julie Henry Fund at Beth Israel Deaconess Hospital; National Research Service Award [5 T32 HP11001-19] FX 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. This study was performed in its entirety while Dr. Smith was a general medicine fellow at Beth Israel Deaconess Medical Center. This research was supported by The Julie Henry Fund at Beth Israel Deaconess Hospital. Dr. Smith was supported by an institutional National Research Service Award, #5 T32 HP11001-19. NR 17 TC 74 Z9 75 U1 2 U2 14 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 JUL PY 2009 VL 54 IS 1 BP 86 EP 93 DI 10.1016/j.annemergmed.2008.08.022 PG 8 WC Emergency Medicine SC Emergency Medicine GA 468VX UT WOS:000267853500018 ER PT J AU Moriyama, B Henning, SA Neuhauser, MM Danner, RL Walsh, TJ AF Moriyama, Brad Henning, Stacey A. Neuhauser, Melinda M. Danner, Robert L. Walsh, Thomas J. TI Continuous-infusion beta-Lactam Antibiotics During Continuous Venovenous Hemofiltration for the Treatment of Resistant Gram-Negative Bacteria SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE Acinetobacter baumannii; beta-lactam; continuous infusion; continuous venovenous hemofiltration; Pseudomonas aeruginosa ID RENAL REPLACEMENT THERAPY; CRITICALLY-ILL PATIENTS; PSEUDOMONAS-AERUGINOSA INFECTION; SINGLE-DOSE PHARMACOKINETICS; RABBIT ENDOCARDITIS MODEL; IN-VITRO; CYSTIC-FIBROSIS; CLAVULANIC ACID; INTERMITTENT INFUSION; ANTIMICROBIAL AGENTS AB OBJECTIVE: To describe the rationale, principles, and dosage calculations for continuous-infusion beta-lactam antibiotics to treat multidrug-resistant bacteria in patients undergoing continuous venovenous hemofiltration (CVVH). DATA SOURCES: A MEDLINE search (1968-November 2008) of the English-language literature was performed using the terms continuous infusion and Pseudomonas or Acinetobacter, hemofiltration or CVVH or hemodiafiltration or CVVHDF or continuous renal replacement therapy or pharmacokinetics; and terms describing different beta-lactam antibiotics. STUDY SELECTION AND DATA EXTRACTION: In vitro, in vivo, and human studies were evaluated that used continuous-infusion beta-lactam antibiotics to treat Pseudomonas aeruginosa and Acinetobacter baumannii infections. Studies were reviewed that described the pharmacokinetics of beta-lactam antibiotics during CVVH as well as other modalities of continuous renal replacement therapy. DATA SYNTHESIS: Continuous infusion of beta-lactam antibiotics, maintaining drug concentrations 4-5 times higher than the minimum inhibitory concentration, is a promising approach for managing infections caused by P. aeruginosa and A. baumannii. Safe yet effective continuous infusion therapy is made difficult by the occurrence of acute renal failure and the need for renal replacement therapy. Case series and pharmacokinetic properties indicate that several beta-lactam antimicrobials that have been studied for continuous infusion, such as cefepime, ceftazidime, piperacillin, ticarcillin, clavulanic acid, and tazobactam, are significantly cleared by hemofiltration. Methodology and formulas are provided that allow practitioners to calculate dosage regimens and reach target drug concentrations for continuous beta-lactam antibiotic infusions during CVVH based on a literature review, pharmacokinetic principles, and our experience at the National Institutes of Health Clinical Center. CONCLUSIONS: Continuous infusion of beta-lactam antibiotics may be a useful treatment strategy for multidrug-resistant gram-negative infections in the intensive care unit. Well-established pharmacokinetic and pharmacodynamic principles can be used to safely reach and maintain steady-state target concentrations of beta-lactam antibiotics in critical illness complicated by acute renal failure requiring CVVH. C1 [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Moriyama, Brad; Henning, Stacey A.] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Neuhauser, Melinda M.] US Dept Vet Affairs, Pharm Benefits Management Serv, Hines, IL USA. [Danner, Robert L.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), CRC 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov FU National Institutes of Health FX This work was supported in part by the intramural research program of the National Institutes of Health. NR 87 TC 9 Z9 10 U1 0 U2 1 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL-AUG PY 2009 VL 43 IS 7-8 BP 1324 EP 1337 DI 10.1345/aph.1L638 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 477IM UT WOS:000268512700020 PM 19584386 ER PT J AU Colwell, AS Driscoll, D Breuing, KH AF Colwell, Amy S. Driscoll, Daniel Breuing, Karl H. TI Mastopexy Techniques After Massive Weight Loss An Algorithmic Approach and Review of the Literature SO ANNALS OF PLASTIC SURGERY LA English DT Article DE massive weight loss; mastopexy; autoaugmentation; breast lift; breast reduction; AlloDerm; spiral flap; ICAP; breast ID ARTERY PERFORATOR FLAP; REDUCTION MAMMAPLASTY; VERTICAL MAMMAPLASTY; AUGMENTATION; BREAST; SUSPENSION; SURGERY; UPDATE; BEWARE; SHAPE AB Mastopexy after massive weight loss (MWL) poses unique challenges that may not be successfully addressed with traditional mastopexy procedures. Several novel techniques have been proposed to improve esthetic outcomes; however, little data exists to guide the plastic surgeon on choice of technique for individual patients. A literature review revealed 10 articles with specific emphasis on mastopexy techniques in MWL patients. These articles focused on ways to improve shape, projection, and long-term results, using autologous tissue alone or combined with breast implants. Key concepts include increasing volume of the breast by utilizing excess axillary tissue (lateral thoracic/spiral/intercostal artery perforator flap), modification of existing superomedial pedicle techniques to maximize breast volume, and increasing breast parenchymal support with suture fixation and dermal suspension. This article offers an algorithmic approach to treat breast ptosis in the MWL patient based on breast volume, axillary tissue, desired scar location, and preferred surgical technique. C1 [Colwell, Amy S.; Driscoll, Daniel] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp,Div Plast Surg, Boston, MA 02115 USA. [Breuing, Karl H.] Harvard Univ, Brigham & Womens Hosp, Div Plast Surg, Sch Med,Dept Surg, Boston, MA 02115 USA. RP Colwell, AS (reprint author), Mass Gen Hosp, Div Plast Surg, 15 Parkman St Wang 435, Boston, MA 02114 USA. EM acolwell@partners.org NR 31 TC 13 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-7043 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD JUL PY 2009 VL 63 IS 1 BP 28 EP 33 DI 10.1097/SAP.0b013e318188b976 PG 6 WC Surgery SC Surgery GA 462GD UT WOS:000267338100009 PM 19546668 ER PT J AU Kay, J Westhovens, R AF Kay, Jonathan Westhovens, Rene TI Methotrexate: the gold standard without standardisation SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Editorial Material ID EARLY RHEUMATOID-ARTHRITIS; CONTROLLED-TRIAL; COMBINATION C1 [Westhovens, Rene] Katholieke Univ Leuven, UZ Gasthuisberg, Dept Musculoskeletal, Div Rheumatol, B-3000 Louvain, Belgium. [Kay, Jonathan] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Kay, Jonathan] Harvard Univ, Sch Med, Boston, MA USA. RP Westhovens, R (reprint author), Katholieke Univ Leuven, UZ Gasthuisberg, Dept Musculoskeletal, Div Rheumatol, B-3000 Louvain, Belgium. EM rene.westhovens@uz.kuleuven.ac.be OI Kay, Jonathan/0000-0002-8970-4260 NR 14 TC 13 Z9 17 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2009 VL 68 IS 7 BP 1081 EP 1082 DI 10.1136/ard.2008.102822 PG 2 WC Rheumatology SC Rheumatology GA 457TP UT WOS:000266956800001 PM 19525405 ER PT J AU Bakaeen, FG Huh, J LeMaire, SA Coselli, JS Sansgiry, S Atluri, PV Chu, DN AF Bakaeen, Faisal G. Huh, Joseph LeMaire, Scott A. Coselli, Joseph S. Sansgiry, Shubhada Atluri, Prasad V. Chu, Danny TI The July Effect: Impact of the Beginning of the Academic Cycle on Cardiac Surgical Outcomes in a Cohort of 70,616 Patients SO ANNALS OF THORACIC SURGERY LA English DT Article ID ARTERY-BYPASS SURGERY; TEACHING HOSPITALS; RESIDENT; IMPROVEMENT; EXPERIENCE; MORTALITY; PROGRAM; SAFETY; LEVEL; RISK AB Background. Because surgical residents' level of experience may be at its nadir early in the academic year, academic seasonality-or the "July effect"-could affect cardiac surgical outcomes. Methods. Prospectively collected data from the Department of Veterans Affairs Continuous Improvement in Cardiac Surgery Program were used to identify 70,616 consecutive cardiac surgical procedures performed between October 1997 and October 2007. Morbidity and mortality rates were compared between early (July 1 to August 31, n = 11,975) and late (September 1 to June 30, n = 58,641) periods in the academic year. A prediction model was constructed by using stepwise logistic regression modeling. Results. The two patient groups had similar demographic and risk variables. Isolated coronary artery bypass grafting accounted for 76.7% of early-period procedures and 75.8% of later-period procedures (p = 0.03). Morbidity rates did not differ significantly between the early (14.0%) and later periods (14.2%; odds ratio [OR], 1.01; 95% confidence interval [CI], 0.96 to 1.07; p = 0.67) and operative mortality was similar, 3.7% vs 3.9% (OR, 0.99; 95% CI, 0.89 to 1.11; p = 0.90). The early portion of the year was associated with longer cardiac ischemia times (84 +/- 40 vs 83 +/- 42 minutes), cardiopulmonary bypass times (126 +/- 52 vs 124 +/- 56 minutes), and total surgical times (295 +/- 90 vs 288 +/- 90 minutes; p < 0.05 for all). Conclusions. The early part of the academic year was associated with slightly longer operative times; however, risk-adjusted outcomes were similar in both periods. This finding should lessen concerns about the quality of cardiac surgical care at the beginning of the academic year. (Ann Thorac Surg 2009;88:70-5) (C) 2009 by The Society of Thoracic Surgeons C1 Baylor Coll Med, Div Cardiothorac Surg, Michael E DeBakey Dept Surg, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. RP Bakaeen, FG (reprint author), Michael E DeBakey VAMC, Dept Cardiothorac Surg, OCL 112,2002 Holcombe Blvd, Houston, TX 77030 USA. EM fbakaeen@bcm.edu FU Offices of Research and Development; Northport and Eastern Colorado Health Care System Denver Veterans Affairs Medical Centers FX Stephen N. Palmer, PhD, ELS, contributed to the editing of this manuscript. The CICSP-X study was initially funded by VA Health Services Research and Development Grant #IHY 99214-1 (Dr Shroyer, Principal Investigator), with ongoing support from the Office of Patient Care Services, VA Central Office, Washington, DC. This project was supported in part by the Offices of Research and Development at the Northport and Eastern Colorado Health Care System Denver Veterans Affairs Medical Centers. Special acknowledgment is given to Randy Johnson, Lisa Schade, and Missy Bell, the team members responsible for the CICSP-X access to care report sections, working under the leadership of Dr Gerald McDonald (VA Central Office). NR 19 TC 35 Z9 35 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2009 VL 88 IS 1 BP 70 EP 75 DI 10.1016/j.athoracsur.2009.04.022 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 464ZV UT WOS:000267550600011 PM 19559195 ER PT J AU O'Brien, SM Shahian, DM Filardo, G Ferraris, VA Haan, CK Rich, JB Normand, SLT DeLong, ER Shewan, CM Dokholyan, RS Peterson, ED Edwards, FH Anderson, RP AF O'Brien, Sean M. Shahian, David M. Filardo, Giovanni Ferraris, Victor A. Haan, Constance K. Rich, Jeffrey B. Normand, Sharon-Lise T. DeLong, Elizabeth R. Shewan, Cynthia M. Dokholyan, Rachel S. Peterson, Eric D. Edwards, Fred H. Anderson, Richard P. TI The Society of Thoracic Surgeons 2008 Cardiac Surgery Risk Models: Part 2-Isolated Valve Surgery SO ANNALS OF THORACIC SURGERY LA English DT Article ID IN-HOSPITAL MORTALITY; REPLACEMENT; PREDICTION AB Background. Adjustment for case-mix is essential when using observational data to compare surgical techniques or providers. That is most often accomplished through the use of risk models that account for preoperative patient factors that may impact outcomes. The Society of Thoracic Surgeons (STS) uses such risk models to create risk-adjusted performance reports for participants in the STS National Adult Cardiac Surgery Database (NCD). Although risk models were initially developed for coronary artery bypass surgery, similar models have now been developed for use with heart valve surgery, particularly as the proportion of such procedures has increased. The last published STS model for isolated valve surgery was based on data from 1994 to 1997 and did not include patients undergoing mitral valve repair. STS has developed new valve surgery models using contemporary data that include both valve repair as well as replacement. Expanding upon existing valve models, the new STS models include several nonfatal complications in addition to mortality. Methods. Using STS data from 2002 to 2006, isolated valve surgery risk models were developed for operative mortality, permanent stroke, renal failure, prolonged ventilation (> 24 hours), deep sternal wound infection, reoperation for any reason, a major morbidity or mortality composite endpoint, prolonged postoperative length of stay, and short postoperative length of stay. The study population consisted of adult patients who underwent one of three types of valve surgery: isolated aortic valve replacement (n = 67,292), isolated mitral valve replacement (n = 21,229), or isolated mitral valve repair (n = 21,238). The population was divided into a 60% development sample and a 40% validation sample. After an initial empirical investigation, the three surgery groups were combined into a single logistic regression model with numerous interactions to allow the covariate effects to differ across these groups. Variables were selected based on a combination of automated stepwise selection and expert panel review. Results. Unadjusted operative mortality (in-hospital regardless of timing, and 30-day regardless of venue) for all isolated valve procedures was 3.4%, and unadjusted in-hospital morbidity rates ranged from 0.3% for deep sternal wound infection to 11.8% for prolonged ventilation. The number of predictors in each model ranged from 10 covariates in the sternal infection model to 24 covariates in the composite mortality plus morbidity model. Discrimination as measured by the c-index ranged from 0.639 for reoperation to 0.799 for mortality. When patients in the validation sample were grouped into 10 categories based on deciles of predicted risk, the average absolute difference between observed versus predicted events within these groups ranged from 0.06% for deep sternal wound infection to 1.06% for prolonged postoperative stay. Conclusions. The new STS risk models for valve surgery include mitral valve repair as well as multiple endpoints other than mortality. Model coefficients are provided and an online risk calculator is publicly available from The Society of Thoracic Surgeons website. C1 [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Brien, Sean M.; DeLong, Elizabeth R.; Dokholyan, Rachel S.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Filardo, Giovanni] Baylor Hlth Care Syst, Inst Hlth Care Res & Improvement, Dallas, TX USA. [Ferraris, Victor A.] Univ Kentucky, Albert B Chandler Med Ctr, Div Cardiovasc & Thorac Surg, Lexington, KY 40536 USA. [Haan, Constance K.; Edwards, Fred H.] Univ Florida, Div Cardiothorac Surg, Jacksonville, FL USA. [Rich, Jeffrey B.] Sentara Cardiovasc Res Inst, Norfolk, VA USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Shewan, Cynthia M.] Soc Thorac Surg, Chicago, IL USA. [Anderson, Richard P.] Soc Thorac Surg, Seattle, WA USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dshahian@partners.org RI O'Brien, Sean/H-6268-2013 NR 10 TC 388 Z9 404 U1 1 U2 17 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 JUL PY 2009 VL 88 IS 1 BP S23 EP S42 DI 10.1016/j.athoracsur.2009.05.056 PG 20 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 463YC UT WOS:000267469100003 PM 19559823 ER PT J AU Shahian, DM O'Brien, SM Filardo, G Ferraris, VA Haan, CK Rich, JB Normand, SLT DeLong, ER Shewan, CM Dokholyan, RS Peterson, ED Edwards, FH Anderson, RP AF Shahian, David M. O'Brien, Sean M. Filardo, Giovanni Ferraris, Victor A. Haan, Constance K. Rich, Jeffrey B. Normand, Sharon-Lise T. DeLong, Elizabeth R. Shewan, Cynthia M. Dokholyan, Rachel S. Peterson, Eric D. Edwards, Fred H. Anderson, Richard P. TI The Society of Thoracic Surgeons 2008 Cardiac Surgery Risk Models: Part 1-Coronary Artery Bypass Grafting Surgery SO ANNALS OF THORACIC SURGERY LA English DT Article ID NATIONAL DATABASE; MORTALITY-RATES; OUTCOMES; PREDICTION; PROGRAM; CURVE AB Background. The first version of The Society of Thoracic Surgeons National Adult Cardiac Surgery Database (STS NCD) was developed nearly 2 decades ago. Since its inception, the number of participants has grown dramatically, patient acuity has increased, and overall outcomes have consistently improved. To adjust for these and other changes, all STS risk models have undergone periodic revisions. This report provides a detailed description of the 2008 STS risk model for coronary artery bypass grafting surgery (CABG). Methods. The study population consisted of 774,881 isolated CABG procedures performed on adult patients aged 20 to 100 years between January 1, 2002, and December 31, 2006, at 819 STS NCD participating centers. This cohort was randomly divided into a 60% training (development) sample and a 40% test (validation) sample. The development sample was used to identify predictor variables and estimate model coefficients. The validation sample was used to assess model calibration and discrimination. Model outcomes included operative mortality, renal failure, stroke, reoperation for any cause, prolonged ventilation, deep sternal wound infection, composite major morbidity or mortality, prolonged length of stay (> 14 days), and short length of stay (< 6 days and alive). Candidate predictor variables were selected based on their availability in versions 2.35, 2.41, and 2.52.1 of the STS NCD and their presence in (or ability to be mapped to) version 2.61. Potential predictor variables were screened for overall prevalence in the study population, missing data frequency, coding concerns, bivariate relationships with outcomes, and their presence in previous STS or other CABG risk models. Supervised backwards selection was then performed with input from an expert panel of cardiac surgeons and biostatisticians. After successfully validating the fit of the models, the development and validation samples were subsequently combined, and the final regression coefficients were estimated using the overall combined (development plus validation) sample. Results. The c-index for the mortality model was 0.812, and the c-indices for other endpoints ranged from 0.653 for reoperation to 0.793 for renal failure in the validation sample. Plots of observed versus predicted event rates revealed acceptable calibration in the overall population and in numerous subgroups. When patients were grouped into categories of predicted risk, the absolute difference between the observed and expected event rates was less than 1.5% for each endpoint. The final model intercept and coefficients are provided. Conclusions. New STS risk models have been developed for CABG mortality and eight other endpoints. Detailed descriptions of model development and testing are provided, together with the final algorithm. Overall model performance is excellent. (Ann Thorac Surg 2009;88:S2-22) (C) 2009 by The Society of Thoracic Surgeons C1 [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Brien, Sean M.; DeLong, Elizabeth R.; Dokholyan, Rachel S.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Filardo, Giovanni] Baylor Hlth Care Syst, Inst Hlth Care Res & Improvement, Dallas, TX USA. [Ferraris, Victor A.] Univ Kentucky, Albert B Chandler Med Ctr, Div Cardiovasc & Thorac Surg, Lexington, KY 40536 USA. [Haan, Constance K.; Edwards, Fred H.] Univ Florida, Div Cardiothorac Surg, Jacksonville, FL USA. [Rich, Jeffrey B.] Sentara Cardiovasc Res Inst, Norfolk, VA USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Shewan, Cynthia M.] Soc Thorac Surg, Chicago, IL USA. [Anderson, Richard P.] Soc Thorac Surg, Seattle, WA USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dshahian@partners.org RI O'Brien, Sean/H-6268-2013 NR 35 TC 343 Z9 352 U1 0 U2 9 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 JUL PY 2009 VL 88 IS 1 SU 1 BP S2 EP S22 DI 10.1016/j.athoracsur.2009.05.053 PG 21 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 463YC UT WOS:000267469100002 PM 19559822 ER PT J AU Shahian, DM O'Brien, SM Filardo, G Ferraris, VA Haan, CK Rich, JB Normand, SLT DeLong, ER Shewan, CM Dokholyan, RS Peterson, ED Edwards, FH Anderson, RP AF Shahian, David M. O'Brien, Sean M. Filardo, Giovanni Ferraris, Victor A. Haan, Constance K. Rich, Jeffrey B. Normand, Sharon-Lise T. DeLong, Elizabeth R. Shewan, Cynthia M. Dokholyan, Rachel S. Peterson, Eric D. Edwards, Fred H. Anderson, Richard P. TI The Society of Thoracic Surgeons 2008 Cardiac Surgery Risk Models: Part 3-Valve Plus Coronary Artery Bypass Grafting Surgery SO ANNALS OF THORACIC SURGERY LA English DT Article ID HEART-VALVE SURGERY; IN-HOSPITAL MORTALITY; NEW-YORK-STATE; OPERATIVE MORTALITY; PREDICTION; STRATIFICATION; REPLACEMENT; EUROSCORE; DATABASE AB Background. Since 1999, The Society of Thoracic Surgeons (STS) has published two risk models that can be used to adjust the results of valve surgery combined with coronary artery bypass graft surgery (CABG). The most recent was developed from data for patients who had surgery between 1994 and 1997 using operative mortality as the only endpoint. Furthermore, this model did not specifically consider mitral valve repair plus CABG, an increasingly common procedure. Consistent with STS policy of periodically updating and improving its risk models, new models for valve surgery combined with CABG have been developed. These models specifically address both perioperative morbidity and mitral valve repair, and they are based on contemporary data. Methods. The final study population consisted of 101,661 procedures, including aortic valve replacement (AVR) plus CABG, mitral valve replacement (MVR) plus CABG, or mitral valve repair (MVRepair) plus CABG between January 1, 2002, and December 31, 2006. Model outcomes included operative mortality, stroke, deep sternal wound infection, reoperation, prolonged ventilation, renal failure, composite major morbidity or mortality, prolonged postoperative length of stay, and short postoperative length of stay. Candidate variables were screened for frequency of missing data, and imputation techniques were used where appropriate. Stepwise variable selection was employed, supplemented by advice from an expert panel of cardiac surgeons and biostatisticians. Several variables were forced into models to insure face validity (eg, atrial fibrillation for the permanent stroke model, sex for all models). Based on preliminary analyses of the data, a single model was employed for valve plus CABG, with indicator variables for the specific type of procedure. Interaction terms were included to allow for differential impact of predictor variables depending on procedure type. After validating the model in the 40% validation sample, the development and validation samples were then combined, and the final model coefficients were estimated using the overall 100% combined sample. The final logistic regression model was estimated using generalized estimating equations to account for clustering of patients within institutions. Results. The c-index for mortality prediction for the overall valve plus CABG population was 0.75. Morbidity model c-indices for specific complications (permanent stroke, renal failure, prolonged ventilation > 24 hours, deep sternal wound infection, reoperation for any reason, major morbidity or mortality composite, and prolonged postoperative length of stay) for the overall group of valve plus CABG procedures ranged from 0.622 to 0.724, and calibration was excellent. Conclusions. New STS risk models have been developed for heart valve surgery combined with CABG. These are the first valve plus CABG models that also include risk prediction for individual major morbidities, composite major morbidity or mortality, and short and prolonged length of stay. (Ann Thorac Surg 2009;88:S43-62) (C) 2009 by The Society of Thoracic Surgeons C1 [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Brien, Sean M.; DeLong, Elizabeth R.; Dokholyan, Rachel S.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Filardo, Giovanni] Baylor Hlth Care Syst, Inst Hlth Care Res & Improvement, Dallas, TX USA. [Ferraris, Victor A.] Univ Kentucky, Albert B Chandler Med Ctr, Div Cardiovasc & Thorac Surg, Lexington, KY 40536 USA. [Haan, Constance K.; Edwards, Fred H.] Univ Florida, Div Cardiothorac Surg, Jacksonville, FL USA. [Rich, Jeffrey B.] Sentara Cardiovasc Res Inst, Norfolk, VA USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Shewan, Cynthia M.] Soc Thorac Surg, Chicago, IL USA. [Anderson, Richard P.] Soc Thorac Surg, Seattle, WA USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dshahian@partners.org RI O'Brien, Sean/H-6268-2013 NR 23 TC 164 Z9 176 U1 0 U2 9 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 JUL PY 2009 VL 88 IS 1 BP S43 EP S62 DI 10.1016/j.athoracsur.2009.05.055 PG 20 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 463YC UT WOS:000267469100004 PM 19559824 ER PT J AU Shahian, DM Edwards, FH AF Shahian, David M. Edwards, Fred H. TI The Society of Thoracic Surgeons 2008 Cardiac Surgery Risk Models: Introduction SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Edwards, Fred H.] Univ Florida, Div Cardiothorac Surg, Jacksonville, FL USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dshahian@partners.org NR 0 TC 60 Z9 62 U1 0 U2 2 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 JUL PY 2009 VL 88 IS 1 BP S1 EP S1 DI 10.1016/j.athoracsur.2009.05.054 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 463YC UT WOS:000267469100001 PM 19559821 ER PT J AU Yang, QH Hornick, JL Granter, SR Wang, LC AF Yang, Qinghong Hornick, Jason L. Granter, Scott R. Wang, Linda C. TI Merkel Cell Carcinoma Lack of KIT Positivity and Implications for the Use of Imatinib Mesylate SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Article DE Merkel cell carcinoma; KIT; immunohistochemistry; imatinib mesylate ID GASTROINTESTINAL STROMAL TUMORS; KINASE INHIBITOR STI571; C-KIT; TYROSINE KINASE; LUNG-CANCER; THERAPEUTIC IMPLICATIONS; DIFFERENTIAL-DIAGNOSIS; CD117 EXPRESSION; GENE-MUTATIONS; WILD-TYPE AB The large variability (7% to 100%) in previously reported rates of receptor tyrosine kinase KIT expression in Merkel cell carcinoma (MCC) may be owing to the use of heat-induced epitope retrieval. High frequency of reported KIT reactivity by immunohistochemistry (IHC) in part prompted the initiation of a phase 2 clinical trial of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, East Hanover, NJ) for the treatment of advanced MCC. Our experience has been that a small number of MCCs (12.5%) are positive for KIT by IHC. We also found a higher rate of apparently KIT-positive MCCs (75%) using heat-induced epitope retrieval. Our anecdotal experience with the use of imatinib mesylate has been disappointing. As IHC detection of KIT expression does not correlate with the presence of KIT-activating mutations, protein expression as tested by IHC should not be used to determine if patients would respond to imatinib mesylate. Indeed, our review of the literature and the apparent lack of efficacy of imatinib mesylate for MCC in a recent phase 2 trial suggest a minor role for KIT signaling in MCC tumorigenesis. C1 [Wang, Linda C.] Harvard Univ, Dana Farber Brigham & Womens Canc Ctr, Dept Dermatol, Sch Med, Boston, MA 02115 USA. [Yang, Qinghong; Hornick, Jason L.; Granter, Scott R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Wang, LC (reprint author), Harvard Univ, Dana Farber Brigham & Womens Canc Ctr, Dept Dermatol, Sch Med, 44 Binney St,SW 550, Boston, MA 02115 USA. EM lcwang@partners.org NR 40 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-3345 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD JUL PY 2009 VL 17 IS 4 BP 276 EP 281 PG 6 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA 464AR UT WOS:000267477100002 PM 19276970 ER PT J AU Laubach, HJ Anderson, RR Luger, T Manstein, D AF Laubach, Hans-Joachim Anderson, Richard Rox Luger, Thomas Manstein, Dieter TI Fractional Photothermolysis for Involuted Infantile Hemangioma SO ARCHIVES OF DERMATOLOGY LA English DT Article ID VASCULAR MALFORMATIONS; FACIAL HEMANGIOMA; CIRCULAR EXCISION; LIPOSUCTION; MANAGEMENT; SCARS; LASER C1 [Laubach, Hans-Joachim; Anderson, Richard Rox; Manstein, Dieter] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Laubach, Hans-Joachim; Luger, Thomas] Univ Munster, Klin & Poliklin Haut & Geschlechtskrankheiten, Munster, Germany. RP Laubach, HJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR 305,50 Blossom St, Boston, MA 02114 USA. EM hlaubach@partners.org FU Reliant Technologies Inc. FX Financial Disclosure: Dr Laubach has received travel expenses and research funding from Reliant Technologies Inc; Dr Manstein has received honoraria, research funding, and royalties from Reliant Technologies Inc; Dr Luger has received research funding form Reliant Technologies Inc; Dr Anderson has received honoraria, research funding, and royalties from Reliant Technologies Inc.; Funding/Support: Reliant Technologies Inc provided a consumable part of their laser device free of cost for this study. NR 27 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUL PY 2009 VL 145 IS 7 BP 748 EP 750 PG 3 WC Dermatology SC Dermatology GA 472MU UT WOS:000268136900002 PM 19620554 ER PT J AU Healy, BC Ali, EN Guttmann, CRG Chitnis, T Glanz, BI Buckle, G Houtchens, M Stazzone, L Moodie, J Berger, AM Duan, Y Bakshi, R Khoury, S Weiner, H Ascherio, A AF Healy, Brian C. Ali, Eman N. Guttmann, Charles R. G. Chitnis, Tanuja Glanz, Bonnie I. Buckle, Guy Houtchens, Maria Stazzone, Lynn Moodie, Jennifer Berger, Annika M. Duan, Yang Bakshi, Rohit Khoury, Samia Weiner, Howard Ascherio, Alberto TI Smoking and Disease Progression in Multiple Sclerosis SO ARCHIVES OF NEUROLOGY LA English DT Article ID CIGARETTE-SMOKING; DIAGNOSTIC-CRITERIA; OPTIC NEUROPATHY; RISK-FACTORS; NICOTINE; EPIDEMIOLOGY; INFECTIONS; CHILDREN AB Background: Although cigarette smokers are at increased risk of developing multiple sclerosis (MS), the effect of smoking on the progression of MS remains uncertain. Objective: To establish the relationship between cigarette smoking and progression of MS using clinical and magnetic resonance imaging outcomes Design: Cross-sectional survey and longitudinal follow-up for a mean of 3.29 years, ending January 15, 2008. Setting: Partners MS Center (Boston, Massachusetts), a referral center for patients with MS. Patients: Study participants included 1465 patients with clinically definite MS (25.1% men), with mean (range) age at baseline of 42.0 (16-75) years and disease duration of 9.4 (0-50.4) years. Seven hundred eighty patients (53.2%) were never-smokers, 428 (29.2%) were ex-smokers, and 257 (17.5%) were current smokers. Main Outcome Measures: Smoking groups were compared for baseline clinical and magnetic resonance imaging characteristics as well as progression and sustained progression on the Expanded Disability Status Scale at 2 and 5 years and time to disease conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction and T2 hyperintense lesion volume were compared. Results: Current smokers had significantly worse disease at baseline than never-smokers in terms of Expanded Disability Status Scale score (adjusted P < .001), Multiple Sclerosis Severity Score (adjusted P < .001.), and brain parenchymal fraction (adjusted P = .004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio, 2.41; 95% confidence interval, 1.09-5.34). At longitudinal analyses, MS in smokers progressed from relapsing-remitting to secondary progressive disease faster than in never-smokers (hazard ratio for current smokers vs never-smokers, 2.50; 95% confidence interval, 1.42-4.41). In addition, in smokers, the T2-weighted lesion volume increased faster (P = .02), and brain parenchymal fraction decreased faster (P = .02). Conclusion: Our data suggest that cigarette smoke has an adverse influence on the progression of MS and accelerates conversion from a relapsing-remitting to a progressive course. C1 [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02215 USA. [Healy, Brian C.; Ali, Eman N.; Guttmann, Charles R. G.; Chitnis, Tanuja; Glanz, Bonnie I.; Buckle, Guy; Houtchens, Maria; Stazzone, Lynn; Moodie, Jennifer; Bakshi, Rohit; Khoury, Samia; Weiner, Howard] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol,Partners MS Ctr, Boston, MA 02115 USA. [Guttmann, Charles R. G.; Berger, Annika M.; Duan, Yang; Bakshi, Rohit] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Imaging,Dept Radiol, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Dept Neurol, Ctr Biostat, Boston, MA 02114 USA. RP Ascherio, A (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 655 Huntington Ave,Bldg 2,3rd Floor, Boston, MA 02215 USA. EM aascheri@hsph.harvard.edu OI khoury, samia/0000-0003-3198-6063 FU Partners Multiple Sclerosis Center; National Institute of Neurological Disorders and Stroke [R01 NS047467]; National Institutes of Health Molecular Epidemiology FX This study was supported by the Partners Multiple Sclerosis Center and by grant R01 NS047467 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health Molecular Epidemiology of Epstein-Barr Virus and Multiple Sclerosis (Dr Ascherio). NR 36 TC 68 Z9 70 U1 2 U2 13 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 JUL PY 2009 VL 66 IS 7 BP 858 EP 864 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 473EQ UT WOS:000268189200007 PM 19597087 ER PT J AU Costello, DJ Chiappa, KH Siao, P AF Costello, Daniel J. Chiappa, Keith H. Siao, Peter TI Progressive Myoclonus Epilepsy With Demyelinating Peripheral Neuropathy and Preserved Intellect SO ARCHIVES OF NEUROLOGY LA English DT Article ID CEREBELLAR PATHOLOGY AB Background: The progressive myoclonic epilepsies (PMEs) are a disparate group of syndromes whose common features include disabling myoclonus, progressive cognitive decline, and seizures, typically with a relentless deterioration over time. Objective: To report a novel PME syndrome. Design: Case report. Setting: Epilepsy service in a tertiary care urban medical center. Patient: A 24-year-old man with progressive myoclonus, seizures, and unique features of preserved intellect and demyelinating peripheral neuropathy. Main Outcome Measure: Detailed clinical assessment, electrophysiologic studies, and survey of the literature. Results: We characterize an unusual PME phenotype with unique features of preserved intellect and electrophysiologic evidence of a generalized demyelinating peripheral neuropathic condition. An extensive diagnostic evaluation did not reveal an underlying cause, and a literature survey did not identify other, similar clinical reports. Conclusion: We describe a novel PME syndrome with preserved intellect and demyelinating peripheral neuropathy. C1 [Costello, Daniel J.; Chiappa, Keith H.] Massachusetts Gen Hosp, Dept Neurol, Epilepsy Serv, Boston, MA 02114 USA. [Siao, Peter] Massachusetts Gen Hosp, Dept Neurol, Neuromuscular & Electrophysiol Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Costello, DJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Epilepsy Serv, ACC 835,55 Fruit St, Boston, MA 02114 USA. EM djcostello@partners.org NR 6 TC 4 Z9 4 U1 0 U2 0 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 JUL PY 2009 VL 66 IS 7 BP 898 EP 901 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 473EQ UT WOS:000268189200014 PM 19597094 ER PT J AU Goyal, S Chauhan, SK Zhang, Q Dana, R AF Goyal, Sunali Chauhan, Sunil K. Zhang, Qiang Dana, Reza TI Amelioration of Murine Dry Eye Disease by Topical Antagonist to Chemokine Receptor 2 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID HUMAN CORNEAL ENDOTHELIUM; GENE-EXPRESSION PROFILES; SJOGRENS-SYNDROME; CHEMOTACTIC CYTOKINES; OCULAR SURFACE; TEAR FLUID; INFLAMMATION; CCR2; KERATOCONJUNCTIVITIS; INTERLEUKIN-8 AB Objective: To determine the effect of a topical antagonist to the chemokine receptor 2 (CCR2) in a murine model of dry eye disease. Methods: The effects of a topical CCR2 antagonist and a vehicle control treatment were studied in murine dry eyes. A controlled environment chamber induced dry eye by exposing mice to high-flow desiccated air. Corneal fluorescein staining and enumeration of corneal CD11b(+) and conjunctival CD3(+) T cells were performed in the different groups. Real-time polymerase chain reaction was performed to quantify expression of different inflammatory cytokine transcripts in the cornea and conjunctiva. Results: Eyes receiving the formulation containing CCR2 antagonist showed a significant decrease in corneal fluorescein staining and decreased infiltration of corneal CD11b(+) cells and conjunctival T cells compared with the vehicle-treated and untreated dry eye groups. The CCR2 antagonist also significantly decreased messenger RNA expression levels of interleukins 1 alpha and 1 beta in the cornea, and tumor necrosis factor alpha and interleukin 1 beta in the conjunctiva. Conclusion: Topical application of CCR2 antagonist is associated with significant improvement in dry eye disease and is reflected by a decrease in inflammation at the clinical, molecular, and cellular levels. C1 [Goyal, Sunali; Chauhan, Sunil K.; Zhang, Qiang; Dana, Reza] Schepens Eye Res Inst, Boston, MA 02114 USA. [Goyal, Sunali; Chauhan, Sunil K.; Zhang, Qiang; Dana, Reza] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Dana, Reza] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Dana, R (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM reza.dana@schepens.harvard.edu FU Johnson & Johnson Vision Care, Inc. FX This study was supported by Johnson & Johnson Vision Care, Inc. NR 34 TC 33 Z9 34 U1 0 U2 3 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 JUL PY 2009 VL 127 IS 7 BP 882 EP 887 PG 6 WC Ophthalmology SC Ophthalmology GA 470CK UT WOS:000267950500007 PM 19597109 ER PT J AU Talbert, ML Ashwood, ER Brownlee, NA Clark, JR Horowitz, RE Lepoff, RB Neumann, A Otis, CN Powell, SZE Sodeman, TM AF Talbert, Michael L. Ashwood, Edward R. Brownlee, Noel A. Clark, Jimmy R. Horowitz, Richard E. Lepoff, Ronald B. Neumann, Ann Otis, Christopher N. Powell, Suzanne Zein-Eldin Sodeman, Thomas M. TI Resident Preparation for Practice A White Paper From the College of American Pathologists and Association of Pathology Chairs SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Editorial Material ID SURGICAL-PATHOLOGY; ANATOMIC PATHOLOGY; CURRICULUM CONTENT; COMPETENCE; PROPOSAL; FUTURE C1 [Talbert, Michael L.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Ashwood, Edward R.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Ashwood, Edward R.] ARUP Labs Inc, Salt Lake City, UT USA. [Brownlee, Noel A.] Greenville Hosp Syst & Pathol Associates & Consul, Dept Pathol, Greenville, SC USA. [Clark, Jimmy R.] ACL Labs, SC, W Allis, WI USA. [Horowitz, Richard E.] USC Sch Med, Dept Pathol, Los Angeles, CA USA. [Horowitz, Richard E.] Los Angeles Vet Affairs Med Ctr, Los Angeles, CA USA. [Lepoff, Ronald B.] Univ Colorado Hosp, Dept Pathol, Aurora, CO USA. [Neumann, Ann] Coll Amer Pathologists, Northfield, IL USA. [Otis, Christopher N.] Bayside Med Ctr, Dept Pathol, Springfield, MA USA. [Powell, Suzanne Zein-Eldin] Methodist Hosp, Dept Pathol, Houston, TX 77030 USA. RP Talbert, ML (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, 940 Stanton L Young,BMSB 451, Oklahoma City, OK 73104 USA. EM michael-talbert@ouhsc.edu NR 18 TC 22 Z9 22 U1 0 U2 0 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 JUL PY 2009 VL 133 IS 7 BP 1139 EP 1147 PG 9 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 464DI UT WOS:000267484900015 PM 19642741 ER PT J AU Cowan, RE Nash, MS Collinger, JL Koontz, AM Boninger, ML AF Cowan, Rachel E. Nash, Mark S. Collinger, Jennifer L. Koontz, Alicia M. Boninger, Michael L. TI Impact of Surface Type, Wheelchair Weight, and Axle Position on Wheelchair Propulsion by Novice Older Adults SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Aged; Biomechanics; Rehabilitation; Wheelchairs ID KINETIC-ANALYSIS; SEAT POSITION; ENERGY-COST; SYSTEM TILT; BIOMECHANICS; SHOULDER; STANDARD; ANGLES AB Impact of surface type, wheelchair weight, and axle position on wheelchair propulsion by novice older adults. Objective: To examine the impact of surface type, wheelchair weight, and rear axle position on older adult propulsion biomechanics. Design: Crossover trial. Setting: Biomechanics laboratory. Participants: Convenience sample of 53 ambulatory older adults with minimal wheelchair experience (65-87y); men, n=20; women, n=33. Intervention: Participants propelled 4 different wheelchair configurations over 4 surfaces: tile, low carpet, high carpet, and an 8% grade ramp (surface, chair order randomized). Chair configurations included (1) unweighted chair with an ante axle position, (2) 9.05kg weighted chair with an anterior axle position, (3) unweighted chair with a posterior axle position (Delta 0.08m), and (4) 9.05kg weighted chair with a posterior axle position (Delta 0.08m). Weight was added to a titanium folding chair, simulating the weight difference between very light and depot wheelchairs. Instrumented wheels measured propulsion kinetics. Main Outcome Measures: Average self-selected velocity, push frequency, stroke length, peak resultant and tangential force. Results: Velocity decreased as surface rolling resistance or chair weight increased. Peak resultant and tangential forces increased as chair weight increased, as surface resistance increased, and with a posterior axle position. The effect of a posterior axle position was greater on high carpet and the ramp. The effect of weight was constant, but was more easily observed on high carpet and ramp. The effects of axle position and weight were independent of one another. Conclusion: Increased surface resistance decreases selfselected velocity and increases peak forces. Increased weight decreases self-selected velocity and increases forces. Anterior axle positions decrease forces, more so on high carpet. The effects of weight and axle position are independent. The greatest reductions in peak forces occur in lighter chairs with anterior axle positions. C1 [Cowan, Rachel E.; Collinger, Jennifer L.; Koontz, Alicia M.; Boninger, Michael L.] Ctr Excellence Wheelchairs & Related Technol, VA Pittsburgh Hlth Care Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. [Collinger, Jennifer L.; Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Boninger, Michael L.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Cowan, Rachel E.; Koontz, Alicia M.; Boninger, Michael L.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Collinger, Jennifer L.; Koontz, Alicia M.] Univ Pittsburgh, Sch Hlth & Rehabil Sci, Pittsburgh, PA USA. [Collinger, Jennifer L.; Koontz, Alicia M.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Nash, Mark S.] Univ Miami, Miller Sch Med, Dept Neurol Surg, Miami, FL 33136 USA. [Cowan, Rachel E.; Nash, Mark S.] Univ Miami, Miller Sch Med, Miami Project Cure Paralysis, Miami, FL 33136 USA. RP Boninger, ML (reprint author), Ctr Excellence Wheelchairs & Related Technol, VA Pittsburgh Hlth Care Syst, Human Engn Res Labs, 5180 Highland Dr 151R-1, Pittsburgh, PA 15206 USA. EM boninger@pitt.edu OI Boninger, Michael/0000-0001-6966-919X FU National Institutes of Health [1 F31 HD053986-01, P30 AG024827, AG023641]; National Science Foundation [DGE0333420]; Department of Veterans Affairs Rehabilitation Research and Development [B3142C] FX Supported by the National Institutes of Health (grant nos. 1 F31 HD053986-01, P30 AG024827, AG023641), the National Science Foundation (DGE0333420, Graduate Research Fellowship), and the Department of Veterans Affairs Rehabilitation Research and Development (grant no. B3142C). NR 21 TC 33 Z9 33 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUL PY 2009 VL 90 IS 7 BP 1076 EP 1083 DI 10.1016/j.apmr.2008.10.034 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 470SA UT WOS:000267999000002 PM 19577019 ER PT J AU Jaffer, FA Libby, P Weissleder, R AF Jaffer, Farouc A. Libby, Peter Weissleder, Ralph TI Optical and Multimodality Molecular Imaging Insights Into Atherosclerosis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Review DE atherosclerosis; molecular imaging; optical; fluorescence; multimodality; nanoparticle ID ULTRASMALL SUPERPARAMAGNETIC PARTICLES; EARLY-STAGE ATHEROSCLEROSIS; CATHEPSIN-K ACTIVITY; MACROPHAGES IN-VIVO; OXIDE-ENHANCED MRI; IRON-OXIDE; CARDIOVASCULAR-DISEASE; MAGNETIC NANOPARTICLES; INTRAPLAQUE HEMORRHAGE; NONINVASIVE DETECTION AB Imaging approaches that visualize molecular targets rather than anatomic structures aim to illuminate vital molecular and cellular aspects of atherosclerosis biology in vivo. Several such molecular imaging strategies stand ready for rapid clinical application. This review describes the growing role of in vivo optical molecular imaging in atherosclerosis and highlights its ability to visualize atheroma inflammation, calcification, and angiogenesis. In addition, we discuss advances in multimodality probes, both in the context of multimodal imaging as well as multifunctional, or "theranostic," nanoparticles. This review highlights particular molecular imaging strategies that possess strong potential for clinical translation. (Arterioscler Thromb Vasc Biol. 2009; 29: 1017-1024.) C1 [Jaffer, Farouc A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Jaffer, Farouc A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jaffer, Farouc A.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Libby, Peter] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Jaffer, Farouc A.; Libby, Peter; Weissleder, Ralph] Harvard Univ, Sch Med, Donald W Reynolds Cardiovasc Clin Res Ctr, Cambridge, MA 02138 USA. RP Jaffer, FA (reprint author), Simches Res Bldg,Room 3206,185 Cambridge St, Boston, MA 02114 USA. EM fjaffer@mgh.harvard.edu OI Jaffer, Farouc/0000-0001-7980-384X FU Howard Hughes Medical Institute; NCI NIH HHS [R24 CA092782-05, R24 CA092782, R24-CA92782]; NHLBI NIH HHS [R01 HL078641, R01 HL078641-04, R01-HL078641, U01 HL080731, U01 HL080731-04, UO1-HL080731] NR 80 TC 100 Z9 104 U1 4 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2009 VL 29 IS 7 BP 1017 EP U98 DI 10.1161/ATVBAHA.108.165530 PG 20 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 459LA UT WOS:000267102500006 PM 19359659 ER PT J AU Butler, J Kalogeropoulos, A Georgiopoulou, V de Rekeneire, N Rodondi, N Smith, AL Hoffmann, U Kanaya, A Newman, AB Kritchevsky, SB Vasan, RS Wilson, PWF Harris, TB AF Butler, Javed Kalogeropoulos, Andreas Georgiopoulou, Vasiliki de Rekeneire, Nathalie Rodondi, Nicolas Smith, Andrew L. Hoffmann, Udo Kanaya, Alka Newman, Anne B. Kritchevsky, Stephen B. Vasan, Ramachandran S. Wilson, Peter W. F. Harris, Tamara B. CA Hlth ABC Study TI Serum Resistin Concentrations and Risk of New Onset Heart Failure in Older Persons The Health, Aging, and Body Composition (Health ABC) Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE heart failure; elderly; resistin ID INSULIN-RESISTANCE; PLASMA RESISTIN; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; INFLAMMATORY MARKERS; MULTIPLE IMPUTATION; ISCHEMIC-STROKE; ADIPOSE-TISSUE; OBESITY; ATHEROSCLEROSIS AB Objective-Resistin is associated with inflammation and insulin resistance and exerts direct effects on myocardial cells including hypertrophy and altered contraction. We investigated the association of serum resistin concentrations with risk for incident heart failure (HF) in humans. Methods and Results-We studied 2902 older persons without prevalent HF (age, 73.6 +/- 2.9 years; 48.1% men; 58.8% white) enrolled in the Health, Aging, and Body Composition (Health ABC) Study. Correlation between baseline serum resistin concentrations (20.3 +/- 10.0 ng/mL) and clinical variables, biochemistry panel, markers of inflammation and insulin resistance, adipocytokines, and measures of adiposity was weak (all rho <0.25). During a median follow-up of 9.4 years, 341 participants (11.8%) developed HF. Resistin was strongly associated with risk for incident HF in Cox proportional hazards models controlling for clinical variables, biomarkers, and measures of adiposity (HR, 1.15 per 10.0 ng/mL in adjusted model; 95% CI, 1.05 to 1.27; P = 0.003). Results were comparable across sex, race, diabetes mellitus, and prevalent and incident coronary heart disease subgroups. In participants with available left ventricular ejection fraction at HF diagnosis (265 of 341; 77.7%), association of resistin with HF risk was comparable for cases with reduced versus preserved ejection fraction. Conclusions-Serum resistin concentrations are independently associated with risk for incident HF in older persons. (Arterioscler Thromb Vasc Biol. 2009; 29: 1144-1149.) C1 [Butler, Javed; Kalogeropoulos, Andreas; Georgiopoulou, Vasiliki; Smith, Andrew L.; Wilson, Peter W. F.] Emory Univ, Atlanta, GA 30322 USA. [de Rekeneire, Nathalie] Epictr, Paris, France. [Rodondi, Nicolas] Univ Lausanne, CH-1015 Lausanne, Switzerland. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kalogeropoulos, Andreas] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Harris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Butler, J (reprint author), Emory Univ Hosp, Div Cardiol, 1364 Clifton Rd NE,Suite AT 430, Atlanta, GA 30322 USA. EM javed.butler@emory.edu RI Kalogeropoulos, Andreas/A-9494-2009; Newman, Anne/C-6408-2013; OI Kalogeropoulos, Andreas/0000-0002-1284-429X; Kritchevsky, Stephen/0000-0003-3336-6781; Newman, Anne/0000-0002-0106-1150; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institute of Aging, National Institutes of Health, Bethesda Md; [N01-AG-6-2101]; [N01-AG-62103]; [N01-AG-6-2106]; [2K24 HL04334] FX This research was supported in part by the Intramural Research Program of the National Institute of Aging, National Institutes of Health, Bethesda Md, and by grants N01-AG-6-2101, N01-AG-62103, and N01-AG-6-2106. Dr Vasan was supported by a research career award 2K24 HL04334. NR 31 TC 41 Z9 42 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2009 VL 29 IS 7 BP 1144 EP U236 DI 10.1161/ATVBAHA.109.186783 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 459LA UT WOS:000267102500025 PM 19372460 ER PT J AU Arany, ZP Foo, SY Chinsomboon, J Girnun, G Cooper, M Ruas, J Bommi-Reddy, A Rangwala, S Baek, KH Rosenzweig, A Spiegelman, B AF Arany, Zolt P. Foo, Shi-Yin Chinsomboon, Jessica Girnun, Geoff Cooper, Marcus Ruas, Jorge Bommi-Reddy, Archana Rangwala, Shamina Baek, Kwan Hyuck Rosenzweig, Anthony Spiegelman, Bruce TI HIF-Independent Regulation of Angiogenesis in Ischemia and Exercise SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT 10th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 29-MAY 01, 2009 CL Washington, DC SP Amer Heart Assoc Council Arteriosclerosis, Thrombosis & Vasc Biol C1 [Arany, Zolt P.; Foo, Shi-Yin; Chinsomboon, Jessica; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Girnun, Geoff; Cooper, Marcus; Ruas, Jorge; Bommi-Reddy, Archana; Rangwala, Shamina; Baek, Kwan Hyuck; Spiegelman, Bruce] Dana Farber Canc Inst, Boston, MA 02115 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2009 VL 29 IS 7 BP E16 EP E17 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 459LA UT WOS:000267102500062 ER PT J AU Higashimori, M Tatro, JB Moore, KJ Galper, JB Mendelsohn, ME Beasley, D AF Higashimori, Mie Tatro, Jeffrey B. Moore, Kathryn J. Galper, Jonas B. Mendelsohn, Michael E. Beasley, Debbie TI Role of Toll-like Receptors 2 and 4 in Early Arterial Inflammation and Lipid Accumulation in Apolipoprotein E-Deficient Mice SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT 10th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 29-MAY 01, 2009 CL Washington, DC SP Amer Heart Assoc Council Arteriosclerosis, Thrombosis & Vasc Biol C1 [Higashimori, Mie; Tatro, Jeffrey B.; Galper, Jonas B.; Mendelsohn, Michael E.; Beasley, Debbie] Tufts Med Cntr, Boston, MA USA. [Moore, Kathryn J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2009 VL 29 IS 7 BP E113 EP E114 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 459LA UT WOS:000267102500545 ER PT J AU Martin, MC Korepta, L Dasilva, C Andersen, ND Monahan, TS Ferran, C LoGerfo, FW AF Martin, Michelle C. Korepta, Lindsey Dasilva, Cleide Andersen, Nicholas D. Monahan, Thomas S. Ferran, Christiane LoGerfo, Frank W. TI MARCKS Silencing Upregulates p27(kip1) Expression in Vascular Smooth Muscle Cells in Vitro SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT 10th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 29-MAY 01, 2009 CL Washington, DC SP Amer Heart Assoc, Council Arteriosclerosis, Thrombosis & Vasc Biol C1 [Martin, Michelle C.; Korepta, Lindsey; Dasilva, Cleide; Andersen, Nicholas D.; Monahan, Thomas S.; Ferran, Christiane; LoGerfo, Frank W.] BIDMC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2009 VL 29 IS 7 BP E120 EP E120 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 459LA UT WOS:000267102500577 ER PT J AU van Gils, JM Fernandes, LR Derby, MC Balcells, M Alvarez-Leite, JI Moore, KJ AF van Gils, Janine M. Fernandes, Luciana R. Derby, Merran C. Balcells, Mercedes Alvarez-Leite, Jaqueline I. Moore, Kathryn J. TI Axonal Guidance Cues Mediate Monocyte Chemotaxis, and Their Expression on Endothelial Cells Is Regulated by Atherosclerotic Stimuli SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT 10th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 29-MAY 01, 2009 CL Washington, DC SP Amer Heart Assoc Council Arteriosclerosis, Thrombosis & Vasc Biol C1 [van Gils, Janine M.; Fernandes, Luciana R.; Derby, Merran C.; Moore, Kathryn J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Balcells, Mercedes] MIT, Cambridge, MA 02139 USA. [Alvarez-Leite, Jaqueline I.] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2009 VL 29 IS 7 BP E61 EP E61 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 459LA UT WOS:000267102500279 ER PT J AU Wong, MC Hu, LH Van Diepen, JA Romijn, JA Voshol, PJ Havekes, LM Shoelson, SE Tamsma, JT Rensen, PC Hiemstra, PS Berbee, JF AF Wong, Man-Chi Hu, Lihui Van Diepen, Janna A. Romijn, Johannes A. Voshol, Peter J. Havekes, Louis M. Shoelson, Steven E. Tamsma, Jouke T. Rensen, Patrick C. Hiemstra, Pieter S. Berbee, Jimmy F. TI Chronic Hepatic Inflammation Severely Aggravates Atherosclerosis Development SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT 10th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 29-MAY 01, 2009 CL Washington, DC SP Amer Heart Assoc Council Arteriosclerosis, Thrombosis & Vasc Biol C1 [Wong, Man-Chi; Hu, Lihui; Van Diepen, Janna A.; Romijn, Johannes A.; Voshol, Peter J.; Tamsma, Jouke T.; Rensen, Patrick C.; Hiemstra, Pieter S.; Berbee, Jimmy F.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Havekes, Louis M.] TNO Biosci, Leiden, Netherlands. [Shoelson, Steven E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2009 VL 29 IS 7 BP E98 EP E98 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 459LA UT WOS:000267102500463 ER PT J AU Jones, KL McHugh, GA Glickstein, LJ Steere, AC AF Jones, Kathryn L. McHugh, Gail A. Glickstein, Lisa J. Steere, Allen C. TI Analysis of Borrelia burgdorferi Genotypes in Patients With Lyme Arthritis High Frequency of Ribosomal RNA Intergenic Spacer Type 1 Strains in Antibiotic-Refractory Arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SENSU-STRICTO; HEMATOGENOUS DISSEMINATION; GENETIC DIVERSITY; JOINT FLUID; NORTH-AMERICA; DISEASE; OSPC; MICE; ASSOCIATION; TURICATAE AB Objective. Most of the Borrelia burgdorferi genotypes have been isolated from erythema migrans (EM) skin lesions in patients with Lyme disease. OspC type K strains, which are 16S-23S ribosomal RNA intergenic spacer type 2 (RST2) strains, are most commonly recovered, but a higher percentage of OspC type A strains (RST1), the next most commonly recovered type, is detectable in blood. The goal of this study was to determine the B burgdorferi genotypes in the joints of patients with Lyme arthritis. Methods. Joint fluid samples from 124 patients seen over a 30-year period were analyzed for OspC types by semi-nested polymerase chain reaction (PCR) and sequencing, and for RSTs by nested PCR and restriction fragment length polymorphism analysis. These results were correlated with clinical outcome. Results. OspC and RST genotypes were identified in 49 of the 124 joint fluid samples (40%). In these 49 samples, OspC type K strains (RST2) were identified in 21 samples (43%), OspC type A strains (RST1) were identified in 11 samples (22%), and 8 other OspC types and all 3 RSTs were identified among the remaining 17 samples (35%). However, among the 17 patients who had been treated with antibiotics according to current guidelines, all 7 patients who were infected with RST1 strains had antibiotic-refractory arthritis, compared with 4 of 6 patients infected with RST2 strains and only I of 4 infected with RST3 strains (P = 0.03). Conclusion. Most of the B burgdorferi genotypes, particularly OspC type K (RST2), were identified in the joint fluid of patients with Lyme arthritis, and the genotype frequencies found in joints reflected those in EM skin lesions. However, RST1 strains were most frequent in patients with antibiotic-refractory arthritis. Our results help to further the understanding of the differential pathogenicity of strains of B burgdorferi. C1 [Steere, Allen C.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Steere, AC (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, 55 Fruit St,CNY 149-8301, Boston, MA 02114 USA. EM asteere@partners.org OI Jones, Kathryn/0000-0003-3815-5713 FU NIAMS NIH HHS [AR-20358, AR-007258, R01 AR020358, R01 AR020358-34, T32 AR007258, T32 AR007258-32] NR 41 TC 27 Z9 27 U1 0 U2 4 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 JUL PY 2009 VL 60 IS 7 BP 2174 EP 2182 DI 10.1002/art.24812 PG 9 WC Rheumatology SC Rheumatology GA 470HN UT WOS:000267965900035 PM 19565522 ER PT J AU Zhou, Y Xiao, XQ Chen, LF Yang, R Shi, JD Du, XL Klocker, H Park, I Lee, C Zhang, J AF Zhou, Ying Xiao, Xiang-Qian Chen, Lin-Feng Yang, Rui Shi, Jian-Dang Du, Xiao-Ling Klocker, Helmut Park, Irwin Lee, Chung Zhang, Ju TI Proliferation and phenotypic changes of stromal cells in response to varying estrogen/androgen levels in castrated rats SO ASIAN JOURNAL OF ANDROLOGY LA English DT Article DE androgens; castration; estrogen; prostatic hyperplasia; rat; stromal cells ID SMOOTH-MUSCLE-CELLS; BENIGN PROSTATIC HYPERPLASIA; MYOSIN ISOFORM EXPRESSION; GENE-EXPRESSION; F344 RATS; ANDROGEN; ESTROGEN; ESTRADIOL; DIFFERENTIATION; PATHOGENESIS AB It is known that human benign prostatic hyperplasia might arise from an estrogen/androgen (E/T) imbalance. We studied the response of castrated rat prostate to different ratios of circulating E/T. The castrated male Wistar rats were randomly injected with E/T at different ratios for 4 weeks. The prostates of E/T (1:100) group showed a distinct prostatic hyperplasia response by prostatic index, hematoxylin and eosin staining, and quantitative immunohistochemical analysis of alpha-smooth muscle actin (SMA). In this group, cells positive for Vimentin, nonmuscle myosin heavy chain (NMMHC) and proliferating cell nuclear antigen (PCNA) increased in the stroma and epithelium. Furthermore, the mRNA levels of smooth muscle myosin heavy chain (SMMHC) and NMMHC increased. So E/T at a ratio of 1:100 can induce a stromal hyperplastic response in the prostate of castrated rats. The main change observed was an increase of smooth muscle cells, whereas some epithelial changes were also seen in the rat prostates. C1 [Zhou, Ying; Xiao, Xiang-Qian; Yang, Rui; Shi, Jian-Dang; Du, Xiao-Ling; Zhang, Ju] Nankai Univ, Dept Biochem & Mol Biol, Coll Life Sci, Bioact Mat Key Lab,Minist Educ, Tianjin 300071, Peoples R China. [Chen, Lin-Feng] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Klocker, Helmut] Innsbruck Med Univ, Dept Urol, A-6020 Innsbruck, Austria. [Park, Irwin; Lee, Chung] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. RP Zhang, J (reprint author), Nankai Univ, Dept Biochem & Mol Biol, Coll Life Sci, Bioact Mat Key Lab,Minist Educ, Tianjin 300071, Peoples R China. EM Shijd@nankai.edu.cn; zhangju@nankai.edu.cn RI Lee, Chung-Chieh/B-7238-2009 FU National Basic Research Program [2009CB918900]; National Natural Science Foundation of China [30672101, 30872592]; Specialized Research Fund for the Doctoral Program of Higher Education [20070055023]; Tianjin Municipal Science and Technology Commission [06YFSYSF02000, 07jczdjc08300] FX This research was funded by the following grants: the National Basic Research Program (973 Program, No. 2009CB918900), the National Natural Science Foundation of China (grant No. 30672101, 30872592), the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20070055023) and the key research project of Tianjin Municipal Science and Technology Commission (grant No. 06YFSYSF02000, 07jczdjc08300). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work. NR 38 TC 12 Z9 13 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD JUL PY 2009 VL 11 IS 4 BP 451 EP 459 DI 10.1038/aja.2009.28 PG 9 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 465QB UT WOS:000267600800007 PM 19483715 ER PT J AU Stephenson, LM Miller, BC Ng, A Eisenberg, J Zhao, ZJ Cadwell, K Graham, DB Mizushima, NN Xavier, R Virgin, HW Swat, W AF Stephenson, Linda M. Miller, Brian C. Ng, Aylwin Eisenberg, Jason Zhao, Zijiang Cadwell, Ken Graham, Daniel B. Mizushima, Noboru N. Xavier, Ramnik Virgin, Herbert W. Swat, Wojciech TI Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes SO AUTOPHAGY LA English DT Article DE T cells; cell differentiation and development; transgenic/knockout mice; ATG5; mitochondria ID HOMEOSTATIC PROLIFERATION; CELL-DEATH; RAT HEPATOCYTES; AUTOPHAGY; DISEASE; IMMUNITY; ATG5; MICE; DEGRADATION; TOLERANCE AB Autophagy is implicated in many functions of mammalian cells such as organelle recycling, survival and differentiation, and is essential for the maintenance of T and B lymphocytes. Here, we demonstrate that autophagy is a constitutive process during T cell development. Deletion of the essential autophagy genes Atg5 or Atg7 in T cells resulted in decreased thymocyte and peripheral T cell numbers, and Atg5-deficient T cells had a decrease in cell survival. We employed functional-genetic and integrative computational analyses to elucidate specific functions of the autophagic process in developing T-lineage lymphocytes. Our whole-genome transcriptional profiling identified a set of 699 genes differentially expressed in Atg5-deficient and Atg5-sufficient thymocytes (Atg5-dependent gene set). Strikingly, the Atg5-dependent gene set was dramatically enriched in genes encoding proteins associated with the mitochondrion. In support of a role for autophagy in mitochondrial maintenance in T lineage cells, the deletion of Atg5 led to increased mitochondrial mass in peripheral T cells. We also observed a correlation between mitochondrial mass and Annexin-V staining in peripheral T cells. We propose that autophagy is critical for mitochondrial maintenance and T cell survival. We speculate that, similar to its role in yeast or mammalian liver cells, autophagy is required in T cells for the removal of damaged or aging mitochondria and that this contributes to the cell death of autophagy-deficient T cells. C1 [Stephenson, Linda M.; Miller, Brian C.; Zhao, Zijiang; Cadwell, Ken; Graham, Daniel B.; Virgin, Herbert W.; Swat, Wojciech] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA. [Virgin, Herbert W.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Ng, Aylwin; Eisenberg, Jason; Xavier, Ramnik] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Mizushima, Noboru N.] Tokyo Med & Dent Univ, Dept Physiol & Cell Biol, Tokyo, Japan. [Mizushima, Noboru N.] Japan Sci & Technol Agcy, Kawaguchi, Saitama, Japan. RP Swat, W (reprint author), Washington Univ, Dept Pathol & Immunol, Sch Med, 660 S Euclid Ave,Box 8118, St Louis, MO 63110 USA. EM swat@wustl.edu RI Mizushima, Noboru/C-3635-2009 OI Cadwell, Ken/0000-0002-5860-0661; Mizushima, Noboru/0000-0002-6258-6444 FU NIH [P30-AR048335, R01-A1061077, CA74730, U54A1057160, R01-A1062773, R01-DK83756, 5-T32-A107163-27]; Ministry of Education, Culture, Sports, Science and Technology, Japan; Toray Science Foundation; Crohn's and Colitis Foundation of America; Damon Runyon Cancer Research Foundation [DRG-1972-08] FX Financial support for this work was provided by NIH grants P30-AR048335 and R01-A1061077 MS.), CA74730 and U54A1057160 (H.WV), R01-A1062773 and R01-DK83756 (RX), 5-T32-A107163-27 (L.M.S.), Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Toray Science Foundation (N.M). A. N. is a recipient of a fellowship award from the Crohn's and Colitis Foundation of America. K.C. is the Lallage Feazel Wall Fellow of the Damon Runyon Cancer Research Foundation, DRG-1972-08. NR 46 TC 94 Z9 96 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD JUL 1 PY 2009 VL 5 IS 5 BP 625 EP 635 PG 11 WC Cell Biology SC Cell Biology GA 473KQ UT WOS:000268205300006 PM 19276668 ER PT J AU Sharpe, AL Phillips, TJ AF Sharpe, Amanda L. Phillips, Tamara J. TI Central urocortin 3 administration decreases limited-access ethanol intake in nondependent mice SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE alcohol drinking; corticotrophin-releasing factor(2); ingestion; microinjections; mouse; urocortin 3 ID CORTICOTROPIN-RELEASING-FACTOR; MESSENGER-RNA EXPRESSION; IMPAIRED STRESS-RESPONSE; ANXIETY-LIKE BEHAVIOR; FACTOR-RECEPTOR; DEPENDENT RATS; CENTRAL NUCLEUS; CRF RECEPTORS; FOOD-INTAKE; BRAIN AB Stress and alcohol abuse are co-related. Acute alcohol is anxiolytic and stress is cited as a factor in relapse to alcohol use. A primary mediator of the stress response is the neuropeptide corticotropin-releasing factor (CRF). The CRF family of endogenous ligands includes urocortin 3 (Ucn 3), which binds selectively to the CRF type 2 receptor and has been implicated in ethanol consumption in dependent and withdrawing rats. The objective of this study was to examine the effect of Ucn 3, delivered centrally to nondependent mice, on limited-access ethanol consumption. Adult MUM mice were trained to self-administer 10% ethanol during daily, 2-h limited-access sessions, using lickometers to assess drinking patterns for both ethanol and water. Sterile saline or 0.3, 1, or 3 nmol of Ucn 3 was microinjected into the lateral ventricle immediately before the limited-access session in a within-subjects design. There was a significant decrease in ethanol (both ml and g/kg), but not water, intake following Ucn 3 treatment, explained by a change in size of the largest lick run. Food intake at both 2 h and 24 h after injection was statistically unaffected by Ucn 3 administration. These results establish a role for CRF type 2 receptors in a nondependent mouse model of ethanol self-ad ministration. Behavioural Pharmacology 20:346-351 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Sharpe, Amanda L.; Phillips, Tamara J.] Oregon Hlth & Sci Univ, Portland Alcohol Res Ctr, Dept Behav Neurosci, Portland, OR 97201 USA. [Phillips, Tamara J.] Portland VA Med Ctr, Res Serv, Portland, OR USA. RP Sharpe, AL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol MC7756, 7703 Floyd Curl, San Antonio, TX 78229 USA. EM sharpea@uthscsa.edu FU National Institute on Alcohol Abuse and Alcoholism [AA014747, AA013331, AA010760]; Department of Veterans Affairs FX This study was supported by NIH grants from the National Institute on Alcohol Abuse and Alcoholism AA014747 to A.L.S., AA013331 to TJ.P., and AA010760 to TJ.P, and by the Department of Veterans Affairs. NR 34 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD JUL PY 2009 VL 20 IS 4 BP 346 EP 351 DI 10.1097/FBP.0b013e32832f01ba PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 477QW UT WOS:000268534600007 PM 19581799 ER PT J AU Coaxum, SD Garnovskaya, MN Gooz, M Baldys, A Raymond, JR AF Coaxum, Sonya D. Garnovskaya, Maria N. Gooz, Monika Baldys, Aleksander Raymond, John R. TI Epidermal growth factor activates Na+/H+ exchanger in podocytes through a mechanism that involves Janus kinase and calmodulin SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Cytosensor microphysiometer; ECAR; Phosphorylation; AG1478 ID RECEPTOR TYROSINE KINASE; NEPHROTIC SYNDROME; EGF-RECEPTOR; INTRACELLULAR PH; 5-HT1A RECEPTOR; CELL BIOLOGY; PHOSPHORYLATION; INJURY; INHIBITION; PROTEINS AB Sodium-proton exchanger type 1 (NHE-1) is ubiquitously expressed, is activated by numerous growth factors, and plays significant roles in regulating intracellular pH and cellular volume, proliferation and cytoskeleton. Despite its importance, little is known about its regulation in renal glomerular podocytes. In the current work, we studied the regulation of NHE-1 activity by the epidermal growth factor receptor (EGFR) in cultured podocytes. RT-PCR demonstrated mRNAs for NHE-1 and NHE-2 in differentiated podocytes, as well as for EGFR subunits EGFR/ErbB1, Erb3, and ErbB4. EGF induced concentration-dependent increases in proton efflux in renal podocytes as assessed using a Cytosensor microphysiometer, were diminished in the presence of 5-(N-methyl-N-isobutyl) amiloride or in a sodium-free solution. Furthermore, pharmacological inhibitors of Janus kinase (Jak2) and calmodulin (CaM) attenuated EGF-induced NHE-1 activity. Co-immunoprecipitation studies determined that EGF induced formation of complexes between Jak2 and CaM, as well as between CaM and NHE-1. In addition, EGF increased levels of tyrosine phosphorylation of Jak2 and CaM. The EGFR kinase inhibitor, AG1478, blocked activation of NHE-1, but did not block EGF-induced phosphorylation of Jak2 or CaM. These results suggest that EGF induces NHE-1 activity in podocytes through two pathways: (1) EGF -> EGFR -> Jak2 activation (independent of EGFR tyrosine kinase activity) -> tyrosine phosphorylation of CaM -> CaM binding to NHE-1 -> conformational change of NHE-1 -> activation of NHE-1; and (2) EGF -> EGFR -> EGFR kinase activation -> association of CaM with NHE-1 (independent of Jak2) -> conformational change of NHE-1 -> activation of NHE-1. (C) 2009 Elsevier B.V. All rights reserved. C1 [Raymond, John R.] Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Med & Res Serv, Charleston, SC USA. RP Raymond, JR (reprint author), Med Univ S Carolina, Dept Med, Div Nephrol, Colcock Hall,Off Provost,179 Ashley Ave, Charleston, SC 29425 USA. EM raymondj@musc.edu FU National Institutes of Health [DK52448, GM63909, DK52448-S2]; American Heart Association [0655445U] FX The authors want to thank Dr. Peter Mundel for his advice and assistance, and donation of podocytes. We also would like to thank the Hollings Cancer Center Molecular Imaging Facility at MUSC. This work was supported by grants from the Department of Veterans Affairs (Merits Awards and a REAP award to JRR and MNG), the National Institutes of Health (DK52448 and GM63909 to JRR, and DK52448-S2 to SDC), the American Heart Association (GIA 0655445U to MNG), and a laboratory endowment jointly supported by the M.U.S.C. Division of Nephrology and Dialysis Clinics, Inc. (JRR). The work also was supported by VA shared equipment grants (confocal microscope and micro physiometer). NR 50 TC 28 Z9 28 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JUL PY 2009 VL 1793 IS 7 BP 1174 EP 1181 DI 10.1016/j.bbamcr.2009.03.006 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 467VY UT WOS:000267772400006 PM 19341767 ER PT J AU Martin, PJ Bachier, CR Klingemann, HG McCarthy, PL Szabolcs, P Uberti, JP Schuster, MW Weisdorf, D Chao, NJ Kebriaei, P Shpall, EJ MacMillan, ML Soiffer, RJ AF Martin, Paul J. Bachier, Carlos R. Klingemann, Hans-Georg McCarthy, Philip L. Szabolcs, Paul Uberti, Joseph P. Schuster, Michael W. Weisdorf, Daniel Chao, Nelson J. Kebriaei, Partow Shpall, Elizabeth J. MacMillan, Margaret L. Soiffer, Robert J. TI Endpoints for Clinical Trials Testing Treatment of Acute Graft-versus-Host Disease: A Joint Statement SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE Acute graft-versus-host disease; Clinical trials; Endpoints; Guidelines ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; HEMATOPOIETIC-CELL TRANSPLANTATION; ALLOGENEIC MARROW TRANSPLANTATION; RANDOMIZED-TRIAL; CROHNS-DISEASE; MULTIPLE-MYELOMA; RESPONSE CRITERIA; GRADING SYSTEMS; INITIAL THERAPY AB Currently, no agents are approved by the United States Food and Drug Administration (FDA) for either prevention or treatment of acute graft-versus-host disease (aGVHD). Formal precedents establishing a comparative basis for assessing the efficacy and safety of new investigational agents are still lacking. As a step toward addressing this problem, a panel of experts met on 2 occasions to reach consensus on recommendations for terminology describing a clinically meaningful primary endpoint in studies assessing treatment for aGVHD. The panel recommended terminology for "very good partial response" (VGPR) that includes both diagnostic and functional criteria. The central hypothesis leading to this proposal is that the potential harm of giving more treatment than needed to produce or maintain complete response exceeds the harm of slight under-treatment that may be associated with less than complete response. VGPR clearly cannot be used as the sole outcome measure in GVHD treatment trials, and must be considered in the context of survival and safety. The proposed use of VGPR as the primary endpoint in GVHD treatment trials will remain provisional until its use has been validated through experience. C1 [Martin, Paul J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Bachier, Carlos R.] Texas Transplant Inst, San Antonio, TX USA. [Klingemann, Hans-Georg] Tufts Med Ctr, Boston, MA USA. [McCarthy, Philip L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Szabolcs, Paul; Chao, Nelson J.] Duke Univ, Med Ctr, Durham, NC USA. [Uberti, Joseph P.] Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [Schuster, Michael W.] New York Presbyterian Hosp, New York, NY USA. [Weisdorf, Daniel; MacMillan, Margaret L.] Univ Minnesota, Minneapolis, MN USA. [Kebriaei, Partow; Shpall, Elizabeth J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Soiffer, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Martin, PJ (reprint author), Fred Hutchinson Canc Res Ctr, POB 19024,1100 Fairview Ave N,D2-100, Seattle, WA 98109 USA. EM pmartin@fherc.org FU National Institutes of Health, Department of Health and Human Services [CA18029] FX The consensus meetings were held on September 11, 2007, and on May, 23, 2008, and were sponsored by Osiris Therapeutics, Inc., Columbia, MD. Osiris provided honoraria to the participants (except P.J.M..), but did not contribute to the meeting Output or to the content of this manuscript. Effort by P.J.M. was supported by grant CA18029 from the National Institutes of Health, Department of Health and Human Services. NR 47 TC 26 Z9 26 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 JUL PY 2009 VL 15 IS 7 BP 777 EP 784 DI 10.1016/j.bbmt.2009.03.012 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 465MD UT WOS:000267588300002 PM 19539208 ER PT J AU Stiff, PJ Bensinger, W Abidi, MH Gingrich, R Artz, AS Nademanee, A Hansen, KS Sobczak, C Cutler, C Bolwell, B Shore, TB Lazarus, HM Yeager, AM Lovelace, W Guo, M Dreiling, L AF Stiff, Patrick J. Bensinger, William Abidi, Muneer H. Gingrich, Roger Artz, Andrew S. Nademanee, Auayporn Hansen, Keith S. Sobczak, Christopher Cutler, Corey Bolwell, Brian Shore, Tsiporah B. Lazarus, Hillard M. Yeager, Andrew M. Lovelace, Wade Guo, Matthew Dreiling, Lyndah TI Clinical and Ultrasonic Evaluation of Spleen Size during Peripheral Blood Progenitor Cell Mobilization by Filgrastim: Results of an Open-Label Trial in Normal Donors SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Stem cell; Mobilization; Spenomegaly; Spleen size ID COLONY-STIMULATING FACTOR; SPONTANEOUS SPLENIC RUPTURE; HEMATOPOIETIC STEM-CELLS; G-CSF; MULTIPLE-MYELOMA; HEALTHY DONORS; PATIENT; TRANSPLANTATION; PEGFILGRASTIM; CANCER AB Rare reports of splenic rupture have been associated with filgrastim treatment during peripheral blood progenitor cell (PBPC) mobilization in allogeneic donors. We performed a prospective study of spleen volume change in 309 normal donors who received filgrastim according to local institutional practices. Splenic assessments consisted of ultrasonography and clinical examination at baseline and on the first day of leukapheresis in 304 donors. Of these, 90 donors were also examined 2 and 4 days after the first leukapheresis and 7 days after the last leukapheresis. Median spleen volume increased 1.47-fold (range: 0.63 to 2.60) on the first leukapheresis day and declined to near pretreatment levels at 7 days after last leukapheresis. Nine percent of donors had >= 2-fold increase in splenic volume. Spleen palpability did not correlate with change in spleen volume. No donors experienced a splenic rupture. There was no correlation between change in spleen volume and filgrastim dosage, number of doses/day, peak absolute neutrophil count (ANC), CD34(+) yield, or donor baseline weight. Most donors experienced >= 1 adverse event, with 6 donors reporting serious adverse events. We conclude that the increase in splenic volume during PBPC mobilization in donors was transient, and that filgrastim was well tolerated in this study. This trial was registered at www.ClinicalTrials.gov as NCT00115128. C1 [Stiff, Patrick J.] Loyola Univ, Med Ctr, Div Hematol Oncol, Maywood, IL 60153 USA. [Bensinger, William] Fred Hutchinson Canc Res Ctr, Div Oncol, Seattle, WA 98104 USA. [Abidi, Muneer H.] Wayne State Univ, Bone Marrow Transplant Program, Detroit, MI USA. [Gingrich, Roger] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Artz, Andrew S.] Univ Chicago, Med Ctr, Div Hematol Oncol, Chicago, IL 60637 USA. [Nademanee, Auayporn] City Hope Natl Med Ctr, Dept Hematol & Bone Marrow Transplant, Duarte, CA USA. [Hansen, Keith S.] NW Marrow Transplant Program, Autologous Stem Cell Transplant Program, Portland, OR USA. [Sobczak, Christopher] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Sobczak, Christopher] Med Coll Wisconsin, Dept Internal Med, Milwaukee, WI 53226 USA. [Cutler, Corey] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Bolwell, Brian] Cleveland Clin, Taussig Canc Ctr, Dept Hematol Oncol & Blood Disorders, Cleveland, OH 44106 USA. [Shore, Tsiporah B.] New York Presbyterian Hosp Cornell, Div Hematol Oncol, New York, NY USA. [Lazarus, Hillard M.] Univ Hosp, Case Med Ctr, Dept Med, Cleveland, OH USA. [Yeager, Andrew M.] Arizona Canc Ctr, Blood & Marrow Transplantat Program, Tucson, AZ USA. [Lovelace, Wade; Guo, Matthew; Dreiling, Lyndah] Amgen Inc, Thousand Oaks, CA 91320 USA. RP Stiff, PJ (reprint author), Loyola Univ Hlth Syst, 2160 S 1st Ave, Maywood, IL 60153 USA. EM pstiff@lumc.edu OI Abidi, Muneer/0000-0002-9936-6031 FU Amgen Inc. FX This study was supported by research funding from Amgen Inc. Joan O'Byrne, a paid consultant to Amgen Inc., and Loretta Spotila, a paid consultant to RPS, Inc., assisted with the preparation of this manuscript. NR 27 TC 9 Z9 9 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 JUL PY 2009 VL 15 IS 7 BP 827 EP 834 DI 10.1016/j.bbmt.2009.03.015 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 465MD UT WOS:000267588300008 PM 19539214 ER PT J AU Ho, VT Aldridge, J Kim, HT Cutler, C Koreth, J Armand, P Antin, JH Soiffer, RJ Alyea, EP AF Ho, Vincent T. Aldridge, Julie Kim, Haesook T. Cutler, Corey Koreth, John Armand, Philippe Antin, Joseph H. Soiffer, Robert J. Alyea, Edwin P. TI Comparison of Tacrolimus and Sirolimus (Tac/Sir) versus Tacrolimus, Sirolimus, and Mini-Methotrexate (Tac/Sir/MTX) as Acute Graft-versus-Host Disease Prophylaxis after Reduced-Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Graft-versus-host disease; Sirolimus; Rapamycin; Tacrolimus; Methotrexate; Transplantation ID LOW-DOSE METHOTREXATE; REGULATORY T-CELLS; HEMATOLOGIC MALIGNANCIES; MYCOPHENOLATE-MOFETIL; COMPETING RISK; DONOR; RAPAMYCIN; IMMUNOSUPPRESSION; INHIBITORS; LEUKEMIA AB Previous studies have shown that adding sirolimus to a tacrolimus/mini-methotrexate regimen (Tac/Sir/MTX) as graft-versus-host disease (GVHD) prophylaxis produces low rates of acute GVHD (aGVHD) after reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). To assess whether posttransplantation methotrexate MTX can be safely eliminated altogether, we conducted a prospective clinical trial testing the combination of T and Sir alone (tac/sir) as GVHD prophylaxis after RIC SCT from matched related donors. We compared the results with patients who received (Tac/Sir/MTX) as GVHD prophylaxis after RIC SCT from matched related donors in a previous prospective study. Patients in both groups received i.v. fludarabine (Flu) 30 mg/m(2)/day and i.v. busulfan (Bu) 0.8 mg/kg/day on days -5 to -2 as conditioning, followed by transplantation of unmanipulated filgrastim-mobilized peripheral blood stem cells (PBSCS). After transplantation, patients in both groups received Tac and Sir orally starting on day -3, with doses adjusted to achieve trough serum levels of 5 to 10 ng/mL and 3 to 12 ng/mL, respectively. The patients in the Tac/Sir/MTX group also received mini-MTX therapy (S mg/m(2) i.v.) on days + 1, + 3, and + 6. Filgrastim 5 mu g/kg/day s.c. was started on day + I and continued until neutrophil engraftment. Twenty-nine patients received the Tac/Sir regimen, and 46 patients received the Tac/Sir/MTX regimen. The 2 groups were balanced in terms of age, sex, and disease characteristics. Engraftment was brisk and donor chimerism after transplantation robust in both groups. The cumulative incidence of grade II-IV aGVHD was similar in the 2 groups (17% for Tac/Sir versus 11% for Tac/Sir/MTX; P = .46). There also were no differences between the 2 groups in cumulative incidence of extensive chronic GVHD (cGVHD), treatment-related mortality (TRM), disease relapse, or survival. The Tac/Sir combination for GVHD prophylaxis is well tolerated and associated with a low incidence of aGVHD in matched related donor RIC SCT The omission of mini-MTX from the Tac/Sir GVHD prophylaxis regimen appears to have no adverse effect on the development of aGVHD. C1 [Ho, Vincent T.; Cutler, Corey; Koreth, John; Armand, Philippe; Antin, Joseph H.; Soiffer, Robert J.; Alyea, Edwin P.] Harvard Univ, Sch Med, Ctr Hematol Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Aldridge, Julie; Kim, Haesook T.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Ho, VT (reprint author), Harvard Univ, Sch Med, Ctr Hematol Oncol, Dana Farber Canc Inst, 44 Binney St,D1B06, Boston, MA 02115 USA. EM Vincent_Ho@DFCI.Harvard.edu RI ieong, bee/C-5840-2012 FU Ted and Eileen Pasquarello Research Fund; National Institutes of Health [P01 HL070149-02] FX Supported in part by the Ted and Eileen Pasquarello Research Fund and by National Institutes of Health Grant P01 HL070149-02. NR 23 TC 36 Z9 37 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2009 VL 15 IS 7 BP 844 EP 850 DI 10.1016/j.bbmt.2009.03.017 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 465MD UT WOS:000267588300010 PM 19539216 ER PT J AU Browne, ML Rasmussen, SA Hoyt, AT Waller, DK Druschel, CM Caton, AR Canfield, MA Lin, AE Carmichael, SL Romitti, PA AF Browne, Marilyn L. Rasmussen, Sonja A. Hoyt, Adrienne T. Waller, D. Kim Druschel, Charlotte M. Caton, Alissa R. Canfield, Mark A. Lin, Angela E. Carmichael, Suzan L. Romitti, Paul A. CA Natl Birth Defects Prevention TI Maternal Thyroid Disease, Thyroid Medication Use, and Selected Birth Defects in the National Birth Defects Prevention Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE thyroid hormones; thyroxine; thyroid disease; congenital abnormalities; birth defects ID RISK-FACTORS; WOMEN; CRANIOSYNOSTOSIS; MALFORMATIONS AB BACKGROUND: Although thyroid disorders are present in approximately 3%, of pregnant women, little is known about the association between maternal thyroid disease and birth defects. METHODS: We assessed the association between maternal thyroid disease, thyroid medication use, and 38 types of birth defects among 14,067 cases and 5875 controls in the National Birth Defects Prevention Study, a multisite, population-based, case-control study. Infants in this study were born between October 1997 and December 2004. Information on exposures including maternal diseases and use of medications was collected by telephone interview. RESULTS: We found statistically significant associations between maternal thyroid disease and left ventricular outflow tract obstruction heart defects (1.5; 95%, CI, 1.0-2.3), hydrocephaly (2.9; 951, CI, 1.6-5.2), hypospadias (1.6; 95%, CI, 1.0-2.5), and isolated anorectal atresia (2.4; 95%, CI, 1.2-4.6). Estimates for the association between periconceptional use of thyroxine and specific types of birth defects were similar to estimates for any thyroid disease. Given that antithyroid medication use was rare, we could not adequately assess risks for their use for most case groups. CONCLUSIONS: Our results are consistent with the positive associations between maternal thyroid disease or thyroid medication use and both hydrocephaly and hypospadias observed in some previous studies. New associations with left ventricular outflow tract obstruction heart defects and anorectal atresia may be chance findings. Birth Defects Research (Part A) 55:621-628, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Browne, Marilyn L.; Hoyt, Adrienne T.; Druschel, Charlotte M.; Caton, Alissa R.] New York State Dept Hlth, Congenital Malformat Registry, Troy, NY USA. [Rasmussen, Sonja A.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Waller, D. Kim] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Canfield, Mark A.] Texas Dept State Hlth Serv, Austin, TX USA. [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA USA. [Carmichael, Suzan L.] Calif Res Div, Oakland, CA USA. [Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. RP Browne, ML (reprint author), 547 River St,Room 200, Troy, NY 12180 USA. EM mlb10@health.state.ny.us RI Publications, NBDPS/B-7692-2013 FU Centers for Disease Control and Prevention [U50/CCU223184] FX Supported by a cooperative agreement from the Centers for Disease Control and Prevention (U50/CCU223184). Coding of drug information in the NBDPS used the Stone Epidemiology Center Drug Dictionary, under license from the Slone Epidemiology Center at Boston University. NR 24 TC 16 Z9 17 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD JUL PY 2009 VL 85 IS 7 BP 621 EP 628 DI 10.1002/bdra.20573 PG 8 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 476GE UT WOS:000268426000005 PM 19215015 ER PT J AU Wo, JY Shipley, WU Dahl, DM Coen, JJ Heney, NM Kaufman, DS Zietman, AL AF Wo, Jennifer Y. Shipley, William U. Dahl, Douglas M. Coen, John J. Heney, Niall M. Kaufman, Donald S. Zietman, Anthony L. TI The results of concurrent chemo-radiotherapy for recurrence after treatment with bacillus Calmette-Guerin for non-muscle-invasive bladder cancer: is immediate cystectomy always necessary? SO BJU INTERNATIONAL LA English DT Article DE BCG; failure; selective bladder-preserving chemo-radiotherapy; non-muscle invasive bladder cancer ID TRANSITIONAL-CELL CARCINOMA; INTRAVESICAL THERAPY; TRANSURETHRAL RESECTION; RADICAL CYSTECTOMY; MANAGEMENT; TRIAL; RISK; PRESERVATION AB OBJECTIVES To report our original experience in patients in whom bacille Calmette-Guerin (BCG) therapy has failed for T1 bladder cancer with subsequent progression to T2 disease treated with chemo-radiotherapy, as the management of recurrent high-grade T1 bladder cancer after failed BCG therapy is challenging, and radical cystectomy is the standard treatment because there are no well established second-line bladder-preserving therapies. PATIENTS AND METHODS From 1988 to 2002, 18 patients with T2 recurrence after failure of BCG therapy for T1 bladder cancer were treated with chemo-radiotherapy at the authors' institution. Patients received a visibly complete transurethral resection of the bladder tumour (TURBT) and concurrent chemo-radiotherapy with a mid-treatment evaluation after 40 Gy. Patients with less than a complete response had a prompt cystectomy; the others completed radiotherapy to 64-65 Gy. The primary treatment outcome was freedom from cystectomy due to recurrence not treatable by conservative measures; secondary outcomes included disease-specific (DSS) and overall survival (OS). RESULTS With a median follow-up of 7.0 years, only one patient had persistent tumour at re-staging TURBT and had an immediate cystectomy. Of the remaining 17 patients, 10 (59%) were free of any bladder recurrence. The actuarial 7-year DSS and OS were 70% and 58%, respectively. At 7 years, 54% of patients were alive with intact bladders and free of invasive recurrence. CONCLUSIONS In this study we specifically evaluated patients with apparently small muscle-invasive recurrences after BCG treatment for T1 bladder cancer. Selective bladder preservation with chemo-radiotherapy is possible, with low morbidity and a high chance of long-term bladder control. If successful in treating T2 recurrences after BCG therapy, it now seems timely to critically evaluate chemo-radiotherapy as an alternative to immediate cystectomy in the management of patients with T1 recurrences after BCG. C1 [Shipley, William U.; Coen, John J.; Zietman, Anthony L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. [Dahl, Douglas M.; Heney, Niall M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. [Kaufman, Donald S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med Oncol, Boston, MA 02114 USA. [Wo, Jennifer Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02114 USA. RP Shipley, WU (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, 100 Blossom St Cox 3, Boston, MA 02114 USA. EM wshipley@partners.org NR 16 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 1464-4096 J9 BJU INT JI BJU Int. PD JUL PY 2009 VL 104 IS 2 BP 179 EP 183 DI 10.1111/j.1464-410X.2008.08299.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 463IP UT WOS:000267425900007 PM 19154448 ER PT J AU Stifani, S Ma, QF AF Stifani, Stefano Ma, Qiufu TI 'Runxs and regulations' of sensory and motor neuron subtype differentiation: Implications for hematopoietic development SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Acute myeloid leukemia; Differentiation; Dorsal root ganglion; Motor neurons; Nervous system; Proliferation; Runx; Sensory neurons; Spinal cord ID MULTIPLE CHROMOSOMAL TRANSLOCATIONS; ROOT GANGLION NEURONS; CORE-BINDING FACTORS; T-CELL DEVELOPMENT; TRANSCRIPTION FACTOR; OSTEOBLAST DIFFERENTIATION; NERVOUS-SYSTEM; DEPENDENT PHOSPHORYLATION; GENE-EXPRESSION; CD4 REPRESSION AB Runt-related ( RUNX) transcription factors are evolutionarily conserved regulators of a number of developmental mechanisms. RUNX proteins often control the balance between proliferation and differentiation and alterations of their functions are associated with different types of cancer and other human pathologies. Moreover, RUNX factors control important steps during the developmental acquisition of mature phenotypes. A number of investigations are beginning to shed light on the involvement of RUNX family members in the development of the nervous system. This review summarizes recent progress in the study of the roles of mammalian RUNX proteins during the differentiation of sensory and motor neurons in the peripheral and central nervous system, respectively. The implications of those findings for RUNX-mediated regulation of hematopoietic development will also be discussed. (C) 2009 Elsevier Inc. All rights reserved. C1 [Stifani, Stefano] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. [Ma, Qiufu] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ma, Qiufu] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Stifani, S (reprint author), McGill Univ, Montreal Neurol Inst, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. EM stefano.stifani@mcgill.ca; qiufu_ma@dfci.harvard.edu OI Stifani, Stefano/0000-0002-2376-7701 FU The Leukemia and Lymphoma Society in Provincetown, Massachusetts; Canadian Institutes of Health Research [MOP-84577, MOP-42479]; NIH-National Institute of Dental and Craniofacial [1R01DE018025]; NIH-National Institute of Neurological Disorders and Stroke [5P01NS047572] FX This paper is based on presentations at the 15th International RUNX Workshop sponsored by The Leukemia and Lymphoma Society in Provincetown, Massachusetts from September 14-17, 2008. S. S. is a Chercheur National of the Fonds de la Recherche en Sante du Quebec and research in his laboratory is funded in part by the Canadian Institutes of Health Research grants MOP-84577 and MOP-42479. Q. M. is a Claudia Adams Barr Scholar, and research done in his lab is supported by NIH-National Institute of Dental and Craniofacial Research Grant 1R01DE018025 and NIH-National Institute of Neurological Disorders and Stroke Grant 5P01NS047572. NR 66 TC 16 Z9 16 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JUL-AUG PY 2009 VL 43 IS 1 BP 20 EP 26 DI 10.1016/j.bcmd.2009.03.001 PG 7 WC Hematology SC Hematology GA 510GQ UT WOS:000271076500004 PM 19349198 ER PT J AU Russell, M Stark, J Nayak, S Miller, KK Herzog, DB Klibanski, A Misra, M AF Russell, Melissa Stark, Jenna Nayak, Shriddha Miller, Karen K. Herzog, David B. Klibanski, Anne Misra, Madhusmita TI Peptide YY in adolescent athletes with amenorrhea, eumenorrheic athletes and non-athletic controls SO BONE LA English DT Article DE Athletes; Adolescents; Peptide YY; Bone density; Bone turnover ID GONADOTROPIN-RELEASING-HORMONE; MAPK SIGNALING PATHWAY; BONE-MINERAL DENSITY; ANOREXIA-NERVOSA; HYPOTHALAMIC AMENORRHEA; LUTEINIZING-HORMONE; ENERGY DEFICIENCY; HUMAN OSTEOBLASTS; EXERCISING WOMEN; GROWTH-HORMONE AB Background: Bone mineral density (BMD) is lower in amenorrheic athletes (AA) compared with eumenorrheic athletes (EA). Decreased energy availability and altered levels of appetite regulating hormones (ghrelin and leptin) in AA contribute to hypogonadism, an important Cause of low BMD. The role of other nutritionally regulated hormones such as peptide YY (PYY) and adiponectin in mediating gonadal status and bone metabolism remains to be determined. Objectives: Our objective was to determine whether PYY and adiponectin are higher in AA Compared with EA and contribute to hypogonadism and impaired bone metabolism in AA. Methods: We determined PYY and adiponectin in 16 AA, 15 EA and 16 non-athletic controls 12-18 years old, and other nutritionally dependent hormones including ghrelin, leptin and IGF-1. We also measured testosterone, estradiol, PINP and NTX (markers of bone formation and resorption) and BMD. Results: PYY was higher in AA than EA (111 +/- 52 vs. 61 +/- 29 pg/ml, p<0.05), whereas adiponectin did not differ between groups. Although activity scores did not differ, BMI was lower in AA than EA and a larger proportion (62.5% vs. 6.7%) reported disordered eating, indicating lower energy availability. PYY and adiponectin were independent predictors of testosterone in a regression model (p = 0.01 and 0.04), but did not predict estradiol. PYY, but not adiponectin, was an independent and negative predictor of PINP (p = 0.002) and lumbar bone mineral apparent density Z-scores (p = 0.045) in this model. Conclusion: High PYY levels (but not adiponectin) differentiate AA from EA, and may be an important factor contributing to low bone density in athletes. (C) 2009 Elsevier Inc. All rights reserved. C1 [Russell, Melissa; Stark, Jenna; Nayak, Shriddha; Miller, Karen K.; Klibanski, Anne; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Russell, Melissa; Stark, Jenna; Nayak, Shriddha; Miller, Karen K.; Herzog, David B.; Klibanski, Anne; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA USA. [Russell, Melissa; Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. [Herzog, David B.] Massachusetts Gen Hosp, Harris Ctr, Boston, MA 02114 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM mmisra@partners.org FU NCRR NIH HHS [M01 RR001066, K23 RR018851-05, M01-RR-01066, K23 RR018851]; NIDDK NIH HHS [P30 DK040561, P30 DK040561-14, P30DK040561, R01 DK 062249, R01 DK062249] NR 48 TC 35 Z9 35 U1 0 U2 4 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 JUL PY 2009 VL 45 IS 1 BP 104 EP 109 DI 10.1016/j.bone.2009.03.668 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 458PT UT WOS:000267036700012 PM 19344792 ER PT J AU Stewart, AJ Devlin, PM Mutyala, S AF Stewart, Alexandra J. Devlin, Phillip M. Mutyala, Subhakar TI Counterpoint: The dose rate argument-Does size matter after all? SO BRACHYTHERAPY LA English DT Editorial Material ID RATE INTRACAVITARY BRACHYTHERAPY; CERVIX CANCER BRACHYTHERAPY; UTERINE CERVIX; INTERSTITIAL BRACHYTHERAPY; ENDOMETRIAL CANCER; RANDOMIZED-TRIAL; RATE TANDEM; CARCINOMA; RADIATION; RECOMMENDATIONS C1 [Devlin, Phillip M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Stewart, Alexandra J.] Royal Surrey Cty Hosp, Dept Radiotherapy, Surrey, England. [Mutyala, Subhakar] Montefiore Med Ctr, Dept Radiat Oncol, Bronx, NY 10467 USA. RP Devlin, PM (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St,L2, Boston, MA 02115 USA. EM pdevlin@lroc.harvard.edu NR 39 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-4721 J9 BRACHYTHERAPY JI Brachytherapy PD JUL-SEP PY 2009 VL 8 IS 3 BP 273 EP 275 DI 10.1016/j.brachy.2009.06.003 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 482YG UT WOS:000268926000002 PM 19643374 ER PT J AU Mutyala, S Devlin, PM Stewart, AJ AF Mutyala, Subhakar Devlin, Phillip M. Stewart, Alexandra J. TI Rebuttal to Drs. Davidson, Hendry, and West: Once burned, twice shy? SO BRACHYTHERAPY LA English DT Editorial Material ID DOSE-RATE BRACHYTHERAPY; TRIAL; CARCINOMA; RATES C1 [Mutyala, Subhakar] Montefiore Med Ctr, Dept Radiat Oncol, Bronx, NY 10467 USA. [Devlin, Phillip M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Stewart, Alexandra J.] Royal Surrey Cty Hosp, Dept Radiotherapy, Surrey, England. RP Mutyala, S (reprint author), Montefiore Med Ctr, Dept Radiat Oncol, 111 E 210th St, Bronx, NY 10467 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-4721 J9 BRACHYTHERAPY JI Brachytherapy PD JUL-SEP PY 2009 VL 8 IS 3 BP 277 EP 277 DI 10.1016/j.brachy.2009.06.002 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 482YG UT WOS:000268926000004 PM 19643376 ER PT J AU Gow, DW Keller, CJ Eskandar, E Meng, N Cash, SS AF Gow, David W., Jr. Keller, Corey J. Eskandar, Emad Meng, Nate Cash, Sydney S. TI Parallel versus serial processing dependencies in the perisylvian speech network: A Granger analysis of intracranial EEG data SO BRAIN AND LANGUAGE LA English DT Article DE Speech perception; iEEG; Granger causality; Dual pathway model; Spoken word recognition; Functional connectivity; Speech perception; Intracranial recording; Electrophysiology ID FUNCTIONAL NEUROANATOMY; CAUSALITY ANALYSIS; HUMAN BRAIN; PERCEPTION; FMRI; IDENTIFICATION; CONNECTIVITY; POTENTIALS; STREAMS; HUMANS AB In this work, we apply Granger causality analysis to high spatiotemporal resolution intracranial EEG (iEEG) data to examine how different components of the left perisylvian language network interact during spoken language perception. The specific focus is on the characterization of serial versus parallel processing dependencies in the dominant hemisphere dorsal and ventral speech processing streams. Analysis of iEEG data from a large, 64-electrode grid implanted over the left perisylvian region in a single right-handed patient showed a consistent pattern of direct posterior superior temporal gyros influence over sites distributed over the entire ventral pathway for words, non-words, and phonetically ambiguous items that could be interpreted either as words or non-words. For the phonetically ambiguous items, this pattern was overlayed by additional dependencies involving the inferior frontal gyrus, which influenced activation measured at electrodes located in both ventral and dorsal stream speech structures. Implications of these results for understanding the functional architecture of spoken language processing and interpreting the role of the posterior superior temporal gyros in speech perception are discussed. (C) 2009 Elsevier Inc. All rights reserved. C1 [Gow, David W., Jr.] Massachusetts Gen Hosp, Cognit Behav Neurol Grp, Dept Neurol, Boston, MA 02114 USA. [Gow, David W., Jr.; Keller, Corey J.; Meng, Nate] Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02114 USA. [Gow, David W., Jr.] Salem State Coll, Dept Psychol, Salem, MA USA. [Eskandar, Emad] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Gow, DW (reprint author), Massachusetts Gen Hosp, Cognit Behav Neurol Grp, Dept Neurol, 175 Cambridge St,Suite S340, Boston, MA 02114 USA. EM gow@helix.mgh.harvard.edu OI Keller, Corey/0000-0003-0529-3490 FU NIDCD [R013108] FX This work was supported by NIDCD grant R013108. We thank Eric Halgren for early helpful discussions on the work, Christina Congleton and Jennifer Segawa for their assistance in stimulus generation, and Andrew Dykstra for providing some of the code used to analyze the data. NR 43 TC 16 Z9 17 U1 3 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD JUL PY 2009 VL 110 IS 1 BP 43 EP 48 DI 10.1016/j.bandl.2009.02.004 PG 6 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 459JR UT WOS:000267098500006 PM 19356793 ER PT J AU George, MS AF George, Mark S. TI From the Editor-in-Chief's desk SO BRAIN STIMULATION LA English DT Editorial Material C1 [George, Mark S.] Univ S Carolina, Brain Stimulat Basic Translat & Clin Res Neuromod, Charleston, SC USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP George, MS (reprint author), Univ S Carolina, Brain Stimulat Basic Translat & Clin Res Neuromod, Charleston, SC USA. EM georgem@musc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD JUL PY 2009 VL 2 IS 3 BP 121 EP 122 DI 10.1016/j.brs.2009.06.002 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 478UQ UT WOS:000268614300001 PM 20633410 ER PT J AU Castellon, S Ganz, PA AF Castellon, Steven Ganz, Patricia A. TI Neuropsychological studies in breast cancer: in search of chemobrain SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Editorial Material ID COGNITIVE DYSFUNCTION; CHEMOTHERAPY; WOMEN; WORKSHOP; ESTROGEN; THERAPY C1 [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Med, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90095 USA. [Castellon, Steven] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90095 USA. [Castellon, Steven] W Los Angeles Vet Affairs Med Ctr, Dept Mental Hlth & Psychiat, Los Angeles, CA 90073 USA. RP Ganz, PA (reprint author), Univ Calif Los Angeles, Sch Med, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, 650 Charles Young Dr S,Room A2-125 CHS, Los Angeles, CA 90095 USA. EM pganz@mednet.ucla.edu NR 18 TC 15 Z9 15 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2009 VL 116 IS 1 BP 125 EP 127 DI 10.1007/s10549-008-0211-2 PG 3 WC Oncology SC Oncology GA 457QH UT WOS:000266946700011 PM 18923899 ER PT J AU Colleoni, M Bagnardi, V Rotmensz, N Gelber, RD Viale, G Pruneri, G Veronesi, P Torrisi, R Cardillo, A Montagna, E Campagnoli, E Luini, A Intra, M Galimberti, V Scarano, E Peruzzotti, G Goldhirsch, A AF Colleoni, Marco Bagnardi, Vincenzo Rotmensz, Nicole Gelber, Richard D. Viale, Giuseppe Pruneri, Giancarlo Veronesi, Paolo Torrisi, Rosalba Cardillo, Anna Montagna, Emilia Campagnoli, Elisabetta Luini, Alberto Intra, Mattia Galimberti, Viviana Scarano, Eloise Peruzzotti, Giulia Goldhirsch, Aron TI Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Predictive factors; Primary therapy; Breast cancer ID INTERNATIONAL EXPERT PANEL; SURGICAL ADJUVANT BREAST; NEOADJUVANT CHEMOTHERAPY; SYSTEMIC TREATMENT; LOBULAR CARCINOMA; PREDICTIVE-VALUE; PRIMARY TUMOR; RECOMMENDATIONS; ESTROGEN; ASSOCIATION AB The predictive role of the degree of endocrine responsiveness to preoperative chemotherapy (PCT) is unclear. We reviewed pretreatment biopsies of 553 patients with locally advanced breast cancer who were treated with PCT. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to the degree of estrogen (ER) and progesterone receptor (PgR) expression (ER and PgR absent, vs. ER or PgR 0-49%, vs. ER and PgR a parts per thousand yen50% of the cells positive). A statistically significant higher pCR rate was observed at the multivariate analysis for patients with ER and PgR absent tumors (17.7%) versus patients with tumors expressing high ER and PgR (0%) (OR 14.4 P < 0.001). Despite the higher incidence of pCR, a statistically significant worse disease-free survival (DFS), and overall survival (OS) was observed for patients with ER and PgR absent tumors versus patients with tumors expressing high ER and PgR (HR 6.4, 95% CI 3.5-11.6, for DFS; HR 3.6 95% CI 2.4-5.6 for OS). Response and outcome after PCT are correlated with the degree of expression of steroid hormone receptors. Studies on tailored preoperative therapies are needed. C1 [Colleoni, Marco; Torrisi, Rosalba; Cardillo, Anna; Montagna, Emilia; Campagnoli, Elisabetta; Scarano, Eloise] European Inst Oncol, Dept Med, Res Unit Med Senol, I-20141 Milan, Italy. [Bagnardi, Vincenzo; Rotmensz, Nicole] European Inst Oncol, Div Epidemiol & Biostat, I-20141 Milan, Italy. [Bagnardi, Vincenzo] Univ Milano Bicocca, Dept Stat, Milan, Italy. [Bagnardi, Vincenzo] Frontier Sci & Technol Res Fdn Inc, Milan, Italy. [Gelber, Richard D.] Dana Farber Canc Inst, Int Breast Canc Study Grp, Ctr Stat, Boston, MA 02115 USA. [Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Viale, Giuseppe; Pruneri, Giancarlo] European Inst Oncol, Div Pathol, I-20141 Milan, Italy. [Viale, Giuseppe; Pruneri, Giancarlo; Veronesi, Paolo] Univ Milan, Sch Med, Milan, Italy. [Veronesi, Paolo; Luini, Alberto; Intra, Mattia; Galimberti, Viviana] European Inst Oncol, Div Senol, I-20141 Milan, Italy. RP Colleoni, M (reprint author), European Inst Oncol, Dept Med, Res Unit Med Senol, Via Ripamonti 435, I-20141 Milan, Italy. EM marco.colleoni@ieo.it FU European Institute of Oncology FX We thank the patients, nurses and physicians at the European Institute of Oncology. NR 38 TC 63 Z9 71 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2009 VL 116 IS 2 BP 359 EP 369 DI 10.1007/s10549-008-0223-y PG 11 WC Oncology SC Oncology GA 458BR UT WOS:000266988000016 PM 18941889 ER PT J AU Neuhausen, SL Ozcelik, H Southey, MC John, EM Godwin, AK Chung, W Iriondo-Perez, J Miron, A Santella, RM Whittemore, A Andrulis, IL Buys, SS Daly, MB Hopper, JL Seminara, D Senie, RT Terry, MB AF Neuhausen, Susan L. Ozcelik, Hilmi Southey, Melissa C. John, Esther M. Godwin, Andrew K. Chung, Wendy Iriondo-Perez, Jeniffer Miron, Alexander Santella, Regina M. Whittemore, Alice Andrulis, Irene L. Buys, Saundra S. Daly, Mary B. Hopper, John L. Seminara, Daniela Senie, Ruby T. Terry, Mary Beth CA Breast Canc Family Registry TI BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Biospecimen repository; Breast cancer; BRCA1; BRCA2 ID SENSITIVE GEL-ELECTROPHORESIS; UNKNOWN CLINICAL-SIGNIFICANCE; SEQUENCE VARIANTS; TRUNCATING BRCA1; RISK; WOMEN; PREVALENCE AB The Breast Cancer Family Registry is a resource for interdisciplinary and translational studies of the genetic epidemiology of breast cancer. This resource is available to researchers worldwide for collaborative studies. Herein, we report the results of testing for germline mutations in BRCA1 and BRCA2. We have tested 4,531 probands for mutations in BRCA1 and 4,084 in BRCA2. Deleterious mutations in BRCA1 and BRCA2 were identified for 9.8% of probands tested [233/4,531 (5.1%) for BRCA1 and 193/4,084 (4.7%) for BRCA2]. Of 1,385 Ashkenazi Jewish women tested for only the three founder mutations, 17.4% carried a deleterious mutation. In total, from the proband and subsequent family testing, 1,360 female mutation carriers (788 in BRCA1, 566 in BRCA2, 6 in both BRCA1 and BRCA2) have been identified. The value of the resource has been greatly enhanced by determining the germline BRCA1 and BRCA2 mutation statuses of nearly 6,000 probands. C1 [Neuhausen, Susan L.] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA. [Ozcelik, Hilmi] Mt Sinai Hosp, Div Epidemiol & Biostat, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [John, Esther M.] No Calif Canc Ctr, Fremont, CA USA. [Godwin, Andrew K.; Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Chung, Wendy] Columbia Univ, Dept Pediat & Med, New York, NY USA. [Iriondo-Perez, Jeniffer] Res Triangle Inst, Raleigh, NC USA. [Miron, Alexander] Dana Farber Canc Ctr, Dept Canc Biol, Boston, MA USA. [Santella, Regina M.; Senie, Ruby T.; Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Whittemore, Alice] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Andrulis, Irene L.] Mt Sinai Hosp, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Canc Care Ontario,Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Buys, Saundra S.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Hopper, John L.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Parkville, Vic 3052, Australia. [Seminara, Daniela] NCI, Epidemiol & Genet Res Program, Clin & Genet Epidemiol Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Seminara, Daniela] Breast Canc Family Registry, Bethesda, MD USA. RP Neuhausen, SL (reprint author), Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA. EM sneuhaus@uci.edu RI Andrulis, Irene/E-7267-2013 FU National Cancer Institute; National Institutes of Health [CA-95-011]; Breast Cancer Family Registry and Principal Investigators [U01 CA69467]; Columbia University [U01 CA69398]; Fox Chase Cancer Center [U01 CA69631]; Huntsman Cancer Institute [U01 CA69446]; Northern California Cancer Center [U01 CA69417]; University of Melbourne [U01 CA69638]; Research Triangle Institute Informatics Support Center [RFP N02PC45022-46]; National Health and Medical Research Council (NHMRC); Victorian Breast Cancer Research Consortium (VBCRC); Ovarian Cancer SPORE [P50 CA83638] FX This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Huntsman Cancer Institute (U01 CA69446), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). Mutation testing in Australia was supported by grants from the National Health and Medical Research Council (NHMRC) and the Victorian Breast Cancer Research Consortium (VBCRC). Mutation testing at Fox Chase Cancer Center was in part supported by an Ovarian Cancer SPORE grant (P50 CA83638). Mutation testing in Ontario was supported in part by Cancer Care Ontario. We wish to thank members of the Ontario Cancer Genetics Network for their contributions to the study. MCS is a Senior Research Fellow of the NHMRC and JLH is an Australia Fellow and a VBCRC Group Leader. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast CFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Breast CFR. NR 24 TC 30 Z9 30 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2009 VL 116 IS 2 BP 379 EP 386 DI 10.1007/s10549-008-0153-8 PG 8 WC Oncology SC Oncology GA 458BR UT WOS:000266988000018 PM 18704680 ER PT J AU Souglakos, J Philips, J Wang, R Marwah, S Silver, M Tzardi, M Silver, J Ogino, S Hooshmand, S Kwak, E Freed, E Meyerhardt, JA Saridaki, Z Georgoulias, V Finkelstein, D Fuchs, CS Kulke, MH Shivdasani, RA AF Souglakos, J. Philips, J. Wang, R. Marwah, S. Silver, M. Tzardi, M. Silver, J. Ogino, S. Hooshmand, S. Kwak, E. Freed, E. Meyerhardt, J. A. Saridaki, Z. Georgoulias, V. Finkelstein, D. Fuchs, C. S. Kulke, M. H. Shivdasani, R. A. TI Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE KRAS; PIK3CA; BRAF; mutation; prediction; metastatic CRC ID MISMATCH-REPAIR; PLUS IRINOTECAN; KRAS MUTATIONS; POOR SURVIVAL; BRAF V600E; CETUXIMAB; FLUOROURACIL; LEUCOVORIN; GENE; EGFR AB BACKGROUND: We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC). METHODS: We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively. RESULTS: KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P = 0.002) and shorter PFS (P = 0.09). BRAF (P = 0.0005) and PIK3CA (P = 0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy. CONCLUSIONS: These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials. British Journal of Cancer (2009) 101, 465-472. doi:10.1038/sj.bjc.6605164 www.bjcancer.com Published online 14 July 2009 (C) 2009 Cancer Research UK C1 [Souglakos, J.; Georgoulias, V.] Univ Hosp, Dept Med Oncol, Iraklion, Crete, Greece. [Souglakos, J.; Saridaki, Z.; Georgoulias, V.] Univ Crete, Lab Tumor Biol, Iraklion, Crete, Greece. [Philips, J.; Marwah, S.; Silver, J.; Ogino, S.; Hooshmand, S.; Freed, E.; Meyerhardt, J. A.; Fuchs, C. S.; Kulke, M. H.; Shivdasani, R. A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, R.; Silver, M.; Finkelstein, D.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Tzardi, M.] Univ Hosp, Dept Pathol, Pathol Lab, Iraklion, Crete, Greece. [Ogino, S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kwak, E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kwak, E.; Meyerhardt, J. A.; Fuchs, C. S.; Kulke, M. H.; Shivdasani, R. A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Souglakos, J (reprint author), Univ Hosp Heraklion Voutes & Stavrakia, Dept Med Oncol, POB 1352, Iraklion 71110, Crete, Greece. EM georgsec@med.uoc.gr; ramesh_shivdasani@dfci.harvard.edu FU Dana-Farber Cancer Institute-Novartis Drug Discovery Program; National Institutes of Health [P50CA127003]; Hellenic Society of Medical Oncology FX We thank Laura MacConnaill and Levi Garraway for assistance with tumour genotyping and Dr Robert Mayer for critical reading of the paper. The study was supported by the Dana-Farber Cancer Institute-Novartis Drug Discovery Program (RAS), SPORE grant P50CA127003 from the National Institutes of Health and a research fellowship from the Hellenic Society of Medical Oncology (JS). NR 26 TC 157 Z9 167 U1 0 U2 4 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 JUL PY 2009 VL 101 IS 3 BP 465 EP 472 DI 10.1038/sj.bjc.6605164 PG 8 WC Oncology SC Oncology GA 476KP UT WOS:000268439500014 PM 19603024 ER PT J AU Chen, C Reece, DE Siegel, D Niesvizky, R Boccia, RV Stadtmauer, EA Abonour, R Richardson, P Matous, J Kumar, S Bahlis, NJ Alsina, M Vescio, R Coutre, SE Pietronigro, D Knight, RD Zeldis, JB Rajkumar, V AF Chen, Christine Reece, Donna E. Siegel, David Niesvizky, Ruben Boccia, Ralph V. Stadtmauer, Edward A. Abonour, Rafat Richardson, Paul Matous, Jeffrey Kumar, Shaji Bahlis, Nizar J. Alsina, Melissa Vescio, Robert Coutre, Steven E. Pietronigro, Dennis Knight, Robert D. Zeldis, Jerome B. Rajkumar, Vincent TI Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma SO BRITISH JOURNAL OF HAEMATOLOGY 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 DE multiple myeloma; relapsed; refractory; lenalidomide plus dexamethasone; combination therapy ID NEWLY-DIAGNOSED MYELOMA; THROMBOTIC COMPLICATIONS; COMBINATION THERAPY; DRUG-RESISTANCE; THALIDOMIDE; PHASE-2; BORTEZOMIB; ASPIRIN; ANALOGS AB P>Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1-21) and dexamethasone 40 mg/d (days 1-4, 9-12, and 17-20 of cycles 1-4; days 1-4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, similar to 60% were male, median age was 64 years, and 61 center dot 7% had Durie-Salmon stage III disease. Median time on study was 15 center dot 4 weeks (range: 0 center dot 1-49 center dot 1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade >= 3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM. C1 [Rajkumar, Vincent] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Chen, Christine; Reece, Donna E.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Siegel, David] Hackensack Univ Med Ctr, Ctr Canc, Hackensack, NJ USA. [Niesvizky, Ruben] Weill Cornell Med Coll, New York, NY USA. [Boccia, Ralph V.] Ctr Canc & Blood Disorders, Bethesda, MD USA. [Stadtmauer, Edward A.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Abonour, Rafat] Indiana Univ, Simon Canc Ctr, Indianapolis, IN USA. [Richardson, Paul] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Matous, Jeffrey] Rocky Mt Canc Ctr, Denver, CO USA. [Bahlis, Nizar J.] Univ Calgary, Calgary, AB, Canada. [Alsina, Melissa] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Vescio, Robert] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Vescio, Robert] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Coutre, Steven E.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Pietronigro, Dennis; Knight, Robert D.; Zeldis, Jerome B.] Celgene Corp, Summit, NJ USA. RP Rajkumar, V (reprint author), Mayo Clin, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM rajkumar.vincent@mayo.edu RI Kumar, Shaji/A-9853-2008; OI Kumar, Shaji/0000-0001-5392-9284; Rajkumar, S. Vincent/0000-0002-5862-1833 NR 24 TC 42 Z9 42 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 JUL PY 2009 VL 146 IS 2 BP 164 EP 170 DI 10.1111/j.1365-2141.2009.07728.x PG 7 WC Hematology SC Hematology GA 466JL UT WOS:000267657300005 PM 19545290 ER PT J AU Johri, AM Kovacs, KA Kafka, H AF Johri, Amer M. Kovacs, Katherine A. Kafka, Henryk TI An unusual case of infective endocarditis: Extension of a tricuspid valve vegetation into the left atrium through a patent foramen ovale SO CANADIAN JOURNAL OF CARDIOLOGY LA English DT Editorial Material DE Echocardiography; Infective endocarditis; Patent foramen ovale ID COMPLICATION AB Tricuspid valve endocarditis frequently occurs in the setting of intravenous drug use. A case of tricuspid valve endocarditis in a 37-year-old woman with a history of intravenous cocaine use is described. Transthoracic echocardiography showed extension of the tricuspid valve mass through a patent foramen ovale and into the left atrium. One week after intravenous antibiotic treatment, the mass no longer traversed the patent foramen ovale, and only two smaller tricuspid valve vegetations remained. The present case demonstrates the value of performing a complete and thorough transthoracic echocardiography to visualize and evaluate both the right- and left-sided consequences of infective endocarditis in intravenous drug users. It also serves its it useful reminder to physicians caring for such patients that right-sided endocarditis can have important left-sided complications. C1 [Johri, Amer M.; Kafka, Henryk] Queens Univ, Dept Med, Div Cardiol, Kingston, ON K7L 3N6, Canada. [Kovacs, Katherine A.] Queens Univ, Dept Med, Div Gen Internal Med, Kingston, ON K7L 3N6, Canada. RP Johri, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM amerjohri@gmail.com NR 4 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0828-282X J9 CAN J CARDIOL JI Can. J. Cardiol. PD JUL PY 2009 VL 25 IS 7 BP 429 EP 431 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 471LO UT WOS:000268059400008 PM 19584975 ER PT J AU Ebrahimi, F Shafaroodi, H Asadi, S Nezami, BG Ghasemi, M Rahimpour, S Hashemi, M Doostar, Y Dehpour, AR AF Ebrahimi, Farzad Shafaroodi, Hamed Asadi, Shahrzad Nezami, Behtash Ghazi Ghasemi, Mehdi Rahimpour, Sina Hashemi, Mehrdad Doostar, Yousef Dehpour, Ahmad Reza TI Sildenafil decreased cardiac cell apoptosis in diabetic mice: reduction of oxidative stress as a possible mechanism SO CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY LA English DT Article DE antioxidant; apoptosis; diabetes; heart; mice; reactive oxygen species; sildenafil ID CYTOCHROME-C RELEASE; MUSCLE-CELLS; CASPASE-3 ACTIVATION; SUPEROXIDE FORMATION; ENDOTHELIAL-CELLS; HEART-FAILURE; DEATH; RATS; CARDIOMYOPATHY; HYPERGLYCEMIA AB Oxidative stress plays a dominant role in the pathogenesis of cardiac cell apoptosis in diabetic patients. Sildenafil has been demonstrated to have antioxidant effects. In this study, the effects of sildenafil on diabetes-induced cardiac cell apoptosis and the antioxidant status of diabetic mouse hearts were investigated. Diabetic mice showed lower body weight gains and heart weights compared with control mice, and sildenafil treatment did not increase these parameters in diabetic mice. Although apoptotic rates, caspase-3 enzyme activity, and malondialdehyde levels were significantly higher in diabetic mouse hearts than in controls, they were reduced in diabetic mice after sildenafil treatment. At the end of the first week, we observed no significant differences in antioxidant enzyme activities (CAT, GSH-Px, and SOD) in diabetic and control groups, whereas at the end of the second week of sildenafil treatment, antioxidant enzyme activities were higher in the diabetic group. In conclusion, our study indicated that sildenafil was beneficial to hearts of diabetic mice by reducing cardiac cell apoptosis, partially because of its antioxidant effects in the heart. C1 [Ebrahimi, Farzad; Asadi, Shahrzad; Nezami, Behtash Ghazi; Ghasemi, Mehdi; Rahimpour, Sina; Dehpour, Ahmad Reza] Univ Tehran Med Sci, Sch Med, Dept Pharmacol, Tehran, Iran. [Ebrahimi, Farzad] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Shafaroodi, Hamed] Islamic Azad Univ, Tehran Med Branch, Dept Pharmacol, Tehran, Iran. [Hashemi, Mehrdad] Islamic Azad Univ, Tehran Med Branch, Dept Genet, Tehran, Iran. [Doostar, Yousef] Islamic Azad Univ, Tabriz Branch, Dept Pathol, Tehran, Iran. RP Dehpour, AR (reprint author), Univ Tehran Med Sci, Sch Med, Dept Pharmacol, POB 13145-784, Tehran, Iran. EM dehpour@yahoo.com OI dehpour, ahmad reza/0000-0002-8001-5565 NR 57 TC 17 Z9 17 U1 0 U2 3 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 0008-4212 J9 CAN J PHYSIOL PHARM JI Can. J. Physiol. Pharmacol. PD JUL PY 2009 VL 87 IS 7 BP 556 EP 564 DI 10.1139/Y09-036 PG 9 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA 486SH UT WOS:000269217500007 PM 19767879 ER PT J AU Kufe, DW AF Kufe, Donald W. TI Functional targeting of the MUC1 oncogene in human cancers SO CANCER BIOLOGY & THERAPY LA English DT Review DE mucin; MUC1; transformation; dominant-negative mutants; gene signatures; prognosis; druggable target ID CARCINOMA-ASSOCIATED ANTIGEN; GROWTH-FACTOR RECEPTOR; BETA-CATENIN; BREAST-CARCINOMA; MONOCLONAL-ANTIBODY; C-SRC; APOPTOTIC RESPONSE; GENE-TRANSCRIPTION; CYTOPLASMIC TAIL; EPISIALIN MUC1 C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kufe, DW (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Donald_Kufe@dfci.harvard.edu FU National Cancer Institute [CA97098, CA42802, CA100707] FX This work was supported by Grants CA97098, CA42802 and CA100707 awarded by the National Cancer Institute. Dr. Kufe has an ownership interest in Genus Oncology and is a consultant to the company. NR 64 TC 41 Z9 45 U1 0 U2 8 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL 1 PY 2009 VL 8 IS 13 BP 1197 EP 1203 DI 10.4161/cbt.8.13.8844 PG 7 WC Oncology SC Oncology GA 486TC UT WOS:000269220000003 PM 19556858 ER PT J AU Yang, C Hornicek, FJ Wood, KB Schwab, JH Mankin, H Duan, ZF AF Yang, Cao Hornicek, Francis J. Wood, Kirkham B. Schwab, Joseph H. Mankin, Henry Duan, Zhenfeng TI RAIDD expression is impaired in multidrug resistant osteosarcoma cell lines SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE RAIDD; Multidrug resistance; Osteosarcoma; Apoptosis ID DRUG-RESISTANCE; CANCER-CHEMOTHERAPY; OSTEOGENIC-SARCOMA; CRYSTAL-STRUCTURE; ADAPTER MOLECULE; APOPTOSIS; CASPASE-2; PROTEIN; PIDDOSOME; MECHANISM AB To identify the apoptosis genes involved in the multidrug resistant phenotype of osteosarcoma. Multidrug resistant human osteosarcoma cell line (U-2 OS MR) and a drug sensitive parental cell line (U-2 OS) were both treated with paclitaxel and analyzed by the gene array containing 96 apoptosis associated genes. The different expression of the special apoptosis associated genes were further analyzed by Western blot in the multidrug resistant osteosarcoma cell lines (U-2 OS MR, KH OS R2) and the drug sensitive parental cell lines (U-2 OS, KH OS). One of the disregulated gene, RAIDD, was transfected into the multidrug resistant osteosarcoma cells for functional studies. RAIDD showed signs of significant expression in the U-2 OS cells after being treated with paclitaxel (P < 0.01). However, the induction of RAIDD did not occur in U-2 OS MR cells (P = 0.2). Subsequent analysis by Western blot confirmed the deficiency of the expression of RAIDD protein in U-2 OS MR. On the contrary, the expression of RAIDD could be significantly induced by paclitaxel and doxorubicin in U-2 OS cells as both time and dosage were deciding factors. It also demonstrated the cleavage of PARP associated with RAIDD expression in U-2 OS cells, but not however in U-2 OS MR cells after being treated with paclitaxel or doxorubicin. Similar results were found in osteosarcoma multidrug resistant cell line KH OS R2 and the drug sensitive parental cell line KH OS. Furthermore, over-expression of RAIDD in multidrug resistant cell lines could possibly reverse drug resistant phenotypes. This study indicate that impaired expression of RAIDD in drug induced apoptosis may play a role in the multidrug resistance of osteosarcoma cells. C1 [Yang, Cao; Hornicek, Francis J.; Wood, Kirkham B.; Schwab, Joseph H.; Mankin, Henry; Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Yang, Cao; Hornicek, Francis J.; Schwab, Joseph H.; Mankin, Henry; Duan, Zhenfeng] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Yang, Cao] Huazhong Univ Sci & Technol, Dept Orthopaed Surg, Union Hosp, Tongji Med Coll, Wuhan 430022, Peoples R China. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. EM zduan@partners.org OI Duan, Zhenfeng/0000-0002-8543-083X FU Chinese Council of Scholarship; National Cancer Institute, NIH (Nanotechnology Platform Partnership) [R01-CA119617] FX Dr. C. Yang is supported through a grant from the Chinese Council of Scholarship. Dr. Z. Duan is supported, in part, through a grant from the National Cancer Institute, NIH ( Nanotechnology Platform Partnership), R01-CA119617. Support has also been provided by the Gaetagno and Wechsler funds. NR 28 TC 12 Z9 13 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2009 VL 64 IS 3 BP 607 EP 614 DI 10.1007/s00280-008-0912-6 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 458QP UT WOS:000267038900019 PM 19125251 ER PT J AU Passer, BJ Castelo-Branco, P Buhrman, JS Varghese, S Rabkin, SD Martuza, RL AF Passer, B. J. Castelo-Branco, P. Buhrman, J. S. Varghese, S. Rabkin, S. D. Martuza, R. L. TI Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells SO CANCER GENE THERAPY LA English DT Article DE prostate cancer; oncolytic HSV's; taxanes ID SPINDLE ASSEMBLY CHECKPOINT; PROTEIN-SYNTHESIS; REPLICATION; DRUGS; GENE; FLAVOPIRIDOL; COMBINATION; PACLITAXEL; APOPTOSIS; THERAPY AB Genetically engineered oncolytic herpes simplex virus-1 (HSV-1) vectors selectively replicate in tumor cells causing direct killing whereas sparing normal cells. One clinical limitation of using oncolytic HSV vectors is their attenuated growth. We hypothesized that the appropriately chosen chemotherapeutic agent combined with an oncolytic HSV could be an effective means to promote augmented prostate cancer cell killing both in vitro and in vivo. Here we have identified that G47 Delta synergizes with the microtubule-stabilizing taxane agents docetaxel and paclitaxel to enhance the in vitro killing of prostate cancer cells. In vivo efficacy studies show that when combined with docetaxel, G47 Delta could be reduced at least 10-fold. Immunoblot analysis revealed that docetaxel-induced accumulation of the phospho-specific mitotic markers op18/stathmin or histone-H3 was markedly reduced by G47 Delta, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47 Delta, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47 Delta may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo. Cancer Gene Therapy (2009) 16, 551-560; doi:10.1038/cgt.2009.10; published online 6 February 2009 C1 [Passer, B. J.] Massachusetts Gen Hosp, Dept Neurosurg, Brain Tumor Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Passer, BJ (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Brain Tumor Res Ctr, Simches Res Bldg CRPZN 3800,185 Cambridge St, Boston, MA 02114 USA. EM bpasser@partners.org RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 FU RLM [RO1 CA102139] FX This study was in part supported by a grant to RLM (RO1 CA102139). NR 31 TC 20 Z9 21 U1 0 U2 3 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 JUL PY 2009 VL 16 IS 7 BP 551 EP 560 DI 10.1038/cgt.2009.10 PG 10 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 458QQ UT WOS:000267039000002 PM 19197321 ER PT J AU Zhu, AX Duda, DG Sahani, DV Jain, RK AF Zhu, Andrew X. Duda, Dan G. Sahani, Dushyant V. Jain, Rakesh K. TI Development of Sunitinib in Hepatocellular Carcinoma: Rationale, Early Clinical Experience, and Correlative Studies SO CANCER JOURNAL LA English DT Article DE sunitinib; hepatocellular carcinoma; angiogenesis; multitargeted receptor tyrosine kinase inhibitor; clinical trials ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; FACTOR-RECEPTOR-ALPHA; IN-VIVO; MICROVESSEL DENSITY; ANTITUMOR-ACTIVITY; SU11248; CANCER; EXPRESSION; SORAFENIB AB The approval of a multitargeted receptor tyrosine kinase inhibitor, sorafenib, with activity against vascular endothelial growth factor receptor-2 and -3, Raf-1 and B-Raf, platelet-derived growth factor receptor-alpha and -beta, and other kinases, has ushered in the era of molecular targeted agents in advanced hepatocellular carcinoma (HCC). Sunitinib malate is an oral, multitargeted inhibitor of vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha and -beta, and other kinases implicated in tumor growth, angiogenesis, and metastasis. Sunitinib has been approved in metastatic renal cell carcinoma and gastrointestinal stromal tumor and is undergoing active clinical development in HCC. Early evidence of antitumor activity and a promising safety profile for this agent have emerged from single arm phase 11 trials in United States, European, and Asian patients with advanced HCC. Correlative studies of imaging and circulating biomarkers have provided insights into the potential mechanism of action of sunitinib. Additional phase II studies using either single agent or in combination with chemotherapeutic agents are ongoing, and a phase III trial comparing sunitinib and sorafenib in advanced HCC is actively accruing patients. Here, we review the current progress and future directions for the development of sunitinib in advanced HCC. C1 [Zhu, Andrew X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tucker Gosnell Ctr Gastrointestinal Canc,Canc Ctr, Boston, MA 02163 USA. RP Zhu, AX (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tucker Gosnell Ctr Gastrointestinal Canc,Canc Ctr, Boston, MA 02163 USA. EM azhu@partners.org FU NCI NIH HHS [P01 CA080124] NR 46 TC 21 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2009 VL 15 IS 4 BP 263 EP 268 PG 6 WC Oncology SC Oncology GA 482WN UT WOS:000268921000001 PM 19672141 ER PT J AU Flanz, J Smith, A AF Flanz, Jacob Smith, Alfred TI Technology for Proton Therapy SO CANCER JOURNAL LA English DT Review DE proton therapy; proton therapy technology; proton accelerators; proton treatment delivery techniques ID BEAMS AB The technology that is used for the production and delivery of therapeutic proton beams is reviewed. Increased interest in this treatment modality has inspired a new generation of technology development and research into methods that will make proton treatment facilities more widely available (less expensive) and more efficient. Proton beam therapy has been in use for more than 40 years; it remains a treatment modality of interest because it provides a highly conformal dose distribution to a wide variety of disease sites and the potential for improving clinical outcomes. Recent advances in beam scanning technology may represent the ultimate in external beam radiotherapy dose conformality and treatment delivery efficiency. We describe how this new technology can be integrated into a proton therapy facility. C1 [Flanz, Jacob] Massachusetts Gen Hosp, Dept Radiat Oncol, Francis F Burr Proton Therapy Ctr, Boston, MA 02114 USA. [Smith, Alfred] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Ctr Global Oncol, Houston, TX 77030 USA. RP Flanz, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Francis F Burr Proton Therapy Ctr, 30 Fruit St, Boston, MA 02114 USA. EM jflanz@partners.org NR 11 TC 5 Z9 5 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2009 VL 15 IS 4 BP 292 EP 297 PG 6 WC Oncology SC Oncology GA 482WN UT WOS:000268921000005 PM 19672145 ER PT J AU Efstathiou, JA Trofimov, AV Zietman, AL AF Efstathiou, Jason A. Trofimov, Alexei V. Zietman, Anthony L. TI Life, Liberty, and the Pursuit of Protons: An Evidence-Based Review of the Role of Particle Therapy in the Treatment of Prostate Cancer SO CANCER JOURNAL LA English DT Review DE Proton beam therapy; prostate cancer; dose escalation; toxicity; intensity modulated radiation therapy ID RANDOMIZED CONTROLLED-TRIAL; RADIATION-THERAPY; DOSE-ESCALATION; 2ND CANCERS; SKULL BASE; RADIOTHERAPY; BEAM; IRRADIATION; NEUTRON; TUMORS AB Proton beam therapy (PBT) has been in use for a number of decades, though interest in PBT for localized prostate cancer has grown substantially in recent years. Protons offer the theoretical potential of achieving dose escalation and decreasing toxicity by capitalizing on unique physical dose deposition characteristics to avoid normal tissue. Although it has proven effective in a number of malignancies including as a means for dose escalation in prostate cancer, there is little published clinical data to support its comparative superiority over alternative forms of conformal radiation for prostate cancer. This review article explores the current evidence and clinical experience supporting PBT for prostate cancer, the uncertainties and controversies associated with this innovative technology, its potential economic implications, and future promise. C1 [Efstathiou, Jason A.; Trofimov, Alexei V.; Zietman, Anthony L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. RP Efstathiou, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM jefstathiou@partners.org NR 53 TC 18 Z9 18 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2009 VL 15 IS 4 BP 312 EP 318 PG 7 WC Oncology SC Oncology GA 482WN UT WOS:000268921000008 PM 19672148 ER PT J AU Sorensen, AG Batchelor, TT Zhang, WT Chen, PJ Yeo, P Wang, MY Jennings, D Wen, PY Lahdenranta, J Ancukiewicz, M di Tomaso, E Duda, DG Jain, RK AF Sorensen, A. Gregory Batchelor, Tracy T. Zhang, Wei-Ting Chen, Poe-Jou Yeo, Priscilla Wang, Meiyun Jennings, Dominique Wen, Patrick Y. Lahdenranta, Johanna Ancukiewicz, Marek di Tomaso, Emmanuelle Duda, Dan G. Jain, Rakesh K. TI A "Vascular Normalization Index" as Potential Mechanistic Biomarker to Predict Survival after a Single Dose of Cediranib in Recurrent Glioblastoma Patients SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ANTIANGIOGENIC THERAPY; PROGNOSTIC-FACTORS; TUMOR VASCULATURE; KINASE INHIBITOR; GLIOMA; GRADE; ANGIOGENESIS; BEVACIZUMAB; METASTASES AB Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti-vascular endothelial growth factor (VEGF) therapy can "normalize" brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We use advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging-measured changes in vascular permeability/flow (i.e., K(trans)) and in microvessel volume, and the change of circulating collagen W levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in K(trans) microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P < 0.05). When we combined these three parameters into a "vascular normalization index," we found that it closely associated with overall survival (rho = 0.54; P = 0.004) and progression-free survival (rho = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials. [Cancer Res 2009;69(13):5296-300] C1 [Sorensen, A. Gregory; Zhang, Wei-Ting; Chen, Poe-Jou; Yeo, Priscilla; Wang, Meiyun; Jennings, Dominique] Massachusetts Gen Hosp, EL Steele Lab, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Lahdenranta, Johanna; Ancukiewicz, Marek; di Tomaso, Emmanuelle; Duda, Dan G.; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Sorensen, AG (reprint author), Massachusetts Gen Hosp, EL Steele Lab, AA Martinos Ctr Biomed Imaging, 100 Blossom St,Cox 734, Boston, MA 02114 USA. EM sorensen@nmr.mgh.harvard.edu; jain@steele.mgh.harvard.edu FU NIH [P01-CA80124, R01-CA115767, R21-CA117079, K24-CA125440, R01-CA129371, P41-RR014075, M01-RR-01066]; Federal Share/National Cancer Institute; Harvard Clinical and Translational Science Center; Montesi Family Research Fund; Damon Runyon Foundation FX We thank G. Gorospe, C. Koppel, T. Benner, M. Foley, O. Wu, and S. Roberge for outstanding technical assistance. NR 20 TC 194 Z9 200 U1 0 U2 13 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 JUL 1 PY 2009 VL 69 IS 13 BP 5296 EP 5300 DI 10.1158/0008-5472.CAN-09-0814 PG 5 WC Oncology SC Oncology GA 466VP UT WOS:000267691800005 PM 19549889 ER PT J AU Goel, HL Moro, L Murphy-Ullrich, JE Hsieh, CC Wu, CL Jiang, Z Languino, LR AF Goel, Hira Lal Moro, Loredana Murphy-Ullrich, Joanne E. Hsieh, Chung-Cheng Wu, Chin-Lee Jiang, Zhong Languino, Lucia R. TI beta(1) Integrin Cytoplasmic Variants Differentially Regulate Expression of the Antiangiogenic Extracellular Matrix Protein Thrombospondin 1 SO CANCER RESEARCH LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; ENDOTHELIAL GROWTH-FACTOR; CELL-PROLIFERATION; MONOCLONAL-ANTIBODIES; NEOPLASTIC PROSTATE; CANCER PROGRESSION; TUMOR ANGIOGENESIS; MESSENGER-RNA; C-JUN; ADHESION AB beta(1) integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to beta(1), we show here that, in vivo, beta(1) integrins are essential for prostate cancer growth. Among the five known beta(1) integrin cytoplasmic variants, two have been shown to differentially affect prostate cell functions. The beta(1A) variant promotes normal and cancer cell proliferation, whereas the beta(1C) variant, which is down-regulated in prostate cancer, inhibits tumor growth and appears to have a dominant effect On beta(1A). To investigate the mechanism by which beta(1C) inhibits the tumorigenic potential of beta(1A), we analyzed changes in gene expression in cells transfected with either beta(1C) or beta(1A). The results show that beta(1C) expression increases the levels of an extracellular matrix protein, thrombospondin 1 (TSP1), an angiogenesis inhibitor. TSPI protein levels are increased upon beta(1C) expression in prostate cancer cells as well as in beta(1)-null GD25 cells. We show that TSPI does not affect proliferation, apoptosis, or anchorage-independent growth of prostate cancer cells. In contrast, the newly synthesized TSPI, secreted by prostate cancer cells expressing beta(1C), prevents proliferation of endothelial cells. In conclusion, our novel findings indicate that expression of the beta(1C) integrin variant in prostate glands prevents cancer progression by up-regulation of TSP1 levels and inhibition of angiogenesis. [Cancer Res 2009;69(13):5374-82] C1 [Goel, Hira Lal; Moro, Loredana; Hsieh, Chung-Cheng; Languino, Lucia R.] Univ Massachusetts, Dept Canc Biol, Prostate Canc Discovery & Dev Program, Sch Med, Worcester, MA 01605 USA. [Jiang, Zhong] Univ Massachusetts, Dept Pathol, Sch Med, Worcester, MA 01605 USA. [Murphy-Ullrich, Joanne E.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Wu, Chin-Lee] Harvard Univ, Sch Med, Boston, MA USA. RP Languino, LR (reprint author), Univ Massachusetts, Dept Canc Biol, Prostate Canc Discovery & Dev Program, Sch Med, 364 Plantat St, Worcester, MA 01605 USA. EM lucia.languino@umassmed.edu OI Languino, Lucia/0000-0001-9011-7031 FU NIH [CA109874, CA89720, HIL79644, DK78038]; Department of Defense [PCRP DAMD PC040221]; American Cancer Society [93-033]; Diabetes Endocrinology Research Center [DK32520] FX NIH grants CA109874 and CA89720 and Department of Defense grant PCRP DAMD PC040221 (L.R. Languino), American Cancer Society institutional research grant 93-033 (H.L. Goel), and NIH grants HIL79644 and DK78038 (J.E. Murphy-Ullrich).; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.; We thank I-leather Ehlers for help during the preparation of this article and Drs. E. Sahai and G. Taraboletti for reagents. Core resources supported by the Diabetes Endocrinology Research Center (grant DK32520) were also used. NR 55 TC 8 Z9 8 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 JUL 1 PY 2009 VL 69 IS 13 BP 5374 EP 5382 DI 10.1158/0008-5472.CAN-09-0186 PG 9 WC Oncology SC Oncology GA 466VP UT WOS:000267691800015 PM 19549894 ER PT J AU Pomerantz, MM Beckwith, CA Regan, MM Wyman, SK Petrovics, G Chen, YM Hawksworth, DJ Schumacher, FR Mucci, L Penney, KL Stampfer, MJ Chan, JA Ardlie, KG Fritz, BR Parkin, RK Lin, DW Dyke, M Herman, P Lee, S Oh, WK Kantoff, PW Tewari, M McLeod, DG Srivastava, S Freedman, ML AF Pomerantz, Mark M. Beckwith, Christine A. Regan, Meredith M. Wyman, Stacia K. Petrovics, Gyorgy Chen, Yongmei Hawksworth, Dorota J. Schumacher, Fredrick R. Mucci, Lorelei Penney, Kathryn L. Stampfer, Meir J. Chan, Jennifer A. Ardlie, Kristin G. Fritz, Brian R. Parkin, Rachael K. Lin, Daniel W. Dyke, Michelle Herman, Paula Lee, Steve Oh, William K. Kantoff, Philip W. Tewari, Muneesh McLeod, David G. Srivastava, Shiv Freedman, Matthew L. TI Evaluation of the 8q24 Prostate Cancer Risk Locus and MYC Expression SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; CHROMOSOME 8Q24; C-MYC; BREAST-CANCER; RADICAL PROSTATECTOMY; SUSCEPTIBILITY LOCI; VARIANT; CELLS; GENE; OVEREXPRESSION AB Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus. [Cancer Res 2009;69(13):5568-74] C1 [Pomerantz, Mark M.; Beckwith, Christine A.; Dyke, Michelle; Herman, Paula; Lee, Steve; Oh, William K.; Kantoff, Philip W.; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Regan, Meredith M.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Mucci, Lorelei; Penney, Kathryn L.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wyman, Stacia K.; Fritz, Brian R.; Parkin, Rachael K.; Tewari, Muneesh] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA USA. [Lin, Daniel W.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA. [Schumacher, Fredrick R.; Mucci, Lorelei; Tewari, Muneesh] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. [Lin, Daniel W.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Lin, Daniel W.] Dept Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Petrovics, Gyorgy; Chen, Yongmei; Hawksworth, Dorota J.; McLeod, David G.; Srivastava, Shiv] Uniformed Serv Univ Hlth Sci, Dept Surg, Ctr Prostate Dis Res, Rockville, MD USA. [Stampfer, Meir J.; Chan, Jennifer A.] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada. [Stampfer, Meir J.; Chan, Jennifer A.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Stampfer, Meir J.; Chan, Jennifer A.] Univ Calgary, Dept Oncol, Calgary, AB, Canada. [Ardlie, Kristin G.] Broad Inst Harvard & MIT, Cambridge, MA USA. RP Freedman, ML (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Dana Bldg,Rm 710A,44 Binney St, Boston, MA 02115 USA. EM matthew_freedman@dfci.harvard.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 FU NIH [R01 CA129435]; Mayer Foundation; H. L. Snyder Medical Foundation; National Cancer Institute [5P50CA90381]; American Society of Clinical Oncology; Prostate Cancer Foundation; Fred Hutchinson Cancer Research Center New Development funds; Canary Foundation; Pacific Northwest Prostate Cancer Specialized Program of Research Excellence [P50 CA97186]; Chromosome Metabolism Training Grant [5 T32 CA09657-16] FX NIH R01 CA129435 (M.L. Freedman), the Mayer Foundation (M.L. Freedman), the H. L. Snyder Medical Foundation (M,L. Freedman), the Dana-Farber/Harvard Cancer Center Prostate Cancer Specialized Programs of Research Excellence (National Cancer Institute Grant no. 5P50CA90381), the American Society of Clinical Oncology (M.L. Freedman), the Prostate Cancer Foundation (M.M. Pomerantz), the Fred Hutchinson Cancer Research Center New Development funds, including support. from the Canary Foundation (M. Tewari), Pilot Grant from the Pacific Northwest Prostate Cancer Specialized Program of Research Excellence Grant P50 CA97186 (M.Tewari), and Chromosome Metabolism Training Grant 5 T32 CA09657-16 (S.K. Wyman). NR 36 TC 70 Z9 71 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 JUL 1 PY 2009 VL 69 IS 13 BP 5568 EP 5574 DI 10.1158/0008-5472.CAN-09-0387 PG 7 WC Oncology SC Oncology GA 466VP UT WOS:000267691800039 PM 19549893 ER PT J AU Di Vizio, D Kim, J Hager, MH Morello, M Yang, W Lafargue, CJ True, LD Rubin, MA Adam, RM Beroukhim, R Demichelis, F Freeman, MR AF Di Vizio, Dolores Kim, Jayoung Hager, Martin H. Morello, Matteo Yang, Wei Lafargue, Christopher J. True, Lawrence D. Rubin, Mark A. Adam, Rosalyn M. Beroukhim, Rameen Demichelis, Francesca Freeman, Michael R. TI Oncosome Formation in Prostate Cancer: Association with a Region of Frequent Chromosomal Deletion in Metastatic Disease SO CANCER RESEARCH LA English DT Article ID NUCLEAR RIBONUCLEOPROTEIN-K; PLASMA-MEMBRANE; SECRETED CAVEOLIN-1; CELL-MIGRATION; TUMOR-GROWTH; PROTEIN; INVASION; EXPRESSION; MODES; ACTIN AB Oncosomes have recently been described as membrane-derived microvesicles secreted by cancer cells, which transfer oncogenic signals and protein complexes across cell boundaries. Here, we show the rapid formation and secretion of oncosomes from DU145 and LNCaP human prostate cancer cells. Oncosome formation was stimulated by epidermal growth factor receptor activation and also by overexpression of membrane-targeted Akt1. Microvesicles shed from prostate cancer cells contained numerous signal transduction proteins and were capable of activating rapid phospho-tyrosine and Akt pathway signaling, and stimulating proliferation and migration, in recipient tumor cells. They also induced a stromal reaction in recipient normal cells. Knockdown of the actin nucleating protein Diaphanous Related Formin 3 (DRF3/Dia2) by RNA interference enhanced rates of oncosome formation, indicating that these structures resemble, and may be identical to, nonapoptotic membrane blebs, a feature of the amoeboid form of cell motility. Analysis of primary and metastatic human prostate tumors using 100K single nucleotide polymorphism arrays revealed a significantly higher frequency of deletion of the locus encoding DRF3 (DIAPH3) in metastatic tumors (P = 0.001) in comparison with organ-confined tumors. Fluorescence in situ hybridization confirmed increased chromosomal loss of DIAPH3 in metastatic tumors in a different cohort of patients (P = 0.006). These data suggest that microvesicles shed from prostate cancer cells can alter the tumor microenvironment in a manner that may promote disease progression. They also show that DRF3 is a physiologically relevant protein that seems to regulate this process. [Cancer Res 2009;69(13):5601-9] C1 [Freeman, Michael R.] Childrens Hosp, Enders Res Labs, Urol Dis Res Ctr, Boston, MA 02115 USA. [Di Vizio, Dolores; Kim, Jayoung; Hager, Martin H.; Morello, Matteo; Yang, Wei; Adam, Rosalyn M.; Freeman, Michael R.] Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. [Freeman, Michael R.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Cambridge, MA 02138 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol & Canc Biol, Boston, MA USA. [Beroukhim, Rameen] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Cambridge, MA 02138 USA. [True, Lawrence D.] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. [Lafargue, Christopher J.; Rubin, Mark A.; Demichelis, Francesca] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Demichelis, Francesca] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY USA. [Beroukhim, Rameen] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Freeman, MR (reprint author), Childrens Hosp, Enders Res Labs, Urol Dis Res Ctr, Rm 1161,300 Longwood Ave, Boston, MA 02115 USA. EM michael.freeman@childrens.harvard.edu RI Yang, Wei/C-3047-2008; OI Yang, Wei/0000-0003-2575-3570; Rubin, Mark/0000-0002-8321-9950; Demichelis, Francesca/0000-0002-8266-8631 FU National Institutes of Diabetes, Digestive and Kidney Diseases [R3747556]; National Cancer Institute (NCI) [P50 DK65298, R01 CA112303, DAMD17-03-2-0033, K99 CA131472]; DOD PCRP [W81MVH-07-1-0148, W81XWH-08-1-0139]; AUA Foundation/GlaxoSmithKline; Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence [CA97186, NCI P01CA085859, K08CA122833, R01CA116337-01A1] FX National Institutes of Diabetes, Digestive and Kidney Diseases R3747556. P50 DK65298, National Cancer Institute (NCI) R01 CA112303 and DAMD17-03-2-0033 (M.R. Freeman), NCI K99 CA131472 (D. Di Vizio), DOD PCRP W81MVH-07-1-0148 (M.H. Hager), W81XWH-08-1-0139 (W Yang), the AUA Foundation/GlaxoSmithKline (M.H. Hager), the Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence CA97186, NCI P01CA085859 (L. True), K08CA122833 (R. Beroukhim), and R01CA116337-01A1 (M.A. Rubin and F. Demichelis). J. Kim is a Fislibein/ICA Scholar and a New York Academy of Medicine Edwin Beer Scholar. NR 45 TC 115 Z9 115 U1 1 U2 7 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 JUL 1 PY 2009 VL 69 IS 13 BP 5601 EP 5609 DI 10.1158/0008-5472.CAN-08-3860 PG 9 WC Oncology SC Oncology GA 466VP UT WOS:000267691800043 PM 19549916 ER PT J AU Collins, AB Smith, RN Stone, JR AF Collins, A. Bernard Smith, R. Neal Stone, James R. TI Classification of amyloid deposits in diagnostic cardiac specimens by immunofluorescence SO CARDIOVASCULAR PATHOLOGY LA English DT Article DE Amyloid; Amyloidosis; AH Amyloid; AL Amyloid; AA Amyloid; Immunofluorescence; Misdiagnosis; Cardiac; Heart ID CHAIN-ASSOCIATED AMYLOIDOSIS; PRIMARY SYSTEMIC AMYLOIDOSIS; ATRIAL-NATRIURETIC-PEPTIDE; IMMUNOGLOBULIN HEAVY-CHAIN; STEM-CELL TRANSPLANTATION; EMBEDDED BIOPSY SPECIMENS; LAMBDA-LIGHT-CHAIN; IMMUNOHISTOCHEMICAL CLASSIFICATION; AL-AMYLOIDOSIS; ENDOMYOCARDIAL BIOPSY AB Background: At least 12 distinct forms of amyloidosis are known to involve the heart or great vessels. Patient treatment regimens require proper subtyping of amyloid deposits in small diagnostic cardiac specimens. A growing lack of confidence in immunohistochemical staining for subtyping amyloid has arisen primarily as a result of studies utilizing immunoperoxidase staining of formalin-fixed paraffin-embedded tissue. Immunofluorescence staining on fresh frozen tissue is generally considered superior to immunoperoxidase staining for subtyping amyloid; however, this technique has not previously been reported in a series of cardiac specimens. Methods: Amyloid deposits were subtyped in 17 cardiac specimens and 23 renal specimens using an immunofluorescence panel. Results: Amyloid deposits were successfully subtyped as AL, AH, or AA amyloid by immunofluorescence in 82% of cardiac specimens and 87% of renal specimens. In all cases, the amyloid classification was in good agreement with available clinical and laboratory assessments. A cross-study analysis of 163 cases of AL amyloidosis reveals probable systemic misdiagnosis of cardiac AL amyloidosis by the immunoperoxidase technique, but not by the immunofluorescence technique. Conclusions: Amyloid deposits can be reliably subtyped in small diagnostic cardiac specimens using immunofluorescence. The practical aspects of implementing an immunofluorescence C1 [Collins, A. Bernard; Smith, R. Neal; Stone, James R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stone, James R.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Stone, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM jrstone@partners.org FU Department of Pathology, Massachusetts General Hospital FX This work was supported by the Department of Pathology, Massachusetts General Hospital. NR 80 TC 20 Z9 20 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-8807 J9 CARDIOVASC PATHOL JI Cardiovasc. Pathol. PD JUL-AUG PY 2009 VL 18 IS 4 BP 205 EP 216 DI 10.1016/j.carpath.2008.05.004 PG 12 WC Cardiac & Cardiovascular Systems; Pathology SC Cardiovascular System & Cardiology; Pathology GA 474MK UT WOS:000268287900003 PM 18619857 ER PT J AU Garcia, JA Casserly, IP AF Garcia, Joel A. Casserly, Ivan P. TI Use of the Boomerang Catalyst (TM) Advantage Closure Device to Facilitate Complex Multistaged Percutaneous Revascularization Procedures for the Treatment of Critical Limb Ischemia SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE Boomerang catalyst system; peripheral arterial disease; critical limb ischemia; complex percutaneous revascularization ID TRANSLUMINAL ANGIOPLASTY; EXPERIENCE AB An increasing spectrum of complex peripheral arterial disease may be successfully treated using percutaneous revascularization techniques. A pair of challenging peripheral revascularization procedures in patients with critical limb ischemia is presented, where an array of interventional tools and techniques were required, and the off-label use of the Boomerang catalyst system closure device was important in managing a variety of complex arterial access issues and ultimately allowing procedural success. (C) 2009 Wiley-Liss, Inc. C1 [Garcia, Joel A.; Casserly, Ivan P.] Univ Colorado Denver, Aurora, CO 80045 USA. [Garcia, Joel A.] Denver Hlth Med Ctr, Denver, CO USA. [Casserly, Ivan P.] Denver VA Med Ctr, Denver, CO USA. RP Casserly, IP (reprint author), Univ Colorado Denver, Anschutz Med Campus,Leprino Off Bldg,12401 E 17th, Aurora, CO 80045 USA. EM ivan.casserly@ucdenver.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUL 1 PY 2009 VL 74 IS 1 BP 27 EP 36 DI 10.1002/ccd.21962 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 469VG UT WOS:000267928200007 PM 19530181 ER PT J AU Jaff, MR AF Jaff, Michael R. TI Chronically Anticoagulated Patients Who Need Surgery: Can Low-Molecular-Weight Heparins Really Be Used to "Bridge" Patients Instead of Intravenous Unfractionated Heparin? SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article; Proceedings Paper CT Meeting on Vascular Interventional Advances CY SEP 26-29, 2006 CL Las Vegas, NV DE anticoagulants; bridging therapy; venous thromboembolism ID MECHANICAL HEART-VALVE; ANTITHROMBOTIC THERAPY; CLINICAL-OUTCOMES; MANAGEMENT; INTERRUPTION; THROMBOSIS; EMBOLISM; WARFARIN; DISEASE AB Patients at high risk of arterial or venous thromboembolic events often receive chronic treatment with long-term oral anticoagulants such as warfarin. However, if these patients require an invasive procedure, they may require a temporary interruption of their warfarin therapy to minimize their bleeding risk during the procedure. As warfarin has a long half-life and an unpredictable pharmacokinetic profile, short-acting parenteral anticoagulants, such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH), may be of benefit in protecting the patient from thromboemboli while their warfarin dose is withheld. Such "bridging therapy" has traditionally been provided in-hospital with intravenous UFH; however, recent data have suggested that LMWH may be an effective alternative, with potential cost-savings due to the ability to provide bridging therapy in the outpatient setting. (C) 2009 Wiley-Liss, Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vasc Ctr, Boston, MA 02114 USA. RP Jaff, MR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vasc Ctr, 55 Fruit St,GB 832, Boston, MA 02114 USA. EM mjaff@partners.org NR 19 TC 3 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUL 1 PY 2009 VL 74 IS 1 SU S BP S17 EP S21 DI 10.1002/ccd.22000 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 469VI UT WOS:000267928400004 PM 19213061 ER PT J AU Benson, EK Zhao, B Sassoon, DA Lee, SW Aaronson, SA AF Benson, Erica K. Zhao, Bo Sassoon, David A. Lee, Sam W. Aaronson, Stuart A. TI Effects of p21 deletion in mouse models of premature aging SO CELL CYCLE LA English DT Article DE p21; premature aging; cellular senescence; tumorigenesis; Ku80; ATM; TERC ID ATM-DEFICIENT MICE; CELLULAR SENESCENCE; LIFE-SPAN; REPLICATIVE SENESCENCE; ATAXIA-TELANGIECTASIA; HUMAN-CELLS; TELOMERE DYSFUNCTION; HUMAN FIBROBLASTS; GENOME STABILITY; DNA-REPAIR AB An approach to investigate the role of cellular senescence in organismal aging has been to abrogate signaling pathways known to induce cellular senescence and to assess the effects in mouse models of premature aging. Recently, we reported the effect of loss of function of p21, a gene implicated in p53-induced cellular senescence, in the background of the Ku80(-/-) premature aging mouse (Zhao et al., EMBO Rep 2009). Here, we provide an overview of the effects of p21 deletion in different models of premature aging. C1 [Benson, Erica K.; Zhao, Bo; Aaronson, Stuart A.] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. [Sassoon, David A.] Univ Paris 06, INSERM, UMR S 787, Myol Grp, Paris, France. [Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA USA. [Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Aaronson, SA (reprint author), Mt Sinai Sch Med, Dept Oncol Sci, 1 Gustave L Levy Pl,POB 1130, New York, NY 10029 USA. EM stuart.aaronson@mssm.edu FU National Cancer Institute [PO1CA80058] FX This work was supported by grant number PO1CA80058 from the National Cancer Institute. NR 59 TC 3 Z9 3 U1 1 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 1 PY 2009 VL 8 IS 13 BP 2002 EP 2004 DI 10.4161/cc.8.13.8997 PG 3 WC Cell Biology SC Cell Biology GA 465RG UT WOS:000267603900015 PM 19535900 ER PT J AU Nihal, M Ahsan, H Siddiqui, IA Mukhtar, H Ahmad, N Wood, GS AF Nihal, Minakshi Ahsan, Haseeb Siddiqui, Imtiaz A. Mukhtar, Hasan Ahmad, Nihal Wood, Gary S. TI (-)-Epigallocatechin-3-gallate (EGCG) sensitizes melanoma cells to interferon induced growth inhibition in a mouse model of human melanoma SO CELL CYCLE LA English DT Article DE melanoma; chemoprevention; green tea; apoptosis; cell cycle; interferon ID FACTOR-KAPPA-B; GREEN TEA; MALIGNANT-MELANOMA; SIGNALING PATHWAYS; APOPTOSIS; CANCER; CHEMOPREVENTION; FAS; THERAPY; PROLIFERATION AB Melanoma incidence has increased over the last few decades and metastatic melanoma is one of the hardest malignancies to treat. Thus, novel approaches are needed for an effective management of melanoma. Interferon-alpha 2b (IFN), an immunomodulatory cytokine commonly used in melanoma treatment, has shown marginal efficacy and often results in discontinuation of therapy due to toxicity. We earlier demonstrated that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, caused cell cycle arrest and apoptosis of human melanoma cells via modulation in cki-cyclin-cdk machinery and Bcl-2 family proteins. This study was undertaken to determine if EGCG could enhance the anti-proliferative effects of IFN. In this study, we demonstrated that EGCG and/or IFN treatments to melanoma cells resulted in a marked (1) decrease in cell proliferation and colony formation ability, and (2) induction of apoptosis. Interestingly, the combination was found to be more effective than either of the agents alone. Further, the anti-proliferative effects of EGCG and/or IFN were accompanied with an increase in Fas protein levels and a decrease in nuclear factor NF kappa B/p65 in the nucleus as well as NF kappa B promoter activity. EGCG and/or IFN also resulted in an increase in Fas-L mediated apoptosis. Further, EGCG and/or IFN treatments resulted in a decrease in melanoma tumor growth and protein levels of proliferation marker PCNA, in athymic nude mice implanted with melanoma tumors. The combination of the two modalities demonstrated a better response than either of them alone. Our data suggest that EGCG could impart therapeutic advantage if used in conjunction with IFN. C1 [Wood, Gary S.] Univ Wisconsin, Sch Med, Dept Dermatol, Madison, WI 53706 USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Wood, GS (reprint author), Univ Wisconsin, Sch Med, Dept Dermatol, 1300 Univ Ave,Room B25, Madison, WI 53706 USA. EM gwood@dermatol-ogy.wisc.edu RI Ahsan, Haseeb/H-3085-2015 OI Ahsan, Haseeb/0000-0002-5313-5959 FU Department of Veterans Affairs; Dermatology Foundation; NIH [R21 CA116163] FX This work was supported by Merit Review funding from the Department of Veterans Affairs (to G. S. W.), a research grant from Dermatology Foundation (to M.N.) and R21 CA116163 grant from the NIH (to M.N.). We also thank Caleb Creswell for his help in this project. NR 31 TC 19 Z9 20 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 1 PY 2009 VL 8 IS 13 BP 2057 EP 2063 DI 10.4161/cc.8.13.8862 PG 7 WC Cell Biology SC Cell Biology GA 465RG UT WOS:000267603900023 PM 19502799 ER PT J AU Maynard, CJ Cappai, R Volitakis, I Laughton, KM Masters, CL Bush, AI Li, QX AF Maynard, Christa J. Cappai, Roberto Volitakis, Irene Laughton, Katrina M. Masters, Colin L. Bush, Ashley I. Li, Qiao-Xin TI Chronic Exposure to High Levels of Zinc or Copper has Little Effect on Brain Metal Homeostasis or A beta Accumulation in Transgenic APP-C100 Mice SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Alzheimer's disease; Amyloid-beta peptide; Copper; Zinc; APP-C100 ID AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; MOUSE MODEL; PLAQUE-FORMATION; IMMUNE-RESPONSE; EXCESS COPPER; UP-REGULATION; BINDING-SITE; DIETARY ZINC AB Aberrant metal homeostasis may enhance the formation of reactive oxygen species and A beta oligomerization and may therefore be a contributing factor in Alzheimer's disease. This study investigated the effect of chronic high intake of dietary Zn or Cu on brain metal levels and the accumulation and solubility of A beta in vivo, using a transgenic mouse model that over expresses the C-terminal containing A beta fragment of human amyloid precursor protein but does not develop amyloid deposits. Exposure to chronic high Zn or Cu in the drinking water resulted in only slight elevations of the respective metals in the brain. Total A beta levels were unchanged although soluble A beta levels were slightly decreased, without visible plaque formation, enhanced gliosis, antioxidant upregulation or neuronal loss. This study indicates that brain metal levels are only marginally altered by long term oral exposure to extremely high Cu or Zn levels, and that this does not induce A beta-amyloid formation in human A beta expressing, amyloid-free mice, although this is sufficient to modulate A beta solubility in vivo. C1 [Maynard, Christa J.; Cappai, Roberto; Laughton, Katrina M.; Masters, Colin L.; Bush, Ashley I.; Li, Qiao-Xin] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Maynard, Christa J.; Cappai, Roberto; Volitakis, Irene; Laughton, Katrina M.; Masters, Colin L.; Bush, Ashley I.; Li, Qiao-Xin] Mental Hlth Res Inst Victoria, Oxidat Disorders Lab, Parkville, Vic 3052, Australia. [Maynard, Christa J.; Cappai, Roberto; Volitakis, Irene; Laughton, Katrina M.; Masters, Colin L.; Bush, Ashley I.; Li, Qiao-Xin] Mental Hlth Res Inst Victoria, Alzheimers Dis Div, Parkville, Vic 3052, Australia. [Bush, Ashley I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lab Oxidat Biol,Genet & Aging Res Unit, Charlestown, MA 02129 USA. [Bush, Ashley I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. RP Li, QX (reprint author), Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. EM q.li@unimelb.edu.au RI Cappai, Roberto/B-3347-2010; Bush, Ashley/A-1186-2007; OI Cappai, Roberto/0000-0002-9505-8496; Bush, Ashley/0000-0001-8259-9069; Volitakis, Irene/0000-0003-0766-817X FU National Health and Medical Research Council of Australia FX We thank Ms. Tina Cardamone for assisting with immunohistochemistry. This work was supported in part by grants from the National Health and Medical Research Council of Australia. NR 52 TC 11 Z9 12 U1 2 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL PY 2009 VL 29 IS 5 BP 757 EP 767 DI 10.1007/s10571-009-9401-7 PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 458AQ UT WOS:000266983100016 PM 19381799 ER PT J AU Azim, E Shnider, SJ Cederquist, GY Sohur, US Macklis, JD AF Azim, Eiman Shnider, Sara J. Cederquist, Gustav Y. Sohur, U. Shivraj Macklis, Jeffrey D. TI Lmo4 and Clim1 Progressively Delineate Cortical Projection Neuron Subtypes during Development SO CEREBRAL CORTEX LA English DT Article DE callosal; corticospinal; cortical development; Lmo4; Clim1; Ldb2; subcerebral; subtype identity ID DEVELOPING CEREBRAL-CORTEX; LIM-HOMEODOMAIN ACTIVITY; ACTIVITY IN-VIVO; DEVELOPING NEOCORTEX; PYRAMIDAL NEURONS; HOMEOBOX GENES; MOTOR-NEURON; SPECIFICATION; CELL; DIFFERENTIATION AB Molecular controls over the development of the exceptional neuronal subtype diversity of the cerebral cortex are now beginning to be identified. The initial subtype fate decision early in the life of a neuron, and the malleability of this fate when the balance of key postmitotic signals is modified, reveals not only that a neuron is deterministically set on a general developmental path at its birth, but also that this program must he precisely executed during postmitotic differentiation. Here, we show that callosal projection neurons (CPN) and subcerebral projection neurons (subcerebral PN) in layer V of the neocortex share aspects of molecular identity after their birth that are progressively resolved during differentiation. The LIM-homeodomain-related genes Lmo4 and Clim1 are initially expressed by both CPN and subcerebral PN in layer V, and only during mid to late differentiation does expression of Lmo4 and Clim1 become largely segregated into distinct neuronal subtypes. This progressive postmitotic resolution of molecular identity reveals similarities and possibly shared evolutionary origin between layer V CPN and subcerebral PN, and provides insight into how and when these neuronal subtypes achieve their distinct identities during cortical development. C1 [Azim, Eiman; Shnider, Sara J.; Cederquist, Gustav Y.; Sohur, U. Shivraj; Macklis, Jeffrey D.] Harvard Univ, Sch Med, MGH HMS Ctr Nervous Syst Repair, Dept Neurosurg,Program Neurosci, Boston, MA 02114 USA. [Azim, Eiman; Shnider, Sara J.; Cederquist, Gustav Y.; Sohur, U. Shivraj; Macklis, Jeffrey D.] Harvard Univ, Sch Med, MGH HMS Ctr Nervous Syst Repair, Dept Neurol,Program Neurosci, Boston, MA 02114 USA. [Azim, Eiman; Shnider, Sara J.; Cederquist, Gustav Y.; Sohur, U. Shivraj; Macklis, Jeffrey D.] Massachusetts Gen Hosp, Nayef Al Rodhan Labs, Boston, MA 02114 USA. [Azim, Eiman; Shnider, Sara J.; Cederquist, Gustav Y.; Sohur, U. Shivraj; Macklis, Jeffrey D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Azim, Eiman; Shnider, Sara J.; Cederquist, Gustav Y.; Sohur, U. Shivraj; Macklis, Jeffrey D.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Shnider, Sara J.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Macklis, JD (reprint author), Harvard Univ, Sch Med, MGH HMS Ctr Nervous Syst Repair, Dept Neurosurg,Program Neurosci, Boston, MA 02114 USA. EM jeffrey_macklis@hms.harvard.edu OI Cederquist, Gustav/0000-0003-4749-6093; Azim, Eiman/0000-0002-1015-1772 FU National Institutes of Health [NS49553, NS45523, NS41590]; Harvard Stem Cell Institute; Spastic Paraplegia Foundation; Travis Roy Foundation; Massachusetts Spinal Cord Injury Research Fund; Jane and Lee Seidman Fund; Emily and Robert Pearlstein Fund for Nervous System Repair; National Institutes Of Health predoctoral NRSA [F31 NS060421]; NRSA [F31 NS063516] FX National Institutes of Health (NS49553 and NS45523; additional infrastructurc Supported by NS41590); Harvard Stem Cell Institute; Spastic Paraplegia Foundation; Travis Roy Foundation; Massachusetts Spinal Cord Injury Research Fund; Jane and Lee Seidman Fund for CNS Research; Emily and Robert Pearlstein Fund for Nervous System Repair to.J.D.M.; National Institutes Of Health predoctoral NRSA (F31 NS060421) parrially supported E.A.; National Institutes of Health predoctoral NRSA (F31 NS063516) partially supported SJ.S.; Harvard Stem Cell Institute Internship Program partially Supported G.C.; and Cerebral Palsy Research Fund and fellowship from the Lefler Center for the Study of Neurodegenerative Disorders partially Supported U.S.S. NR 42 TC 21 Z9 22 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUL PY 2009 VL 19 BP I62 EP I69 DI 10.1093/cercor/bhp030 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 473JO UT WOS:000268202500008 PM 19366868 ER PT J AU Zier, LS Burack, JH Micco, G Chipman, AK Frank, JA White, DB AF Zier, Lucas S. Burack, Jeffrey H. Micco, Guy Chipman, Anne K. Frank, James A. White, Douglas B. TI Surrogate Decision Makers' Responses to Physicians' Predictions of Medical Futility SO CHEST LA English DT Article ID CARE; LIFE; RISKS; TEXAS; END AB Background: Although physicians sometimes use the futility rationale to limit the use of life-sustaining treatments, little is known about how surrogate decision makers view this rationale. We sought to determine the attitudes of surrogates of patients who are critically ill toward whether physicians can predict futility and whether these attitudes predict surrogates' willingness to discontinue life support when faced with predictions of futility. Methods: This multicenter, mixed qualitative and quantitative study took place at three hospitals in California from 2006 to 2007. We conducted semistructured interviews with surrogate decision makers for 50 patients who were critically ill and incapacitated that addressed their beliefs about medical futility and inductively developed an organizing framework to describe these beliefs. We used a hypothetical scenario with a modified time-trade-off design to examine the relationship between a patient's prognosis and a surrogate's willingness to withdraw life support. We used a mixed-effects regression model to examine the association between surrogates' attitudes about futility and their willingness to limit life support in the face of a very poor prognosis. Validation methods included the use and integration of multiple data sources, multidisciplinary analysis, and member checking. Results: Sixty-four percent of surrogates (n = 32; 95% confidence interval [CI], 49 to 77%) expressed doubt about the accuracy of physicians' futility predictions, 32% of surrogates (n = 16; 95% CI, 20 to 47%) elected to continue life support with a < 1% survival estimate, and 18% of surrogates (n = 9; 95% CI, 9 to 31%) elected to continue treatment when the physician believed that the patient had no chance of survival. Surrogates with religious objections to the futility rationale (n = 18) were more likely to request continued life support (odds ratio, 4; 95% CI, 1.2 to 14.0; p = 0.03) than those with secular or experiential objections (n = 15; odds ratio, 0.95; 95% CI, 0.3 to 3.4; p = 0.90). Conclusions: Doubt about physicians' ability to predict medical futility is common among surrogate decision makers. The nature of the doubt may have implications for responding to conflicts about futility in clinical practice. (CHEST 2009,136.-110-117) C1 [White, Douglas B.] Univ Calif San Francisco, Program Med Eth, Dept Med, San Francisco, CA 94143 USA. [Frank, James A.; White, Douglas B.] Univ Calif San Francisco, Div Pulm & Crit Care Med, Sch Med, San Francisco, CA 94143 USA. [Zier, Lucas S.; Burack, Jeffrey H.; Micco, Guy; Chipman, Anne K.] Univ Calif Berkeley, San Francisco Joint Med Program, Berkeley, CA 94720 USA. [Burack, Jeffrey H.; Micco, Guy] Univ Calif Berkeley, Sch Publ Hlth, Div Community Hlth & Human Dev, Berkeley, CA 94720 USA. [Burack, Jeffrey H.] Alta Bates Summit Med Ctr, E Bay AIDS Res Inst, Oakland, CA USA. [Frank, James A.] San Francisco VA Med Ctr, San Francisco, CA USA. RP White, DB (reprint author), Univ Calif San Francisco, Program Med Eth, Dept Med, 521 Parnassus Ave,Suite C-126,Box 0903, San Francisco, CA 94143 USA. EM dwhite@medicine.ucsf.edu FU University of California; Berkeley-Universitv of California, San Francisco; National Center for Research Resources [KL2 RR0241301]; National Institutes of Health; Greenwall Foundation FX This project was supported by it grant from the University of California, Berkeley-Universitv of California, San Francisco joint Medical Program (Mr. Zier grant from the University of California, San Francisco Dealt s Office Medical St-tident Besearch Program (1kir. Zier), and a grant front the National Center for Research Resources [KL2 RR0241301, a component of the National Institute of Health and the National Institutes of Health Roadmap for Medical Research (Dr. White). Dr. White is also supported by it grant from the Greenwall Foundation Facility Scholars Program. NR 25 TC 32 Z9 32 U1 1 U2 6 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2009 VL 136 IS 1 BP 110 EP 117 DI 10.1378/chest.08-2753 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 467YG UT WOS:000267779000017 PM 19318665 ER PT J AU Fihn, SD AF Fihn, Stephan D. TI Improving Quality Lessons From the Department of Veterans Affairs SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Editorial Material DE Editorials; hypertension ID HEALTH-CARE-SYSTEM; TRANSFORMATION C1 [Fihn, Stephan D.] VA Puget Sound Hlth Care Syst, NW Hlth Serv, Res & Dev Ctr Excellence, Seattle, WA 98101 USA. [Fihn, Stephan D.] Univ Washington, Dept Med & Hlth Serv, Div Gen Internal Med, Seattle, WA 98195 USA. RP Fihn, SD (reprint author), VA Puget Sound Hlth Care Syst, NW Hlth Serv, Res & Dev Ctr Excellence, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM stephan.fihn@va.gov NR 13 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2009 VL 2 IS 4 BP 294 EP 296 DI 10.1161/CIRCOUTCOMES.109.884353 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 575NP UT WOS:000276074200003 PM 20031853 ER PT J AU Singer, DE Chang, YC Fang, MC Borowsky, LH Pomernacki, NK Udaltsova, N Go, AS AF Singer, Daniel E. Chang, Yuchiao Fang, Margaret C. Borowsky, Leila H. Pomernacki, Niela K. Udaltsova, Natalia Go, Alan S. TI Should Patient Characteristics Influence Target Anticoagulation Intensity for Stroke Prevention in Nonvalvular Atrial Fibrillation? The ATRIA Study SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE atrial fibrillation; anticoagulation; prevention and control; stroke ID CLINICAL CLASSIFICATION SCHEMES; RANDOMIZED CONTROLLED-TRIAL; ORAL ANTICOAGULANT; RISK-FACTORS; ANTITHROMBOTIC THERAPY; BLEEDING COMPLICATIONS; INTRACRANIAL HEMORRHAGE; CEREBRAL-ISCHEMIA; NATIONAL REGISTRY; PLUS ASPIRIN AB Background-Randomized trials and observational studies support using an international normalized ratio (INR) target of 2.0 to 3.0 for preventing ischemic stroke in atrial fibrillation. We assessed whether the INR target should be adjusted based on selected patient characteristics. Methods and Results-We conducted a case-control study nested within the ATRIA cohort's 9217 atrial fibrillation patients taking warfarin to define the relationship between INR level and the odds of thromboembolism (TE; mainly stroke) and of intracranial hemorrhage (ICH) relative to INR 2.0 to 2.5. We identified 396 TE cases and 164 ICH cases during follow-up. Each case was compared with 4 randomly selected controls matched on calendar date and stroke risk factors using matched univariable analyses and conditional logistic regression. We explored modification of the INR-outcome relationships by the following stroke risk factors: prior stroke, age, and CHADS(2) risk score. Overall, the odds of TE were low and stable above INR 1.8. Compared with INR 2.0 to 2.5, the relative odds of TE increased strikingly at INR <1.8 (eg, odds ratio, 3.72; 95% CI, 2.67 to 5.19, at INR 1.4 to 1.7). The odds of ICH increased markedly at INR values >3.5 (eg, odds ratio, 3.56; 95% CI: 1.70 to 7.46, at INR 3.6 to 4.5). The relative odds of ICH were consistently low at INR <3.6. There was no evidence of lower ICH risk at INR levels <2.0. These patterns of risk did not differ substantially by history of stroke, age, or CHADS2 risk score. Conclusions-Our results confirm that the current standard of INR 2.0 to 3.0 for atrial fibrillation falls in the optimal INR range. Our findings do not support adjustment of INR targets according to previously defined stroke risk factors. (Circ Cardiovasc Qual Outcomes. 2009;2:297-304.) C1 [Singer, Daniel E.; Chang, Yuchiao; Borowsky, Leila H.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Div Gen Med, Boston, MA 02114 USA. [Fang, Margaret C.; Go, Alan S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Pomernacki, Niela K.; Udaltsova, Natalia; Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. RP Singer, DE (reprint author), Massachusetts Gen Hosp, Clin Epidemiol Unit, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM dsinger@partners.org FU National Institute on Aging [R01 AG15478, K23 AG28978]; National Heart, Lung, and Blood Institute [U19 HL91179]; Massachusetts General Hospital; Johnson Johnson FX Funding for the study was provided by the National Institute on Aging (R01 AG15478 and K23 AG28978), the National Heart, Lung, and Blood Institute (U19 HL91179), and the Eliot B. and Edith C. Shoolman fund of Massachusetts General Hospital. The funding sources had no role in study design, data collection, data analysis, data interpretation, or writing of this manuscript.; Dr Singer has consulted for Medtronic, Bayer Healthcare, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Bristol-Myers Squibb, Pfizer, and Sanofi Aventis and has received research support from Daiichi Sankyo. Dr Go has received research support from Johnson & Johnson. Drs Chang, Fang, and Udaltsova and Ms Borowsky and Ms Pomernacki declare no conflicts of interest. NR 42 TC 57 Z9 58 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2009 VL 2 IS 4 BP 297 EP U30 DI 10.1161/CIRCOUTCOMES.108.830232 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 575NP UT WOS:000276074200004 PM 20031854 ER PT J AU Mancini, GBJ Bates, ER Maron, DJ Hartigan, P Dada, M Gosselin, G Kostuk, W Sedlis, SP Shaw, LJ Berman, DS Berger, PB Spertus, J Mavromatis, K Knudtson, M Chaitman, BR O'Rourke, RA Weintraub, WS Teo, K Boden, WE AF Mancini, G. B. John Bates, Eric R. Maron, David J. Hartigan, Pamela Dada, Marcin Gosselin, Gilbert Kostuk, William Sedlis, Steven P. Shaw, Leslee J. Berman, Daniel S. Berger, Peter B. Spertus, John Mavromatis, Kreton Knudtson, Merril Chaitman, Bernard R. O'Rourke, Robert A. Weintraub, William S. Teo, Koon Boden, William E. CA COURAGE Trial Investigators Coordi TI Quantitative Results of Baseline Angiography and Percutaneous Coronary Intervention in the COURAGE Trial SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE coronary angiography; ventricular ejection fraction; gender identity; delivery of health care; revascularization; stent ID CONTROLLED CLINICAL-TRIAL; 3 THERAPEUTIC STRATEGIES; ARTERY-DISEASE; MASS-II; SURGERY; ANGIOPLASTY; MEDICINE; ANGINA; VIVO AB Background-COURAGE compared outcomes in stable coronary patients randomized to optimal medical therapy plus percutaneous coronary intervention (PCI) versus optimal medical therapy alone. Methods and Results-Angiographic data were analyzed by treatment arm, health care system (Veterans Administration, US non-Veterans Administration, Canada), and gender. Veterans Administration patients had higher prevalence of coronary artery bypass graft surgery and left ventricular ejection fraction <= 50%. Men had worse diameter stenosis of the most severe lesion, higher prevalence of prior coronary artery bypass graft surgery, lower left ventricular ejection fraction, and more 3-vessel disease that included a proximal left anterior descending lesion (P<0.0001 for all comparisons versus women). Failure to cross rate (3%) and visual angiographic success of stent procedures (97%) were similar to contemporary practice in the National Cardiovascular Data Registry. Quantitative angiographic PCI success was 93% (residual lesion <50% in-segment) and 82% (<20% in-stent), with only minor nonsignificant differences among health care systems and genders. Event rates were higher in patients with higher jeopardy scores and more severe vessel disease, but rates were similar irrespective of treatment strategy. Within the PCI plus optimal medical therapy arm, complete revascularization was associated with a trend toward lower rate of death or nonfatal myocardial infarction. Complete revascularization was similar between genders and among health care systems. Conclusions-PCI success and completeness of revascularization did not differ significantly by health care system or gender and were similar to contemporary practice. Angiographic burden of disease affected overall event rates but not response to an initial strategy of PCI plus optimal medical therapy or optimal medical therapy alone. (Circ Cardiovasc Qual Outcomes. 2009;2:320-327.) C1 [Mancini, G. B. John] Univ British Columbia, Vancouver Hosp, Cardiovasc Imaging Res Core Lab, Vancouver, BC V5Z 1M9, Canada. [Bates, Eric R.] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Maron, David J.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Hartigan, Pamela] Connecticut VA Healthcare Syst, Vet Affairs Cooperat Studies Program Coordinating, West Haven, CT USA. [Dada, Marcin] Hartford Hosp, Hartford, CT 06115 USA. [Gosselin, Gilbert] Univ Montreal, Montreal Heart Inst, Montreal, PQ H3C 3J7, Canada. [Kostuk, William] Univ Western Ontario, London Hlth Sci Ctr, London, ON, Canada. [Sedlis, Steven P.] NYU, Sch Med, VA New York Harbor Hlth Care Syst New York Campus, New York, NY 10003 USA. [Shaw, Leslee J.; Mavromatis, Kreton] Emory Univ, Sch Med, Atlanta, GA USA. [Berman, Daniel S.] Univ Calif Los Angeles, Cedars Sinai Heart Inst, Los Angeles, CA USA. [Berger, Peter B.] Geisinger Med Ctr, Danville, PA 17822 USA. [Spertus, John] Univ Missouri, Mid Amer Heart Inst, Kansas City, MO 64110 USA. [Knudtson, Merril] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Chaitman, Bernard R.] St Louis Univ Hosp, St Louis, MO USA. [O'Rourke, Robert A.] S Texas Vet Healthcare Syst, San Antonio, TX USA. [O'Rourke, Robert A.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Weintraub, William S.] Christiana Care Hlth Syst, Newark, DE USA. [Teo, Koon] McMaster Univ, Med Ctr, Hamilton, ON, Canada. [Boden, William E.] SUNY, Sch Med & Biomed Sci, Buffalo Gen Hosp, Kaleida Hlth, New York, NY USA. RP Mancini, GBJ (reprint author), Univ British Columbia, Vancouver Hosp, Cardiovasc Imaging Res Core Lab, 10209-2775 Laurel St, Vancouver, BC V5Z 1M9, Canada. EM mancini@interchange.ubc.ca OI Sedlis, Steven/0000-0002-8194-8017 FU Merck Co; Pfizer Pharmaceuticals; Bristol-Myers-Squibb Medical Imaging; Fujisawa; Kos Pharmaceuticals; Data Scope; AstraZeneca; Key Pharmaceutical Co Ltd; Sanofi Aventis Inc; First Horizon; Nycomed Amersham; Department of Veterans Administration; Astellas Healthcare; Medtronic; GE; Siemens; Molecular Insight Pharma; Sicor; CIHR; Canadian Cardiovascular Society; Merck FX This work was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, in collaboration with the Canadian Institute of Health Research; unrestricted research grants have been obtained from Merck & Co, Pfizer Pharmaceuticals, Bristol-Myers-Squibb Medical Imaging, Fujisawa, Kos Pharmaceuticals, Data Scope, AstraZeneca, Key Pharmaceutical Co Ltd, Sanofi Aventis Inc, First Horizon, and Nycomed Amersham. All industrial funding in support of the trial has been directed through the Department of Veterans Administration.; Dr Mancini has received honoraria from GlaxoSmthKline, Merck, Pfizer, and sanofi-aventis. Dr Berman has received research grants and honoraria from Astellas Healthcare, Medtronic, GE, Siemens, and Molecular Insight Pharma; has ownership interest in Spectrum Dynamics; serves as a consultant for Astellas, Fluoro Pharma, and Magellan; and has received software royalties from CSMC. Dr Berger has ownership interest in Lumen and has served on the consultancy/ad board for PlaCor, Accumetrics, The Medicines Company, and Eli Lilly/Daiichi-Sankyo. Dr Spertus has received research grants from Sicor; other research Support from Roche Diagnostics; has ownership interest in SAQ, KCCQ, and PTQ; and has served as a consultant for United Healthcare. Dr Knudtson has received research grants from CIHR; honoraria from the Canadian Cardiovascular Society; and has served as an expert witness for a defendant in medical civil action suit. Dr Chaitman has received research grants from Merck; served on the speakers' bureau for CV Therapeutics; and serves on the consultancy/ad boards for Sanofi Aventis and Merck. Dr O'Rourke has received research grants from BARI-2D and has served as a consultant for the PACE-MI Study. Dr Weintraub has received research grants from Sanofi Aventis, AstraZeneca, Otsuka, and Bristol Myers Squibb; served as an expert witness for Pfizer nad AstraZeneca; and served as a consultant for GlaxoSmithKline, Indigo Pharmaceuticals, Sanofi Aventis, and CV Therapeutics. Dr Teo has received research grants from CIHR; other research support from Boehringer-Ingelheim; honoraria from Boehringer-Ingelheim; and has served as a consultant for Boehringer-Ingelheim. NR 19 TC 18 Z9 18 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2009 VL 2 IS 4 BP 320 EP U97 DI 10.1161/CIRCOUTCOMES.108.830091 PG 48 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 575NP UT WOS:000276074200007 PM 20031857 ER PT J AU Arnold, SV Morrow, DA Lei, Y Cohen, DJ Mahoney, EM Braunwald, E Chan, PS AF Arnold, Suzanne V. Morrow, David A. Lei, Yang Cohen, David J. Mahoney, Elizabeth M. Braunwald, Eugene Chan, Paul S. TI Economic Impact of Angina After an Acute Coronary Syndrome Insights From the MERLIN-TIMI 36 Trial SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE angina; cost and cost analysis; health status ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; TRANSMYOCARDIAL LASER REVASCULARIZATION; MYOCARDIAL-INFARCTION; ARTERY-DISEASE; HEALTH-STATUS; CLINICAL-OUTCOMES; REFRACTORY ANGINA; INTERVENTION; RANOLAZINE AB Background-Angina in patients with coronary artery disease is associated with worse quality of life; however, the relationship between angina frequency and resource utilization is unknown. Methods and Results-Using data from the MERLIN-TIMI 36 trial, we assessed the association between the extent of angina after an acute coronary syndrome (ACS) and subsequent cardiovascular resource utilization among 5460 stable outpatients who completed the Seattle Angina Questionnaire at 4 months after an ACS and who were then followed for an additional 8 months. Angina frequency was categorized as none (score, 100; 2739 patients), monthly (score, 61 to 99; 1608 patients), weekly (score, 31 to 60; 854 patients), and daily (score, 0 to 30; 259 patients). Multivariable regression models evaluated the association between angina frequency and overall costs attributable to cardiovascular hospitalizations, outpatient visits and procedures, and medications. As compared with no angina, overall costs increased in a graded fashion with higher angina frequency-no angina, $2928 (reference); monthly angina, $3909 (adjusted relative cost ratio, 1.29; 95% CI, 1.21 to 1.39); weekly angina, $4558 (adjusted relative cost ratio, 1.52; 95% CI, 1.48 to 1.67); and daily angina, $6949 (adjusted relative cost ratio, 2.32; 95% CI, 2.01 to 2.69; P for trend <0.001). Differences in costs were attributable primarily to higher rates of ACS hospitalization and coronary revascularization among patients with more severe angina. Conclusion-Among stable outpatients after ACS, a direct graded relationship was found between higher angina frequency and healthcare costs. As compared with patients without angina, patients with daily angina had a >2-fold increase in resource utilization and incremental costs of $4000 after 8 months of follow-up. (Circ Cardiovasc Qual Outcomes. 2009;2:344-353.) C1 [Arnold, Suzanne V.; Lei, Yang; Cohen, David J.; Mahoney, Elizabeth M.; Chan, Paul S.] St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Morrow, David A.; Braunwald, Eugene] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Chan, PS (reprint author), St Lukes Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA. EM pchan@cc-pc.com FU CV Therapeutics FX The MERLIN-TIMI 36 Trial was funded by a grant from CV Therapeutics. NR 36 TC 46 Z9 46 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2009 VL 2 IS 4 BP 344 EP U130 DI 10.1161/CIRCOUTCOMES.108.829523 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 575NP UT WOS:000276074200010 PM 20031860 ER PT J AU Rose, AJ Berlowitz, DR Manze, M Orner, MB Kressin, NR AF Rose, Adam J. Berlowitz, Dan R. Manze, Meredith Orner, Michelle B. Kressin, Nancy R. TI Comparing Methods of Measuring Treatment Intensification in Hypertension Care SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE hypertension; chronic disease; research; quality of health care; ambulatory care ID BLOOD-PRESSURE CONTROL; CLINICAL INERTIA; MEDICATION ADHERENCE; DIABETES CARE; HEALTH-CARE; MANAGEMENT; QUALITY; THERAPY; COHORT AB Background-Greater treatment intensification (TI) improves hypertension control. However, we do not know the ideal way to measure TI for research and quality improvement efforts. We compared the ability of different TI measures to predict blood pressure (BP) control. Methods and Results-We enrolled 819 hypertensive outpatients from an urban academic hospital. Each patient was assigned 3 scores to characterize TI. The any/none score divides patients into those who had any therapy increases during the study versus none. The norm-based method models the chance of a medication increase at each visit, then scores each patient based on whether they received more or fewer medication increases than predicted. The standard-based method is similar to the norm-based method but expects a medication increase whenever the blood pressure is uncontrolled. We compared the ability of these scores to predict the final systolic blood pressure (SBP). The any/none score showed a paradoxical result: any therapy increase was associated with SBP 4.6 mm Hg higher than no increase (P < 0.001). The norm-based method score did not predict SBP in a linear fashion (P = 0.18); further investigation revealed a U-shaped relationship between the norm-based method score and SBP. However, the standard-based method score was a strong linear predictor of SBP (2.1 mm Hg lower for each additional therapy increase per 10 visits, P < 0.001). Similarly, the standard-based method predicted dichotomized blood pressure control, as measured by SBP <140 mm Hg (odds ratio, 1.30; P < 0.001). Conclusions-Our results suggest that standard-based method is the preferred measure of treatment intensity for hypertension care. (Circ Cardiovasc Qual Outcomes. 2009;2:385-391.) C1 [Rose, Adam J.; Berlowitz, Dan R.; Orner, Michelle B.; Kressin, Nancy R.] Bedford VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA 01730 USA. [Rose, Adam J.; Berlowitz, Dan R.; Manze, Meredith; Kressin, Nancy R.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Berlowitz, Dan R.; Manze, Meredith] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Kressin, Nancy R.] VA Boston Healthcare Syst, Boston, MA USA. RP Rose, AJ (reprint author), Bedford VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, 200 Springs Rd,Bldg 70, Bedford, MA 01730 USA. EM adamrose@bu.edu OI Kressin, Nancy/0000-0003-2767-4286 FU National Institutes of Health [HL072814]; Department of Veterans Affairs, Health Services Research and Development Service [RCS 02-066-1] FX This research was supported by a grant from the National Institutes of Health (HL072814, N. R. Kressin, Principal Investigator). Dr Rose is supported by a career development award from the Department of Veterans Affairs, Health Services Research and Development Service. Dr Kressin is supported by a Research Career Scientist award from the Department of Veterans Affairs, Health Services Research and Development Service (RCS 02-066-1). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 26 TC 13 Z9 13 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2009 VL 2 IS 4 BP 385 EP U178 DI 10.1161/CIRCOUTCOMES.108.838649 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 575NP UT WOS:000276074200015 PM 20031865 ER PT J AU Shah, RV Chen-Tournoux, AA Picard, MH van Kimmenade, RRJ Januzzi, JL AF Shah, Ravi V. Chen-Tournoux, Annabel A. Picard, Michael H. van Kimmenade, Roland R. J. Januzzi, James L. TI Serum Levels of the Interleukin-1 Receptor Family Member ST2, Cardiac Structure and Function, and Long-Term Mortality in Patients With Acute Dyspnea SO CIRCULATION-HEART FAILURE LA English DT Article DE echocardiography; heart failure; biomarker; prognosis ID DECOMPENSATED HEART-FAILURE; EMERGENCY-DEPARTMENT PRIDE; NATRIURETIC PEPTIDE LEVELS; MYOCARDIAL-INFARCTION; ADMISSION; BIOMARKER; OUTCOMES; SYSTEM AB Background-ST2, a biomarker of cardiomyocyte stretch, powerfully predicts poor outcomes in patients with acute dyspnea, but nothing is known about associations between soluble ST2 (sST2) and cardiac structure and function, or whether sST2 retains prognostic meaning in the context of such measures. Methods and Results-One hundred thirty-four dyspneic patients with and without decompensated heart failure had echocardiography during index admission and vital status was ascertained at 4 years. Echocardiographic and clinical correlates of sST2 as well as independent predictors of death at 4 years were identified. sST2 correlated with left ventricular end-systolic dimensions/volumes and left ventricular ejection fraction. sST2 was inversely associated with right ventricular fractional area change (rho=-0.18; P=0.046), higher right ventricular systolic pressure (rho=0.26; P=0.005), and right ventricular hypokinesis (P<0.001) and was correlated with tissue Doppler Ea wave peak velocity, but not to other indices of diastolic function. In multivariate regression, independent predictors of sST2 included right ventricular systolic pressure (t=2.29; P=0.002), left ventricular ejection fraction (t=-2.15; P=0.05) and dimensions (end systolic, t=2.57; end diastolic, t=2.98; both P<0.05), amino-terminal pro-B-type natriuretic peptide (t=3.31; P=0.009), heart rate (t=2.59; P=0.01), and presence of jugular venous distension (t=2.00; P=0.05). In a Cox proportional hazards model that included echocardiographic results and other biomarkers, sST2 independently predicted death at 4 years (hazard ratio=2.70; P=0.003). Conclusions-Among dyspneic patients with and without acute heart failure, sST2 concentrations are associated with prevalent cardiac abnormalities on echocardiography, a more decompensated hemodynamic profile and are associated with long-term mortality, independent of echocardiographic, clinical, or other biochemical markers of risk. (Circ Heart Fail. 2009;2:311-319.) C1 [Shah, Ravi V.; Chen-Tournoux, Annabel A.; Picard, Michael H.; Januzzi, James L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Shah, Ravi V.; Picard, Michael H.; Januzzi, James L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [van Kimmenade, Roland R. J.] Univ Hosp Maastricht, Dept Cardiol, Az Maastricht, Netherlands. RP Januzzi, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org RI Kimmenade, R.R.J./L-4432-2015; OI Picard, Michael/0000-0002-9264-3243 FU National Heart, Lung, and Blood Institute Heart Failure Research Network, Boston, Mass; Balson Scholar Fund, Boston, Mass; Interuniversity Cardiology Institute of the Netherlands (ICIN) FX This study was supported by grant from the National Heart, Lung, and Blood Institute Heart Failure Research Network, Boston, Mass (to R.V.S.); in part by the Balson Scholar Fund, Boston, Mass (to J.L.J.); and by a research fellowship of the Interuniversity Cardiology Institute of the Netherlands (ICIN) (to R.R.J.v.K.). NR 19 TC 78 Z9 81 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2009 VL 2 IS 4 BP 311 EP 319 DI 10.1161/CIRCHEARTFAILURE.108.833707 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 477PF UT WOS:000268530300006 PM 19808354 ER PT J AU Spinale, FG Escobar, GP Mukherjee, R Zavadzkas, JA Saunders, SM Jeffords, LB Leone, AM Beck, C Bouges, S Stroud, RE AF Spinale, Francis G. Escobar, G. Patricia Mukherjee, Rupak Zavadzkas, Juozas A. Saunders, Stuart M. Jeffords, Laura B. Leone, Allyson M. Beck, Christy Bouges, Shenikqua Stroud, Robert E. TI Cardiac-Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase in Mice Effects on Myocardial Remodeling With Aging SO CIRCULATION-HEART FAILURE LA English DT Article DE matrix; myocardial remodeling; ventricular function; aging ID TGF-BETA SIGNALS; 1-MATRIX METALLOPROTEINASE; EXTRACELLULAR-MATRIX; VENTRICULAR-FUNCTION; BINDING-PROTEINS; ACTIVATION; MT1-MMP; CELLS; CARDIOMYOPATHY; TRAFFICKING AB Background-The direct consequences of a persistently increased myocardial expression of the unique matrix metallo-proteinase (MMP) membrane type-1 (MT1-MMP) on myocardial remodeling remained unexplored. Methods and Results-Cardiac-restricted MT1-MMPexp was constructed in mice using the full-length human MT1-MMP gene ligated to the myosin heavy chain promoter, which yielded approximately a 200% increase in MT1-MMP when compared with age/strain-matched wild-type (WT) mice. Left ventricular (LV) function and geometry was assessed by echocardiography in 3-month ("young") WT (n=32) and MT1-MMPexp (n=20) mice and compared with 14-month ("middle-aged") WT (n=58) and MT1-MMPexp (n=35) mice. LV end-diastolic volume was similar between the WT and MT1-MMPexp young groups, as was LV ejection fraction. In the middle-aged WT mice, LV end-diastolic volume and ejection fraction was similar to young WT mice. However, in the MT1-MMPexp middle-aged mice, LV end-diastolic volume was approximate to 43% higher and LV ejection fraction 40% lower (both P<0.05). Moreover, in the middle-aged MT1-MMPexp mice, myocardial fibrillar collagen increased by nearly 2-fold and was associated with approximate to 3-fold increase in the processing of the profibrotic molecule, latency-associated transforming growth factor binding protein. In a second study, 14-day survival after myocardial infarction was significantly lower in middle-aged MT1-MMPexp mice. Conclusions-Persistently increased myocardial MT1-MMP expression, in and of itself, caused LV remodeling, myocardial fibrosis, dysfunction, and reduced survival after myocardial injury. These findings suggest that MT1-MMP plays a mechanistic role in adverse remodeling within the myocardium. (Circ Heart Fail. 2009;2:351-360.) C1 [Spinale, Francis G.; Escobar, G. Patricia; Mukherjee, Rupak; Zavadzkas, Juozas A.; Saunders, Stuart M.; Jeffords, Laura B.; Leone, Allyson M.; Beck, Christy; Bouges, Shenikqua; Stroud, Robert E.] Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29425 USA. [Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Div Cardiothorac Surg, Charleston, SC USA. RP Spinale, FG (reprint author), Med Univ S Carolina, Div Cardiothorac Surg, Room 625,114 Doughty St, Charleston, SC 29425 USA. EM wilburnm@musc.edu FU National Institutes of Health [HL059165, PO I HL048788, HL078650]; Veterans' Affairs Health Administration FX This study was supported by National Institutes of Health grants HL059165, PO I HL048788, and HL078650 and a Merit Award from the Veterans' Affairs Health Administration. NR 30 TC 26 Z9 27 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2009 VL 2 IS 4 BP 351 EP 360 DI 10.1161/CIRCHEARTFAILURE.108.844845 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 477PF UT WOS:000268530300011 PM 19808359 ER PT J AU Potash, J Anderson, KC AF Potash, Jesse Anderson, Kenneth C. TI What's Your Line? SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 [Potash, Jesse; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM kenneth_anderson@dfci.harvard.edu NR 0 TC 5 Z9 5 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 JUL 1 PY 2009 VL 15 IS 13 BP 4251 EP 4251 DI 10.1158/1078-0432.CCR-09-1364 PG 1 WC Oncology SC Oncology GA 482SF UT WOS:000268908300001 PM 19549765 ER PT J AU Carpenter, EL Mick, R Rech, AJ Beatty, GL Colligon, TA Rosenfeld, MR Kaplan, DE Chang, KM Domchek, SM Kanetsky, PA Fecher, LA Flaherty, KT Schuchter, LM Vonderheide, RH AF Carpenter, Erica L. Mick, Rosemarie Rech, Andrew J. Beatty, Gregory L. Colligon, Theresa A. Rosenfeld, Myrna R. Kaplan, David E. Chang, Kyong-Mi Domchek, Susan M. Kanetsky, Peter A. Fecher, Leslie A. Flaherty, Keith T. Schuchter, Lynn M. Vonderheide, Robert H. TI Collapse of the CD27+B-Cell Compartment Associated with Systemic Plasmacytosis in Patients with Advanced Melanoma and Other Cancers SO CLINICAL CANCER RESEARCH LA English DT Article ID MEMORY B-CELLS; ANTIGEN-PRESENTING CELLS; LUPUS-ERYTHEMATOSUS; T-CELLS; IMMUNE-RESPONSES; HIV-1 INFECTION; SERUM-LEVELS; LYMPHOCYTES; POPULATION; EXPRESSION AB Purpose: Disturbed peripheral blood B-cell homeostasis complicates certain infections and autoimmune diseases, such as HIV and systemic lupus erythematosus, but has not been reported in cancer. This study aimed to investigate whether B-cell physiology was altered in the presence of melanoma and other cancers. Experimental Design: Flow cytometry was used to identify phenotypic differences in B cells from patients with melanoma and normal donors. In vitro stimulated 8 cells were assessed for responsiveness and also used as stimulators of allogeneic T cells in mixed lymphocyte reactions. Results: We show B-cell dysregulation in patients with advanced melanoma (n = 26) and other solid tumors (n = 13), marked by a relative and absolute loss of CD27+ (memory) B cells and associated with an aberrant systemic plasmacytosis. Functionally, B cells from patients with melanoma inefficiently up-regulated immunoregulatory molecules and weakly secreted cytokines in response to CD40 and toll-like receptor 9 agonists. Stimulated B cells from patients induced proliferation of alloreactive CD4+ T cells, but these T cells poorly secreted IFN gamma and interleukin-2. These effects were recapitulated by using purified normal donor CD27(neg) B cells in these same assays, linking the predominance of CD27(neg) B cells in patients with the observed functional hyporesponsiveness. Indeed, B-cell dysfunction in patients strongly correlated with the extent of loss of CD27+ B cells in peripheral blood. Conclusions: Disturbed B-cell homeostasis is a previously unrecognized feature of patients with advanced melanoma and other cancers and may represent an unanticipated mechanism of immune incompetence in cancer. C1 [Carpenter, Erica L.; Rech, Andrew J.; Beatty, Gregory L.; Colligon, Theresa A.; Vonderheide, Robert H.] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Mick, Rosemarie; Rosenfeld, Myrna R.; Chang, Kyong-Mi; Domchek, Susan M.; Kanetsky, Peter A.; Fecher, Leslie A.; Flaherty, Keith T.; Schuchter, Lynn M.; Vonderheide, Robert H.] Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Kaplan, David E.; Chang, Kyong-Mi] Univ Penn, Sch Med, Gastroenterol Sect, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Beatty, Gregory L.; Domchek, Susan M.; Fecher, Leslie A.; Flaherty, Keith T.; Schuchter, Lynn M.; Vonderheide, Robert H.] Univ Penn, Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Kaplan, David E.; Chang, Kyong-Mi] Univ Penn, Sch Med, Div Gastroenterol, Dept Med, Philadelphia, PA 19104 USA. [Rosenfeld, Myrna R.] Univ Penn, Sch Med, Div Neurooncol, Dept Neurol, Philadelphia, PA 19104 USA. [Mick, Rosemarie; Kanetsky, Peter A.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Vonderheide, RH (reprint author), Univ Penn, Sch Med, Abramson Family Canc Res Inst, 551 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM rhv@exchange.upenn.edu OI Kaplan, David E./0000-0002-3839-336X; Rosenfeld, Myrna/0000-0001-5095-2534 FU NIH [CA093372, CA09140, CA16520, AI47519, RR017625]; Breast Cancer Research Foundation; VA Career Development Award FX NIH grants CA093372 (R.H.Vonderheide), CA09140 (E.L. Carpenter), CA16520 (R.H.Vonderheide), AI47519 (K-M. Chang), and RR017625 (D.E. Kaplan); Breast Cancer Research Foundation (R.H. Vonderheide); VA Career Development Award (D.E. Kaplan); and a gift from Mark and Paula Solomon (R.H. Vonderheide). NR 49 TC 23 Z9 24 U1 0 U2 1 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 JUL 1 PY 2009 VL 15 IS 13 BP 4277 EP 4287 DI 10.1158/1078-0432.CCR-09-0537 PG 11 WC Oncology SC Oncology GA 482SF UT WOS:000268908300007 PM 19549767 ER PT J AU Ogino, S Nosho, K Irahara, N Kure, S Shima, K Baba, Y Toyoda, S Chen, L Giovannucci, EL Meyerhardt, JA Fuchs, CS AF Ogino, Shuji Nosho, Katsuhiko Irahara, Natsumi Kure, Shoko Shima, Kaori Baba, Yoshifumi Toyoda, Saori Chen, Li Giovannucci, Edward L. Meyerhardt, Jeffrey A. Fuchs, Charles S. TI A Cohort Study of Cyclin D1 Expression and Prognosis in 602 Colon Cancer Cases SO CLINICAL CANCER RESEARCH LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; TUMOR-INFILTRATING LYMPHOCYTES; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; BETA-CATENIN; LINE-1 HYPOMETHYLATION; MISMATCH REPAIR; POOR-PROGNOSIS; BRAF MUTATION; CARCINOMA AB Purpose: Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (CDKN1B) and p21 (CDKN1A, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation]. Experimental Design: Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, KRAS, and BRAF. Results: Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (P = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; P = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% Cl, 0.39-0.84; P = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% Cl, 0.57-0.98; P = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (P(interaction) = 0.008). Compared with tumors that were both cyclin D1 - negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65). Conclusions: Cyclin D1 overexpression is associated with longer survival in colon cancer. C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Mol Oncol Pathol,Med Sch,Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji; Chen, Li] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Mol Oncol Pathol,Med Sch,Dept Med Oncol, 44 Binney St,Room JF 215C, Boston, MA 02115 USA. EM shuji.ogino@dfci.harvard.edu FU U.S. NIH [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA97992, K07 CA122826]; Bennett Family Fund; Entertainment Industry Foundation National Colorectal Cancer Research Alliance; Japan Society for Promotion of Science FX U.S. NIH P01 CA87969 (S. Hankinson), P01 CA55075 (W. Willett), P50 CA127003 (C.S. Fuchs), K07 CA97992 (J.A. Meyerhardt), and K07 CA122826 (S. Ogino); the Bennett Family Fund; and the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. K. Nosho was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Cancer Institute or NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript. NR 51 TC 34 Z9 35 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 JUL 1 PY 2009 VL 15 IS 13 BP 4431 EP 4438 DI 10.1158/1078-0432.CCR-08-3330 PG 8 WC Oncology SC Oncology GA 482SF UT WOS:000268908300023 PM 19549773 ER PT J AU Tan, G Thornby, J Hammond, DC Strehl, U Canady, B Arnemann, K Kaiser, DA AF Tan, Gabriel Thornby, John Hammond, D. Corydon Strehl, Ute Canady, Brittany Arnemann, Kelly Kaiser, David A. TI Meta-Analysis of EEG Biofeedback in Treating Epilepsy SO CLINICAL EEG AND NEUROSCIENCE LA English DT Article DE EEG Biofeedback; Epilepsy; Meta-Analysis; Neurofeedback; Neurotherapy; Seizure ID SENSORIMOTOR RHYTHM; SEIZURE PREDICTION; SLEEP EEG; CAT AB About one third of patients with epilepsy do not benefit from medical treatment. For these patients electroencephalographic (EEG) biofeedback is a viable alternative. EEG biofeedback, or neurofeedback, normalizes or enhances EEG activity by means of operant conditioning. While dozens of scientific reports have been published on neurofeedback for seizure disorder, most have been case series with too few subjects to establish efficacy, The purpose of this paper is to meta-analyze existing research on neurofeedback and epilepsy. We analyzed every EEG biofeedback study indexed in MedLine, PsychInfo, and PsychLit databases between 1970 and 2005 on epilepsy that provided seizure frequency change in response to feedback. Sixty-three studies have been published, 10 of which provided enough outcome information to be included in a meta-analysis. All studies consisted of patients whose seizures were not controlled by medical therapies, which is a very important factor to keep in mind when interpreting the results. Nine of 10 studies reinforced sensorimotor rhythms (SMR) while 1 study trained slow cortical potentials (SCP). All studies reported an overall mean decreased seizure incidence following treatment and 64 out of 87 patients (74%) reported fewer weekly seizures in response to EEG biofeedback. Treatment effect was mean log (post/pre) where pre and post represent number of seizures per week prior to treatment and at final evaluation, respectively. Due to prevalence of small groups, Hedges's g was computed for effect size, As sample heterogeneity was possible (Q test, p=.18), random effects were assumed and the effect of intervention was -0.233, SE=0.057, z=-4.11, P<.001. Based on this meta-analysis, EEG operant conditioning was found to produce a significant reduction on seizure frequency. This finding is especially noteworthy given the patient group, individuals who had been unable to control their seizures with medical treatment. C1 [Tan, Gabriel; Thornby, John] Michael E DeBakey Vet Affairs Hosp, Houston, TX USA. [Tan, Gabriel; Thornby, John] Baylor Coll Med, Houston, TX 77030 USA. [Hammond, D. Corydon] Univ Utah, Sch Med, Salt Lake City, UT USA. [Strehl, Ute] Univ Tubingen, Tubingen, Germany. [Canady, Brittany] Geisinger Med Ctr, Danville, PA 17822 USA. [Arnemann, Kelly] Audie L Murphy Vet Affairs Hosp, San Antonio, TX USA. [Kaiser, David A.] Wavestate Inc, Marina Del Rey, CA USA. RP Tan, G (reprint author), Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd 145, Houston, TX 77030 USA. EM tan.gabriel@va.gov NR 40 TC 63 Z9 64 U1 3 U2 14 PU EEG & CLINICAL NEUROSCIENCE SOC (E C N S) PI WHEATON PA 805 W LIBERTY DR, PO BOX 725, WHEATON, IL 60187 USA SN 1550-0594 J9 CLIN EEG NEUROSCI JI Clin. EEG Neurosci. PD JUL PY 2009 VL 40 IS 3 BP 173 EP 179 PG 7 WC Clinical Neurology; Neurosciences; Neuroimaging; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 477NV UT WOS:000268526700006 PM 19715180 ER PT J AU Kanwal, F Gralnek, IM Hays, RD Zeringue, A Durazo, F Han, SB Saab, S Bolus, R Spiegel, BMR AF Kanwal, Fasiha Gralnek, Ian M. Hays, Ron D. Zeringue, Angelique Durazo, Francisco Han, Steven B. Saab, Sammy Bolus, Roger Spiegel, Brennan M. R. TI Health-Related Quality of Life Predicts Mortality in Patients With Advanced Chronic Liver Disease SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID SERUM SODIUM; HEART-FAILURE; UNITED-STATES; SURVIVAL; TRANSPLANTATION; MELD; CIRRHOSIS; CANCER; MODEL; POPULATION AB BACKGROUND & AIMS: It is well-established that cirrhosis negatively impacts health-related quality of life (HRQOL). However, it is less clear how to use this information in everyday clinical practice. If HRQOL predicted survival in cirrhosis, then measuring HRQOL would have important clinical implications. We sought to measure the association between HRQOL and survival in patients with cirrhosis and investigated whether the relationship between HRQOL and Survival is independent of Model for End-Stage Liver Disease (MELD). METHODS: We measured HRQOL in 156 patients with cirrhosis awaiting liver transplantation by using the Short Form Liver Disease Quality of Life instrument. We followed patients prospectively and used Cox proportional hazard models to measure the independent effect of baseline HRQOL on survival, adjusting for MELD and other covariates. RESULTS: During a mean 9-month follow-up, 26 (17%) patients died, and 30 (20%) received liver transplants. In unadjusted analysis, higher baseline HRQOL predicted lower mortality (hazard ratio, 0.96; 95% confidence interval, 0.94-0.99). Specifically, for each 1-point increase in HRQOL, there was a 4% decrease in mortality. These results did not change after adjusting for MELD scores, patient demographics, or psychosocial characteristics; the MELD score accounted for 1% of the variation in HRQOL scores (P=.18). Survival was most strongly predicted by activities of daily living, health distress, sleep disturbance, and perceived disease stigma. CONCLUSIONS: Higher HRQOL predicts lower mortality in patients with cirrhosis. This relationship is independent of MELD; MELD does not capture liver-specific HRQOL. Beyond its use as a secondary outcome in clinical trials, HRQOL could be used to predict survival of patients with advanced liver disease. C1 [Kanwal, Fasiha; Zeringue, Angelique] John Cochran VA Med Ctr, St Louis, MO USA. [Kanwal, Fasiha] St Louis Univ, Div Gastroenterol, St Louis, MO 63103 USA. [Kanwal, Fasiha; Bolus, Roger; Spiegel, Brennan M. R.] Univ Calif Los Angeles, VA Ctr Outcomes Res & Educ, Los Angeles, CA USA. [Gralnek, Ian M.] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. [Hays, Ron D.; Spiegel, Brennan M. R.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Hays, Ron D.] RAND Corp, Santa Monica, CA USA. [Durazo, Francisco; Han, Steven B.; Saab, Sammy; Spiegel, Brennan M. R.] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Han, Steven B.; Spiegel, Brennan M. R.] VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol & Hepatol, Los Angeles, CA USA. RP Spiegel, BMR (reprint author), 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu RI Zeringue, Angelique/I-1755-2012; Hays, Ronald/D-5629-2013 FU NIA NIH HHS [P30AG021684-07]; NIDDK NIH HHS [2P30 DK 041301-17] NR 33 TC 47 Z9 47 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JUL PY 2009 VL 7 IS 7 BP 793 EP 799 DI 10.1016/j.cgh.2009.03.013 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 476HP UT WOS:000268430500017 PM 19306949 ER PT J AU Ross, RW Zietman, AL Xie, WL Coen, JJ Dahl, DM Shipley, WU Kaufman, DS Islam, T Guimaraes, AR Weissleder, R Harisinghani, M AF Ross, Robert W. Zietman, Anthony L. Xie, Wanling Coen, John J. Dahl, Douglas M. Shipley, William U. Kaufman, Donald S. Islam, Tina Guimaraes, Alexander R. Weissleder, Ralph Harisinghani, Mukesh TI Lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) identifies occult lymph node metastases in prostate cancer patients prior to salvage radiation therapy SO CLINICAL IMAGING LA English DT Article DE Nanoparticle MR imaging; Ferumoxtran-10; Lymph nodes; Metastases; Salvage radiation therapy ID RADICAL RETROPUBIC PROSTATECTOMY; SUPERPARAMAGNETIC IRON-OXIDE; PSA FAILURE; RADIOTHERAPY; ANTIGEN AB Twenty-six patients with prostate cancer status post-radical prostatectomy who were candidates for salvage radiation therapy (SRT) underwent lymphotropic nanoparticle enhanced MRI (LNMRI) using superparamagnetic nanoparticle ferumoxtran-10. LNMRI was well tolerated, with only two adverse events, both Grade 2. Six (23%) of the 26 patients, previously believed to be node negative, tested lymph node positive by LNMRI. A total of nine positive lymph nodes were identified in these six patients, none of which were enlarged based on size criteria. (C) 2009 Elsevier Inc. All rights reserved. C1 [Islam, Tina] Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Zietman, Anthony L.; Coen, John J.; Shipley, William U.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Dahl, Douglas M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kaufman, Donald S.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Ross, Robert W.; Xie, Wanling] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zietman, Anthony L.; Coen, John J.; Dahl, Douglas M.; Shipley, William U.; Kaufman, Donald S.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Islam, T (reprint author), Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, 55 Fruit St, Boston, MA 02114 USA. EM islam.tina@mgh.harvard.edu FU Bertucci Foundation and an American Society of Clinical Oncology Career Development Award; AMAG Pharmaceuticals, Inc. (Cambridge, MA, USA) FX Support provided by the Bertucci Foundation and an American Society of Clinical Oncology Career Development Award ( to RWR). Imaging agent provided by AMAG Pharmaceuticals, Inc. (Cambridge, MA, USA). No conflicts of interest are reported. NR 17 TC 53 Z9 54 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-7071 J9 CLIN IMAG JI Clin. Imaging PD JUL-AUG PY 2009 VL 33 IS 4 BP 301 EP 305 DI 10.1016/j.clinimag.2009.01.013 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 533GL UT WOS:000272811600008 PM 19559353 ER PT J AU Jones, KL Seward, RJ Ben-Menachem, G Glickstein, LJ Costello, CE Steere, AC AF Jones, Kathryn L. Seward, Robert J. Ben-Menachem, Gil Glickstein, Lisa J. Costello, Catherine E. Steere, Allen C. TI Strong IgG antibody responses to Borrelia burgdorferi glycolipids in patients with Lyme arthritis, a late manifestation of the infection SO CLINICAL IMMUNOLOGY LA English DT Article DE Lyme disease; Bacterial infection; Borrelia burgdorferi; Antibodies; Glycolipid antigens ID T-CELLS; CHOLESTERYL GALACTOSIDE; DISEASE; RECOMBINANT; ANTIGENS; PEPTIDE; VACCINE AB In this study, the membrane lipids of B. burgdorferi were separated into 16 fractions; the components in each fraction were identified, and the immunogenicity of each fraction was determined by ELISA using sera from Lyme disease patients. Only the 2 glycolipids, acylated cholesteryl galactoside (ACG, BbGL-I) and monogalactosyl diacylglycerol (MgaID, BbGL-II), were immunogenic. Early in the infection, 24 of 84 patients (29%) who were convalescent from erythema migrans and 19 of the 35 patients (54%) with neuroborreliosis had weak IgG responses to purified MgaID, and a smaller percentage of patients had early responses to synthetic ACG. However, almost all of 75 patients with Lyme arthritis, a late disease manifestation, had strong IgG reactivity with both glycolipids. Thus, almost all patients with Lyme arthritis have strong IgG antibody responses to B. burgdorferi glycolipid antigens. (C) 2009 Elsevier Inc. All rights reserved. C1 [Jones, Kathryn L.; Seward, Robert J.; Glickstein, Lisa J.; Steere, Allen C.] Harvard Univ, Ctr Immunol & Inflammatory Dis, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol,Med Sch, Boston, MA 02114 USA. [Ben-Menachem, Gil] NICHHD, NIH, Bethesda, MD 20892 USA. [Seward, Robert J.; Costello, Catherine E.] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. RP Steere, AC (reprint author), Harvard Univ, Ctr Immunol & Inflammatory Dis, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol,Med Sch, 55 Fruit St,Charlestown Navy Yard 149-8301, Boston, MA 02114 USA. EM asteere@partners.org OI Costello, Catherine/0000-0003-1594-5122; Jones, Kathryn/0000-0003-3815-5713 FU National Institutes of Health [RO1 AR-20358, P41 RR10888, S10 RR 15942, AR-007258]; English, Bonter, Mitchell Foundation; Eshe Fund; Lyme/Arthritis Research Fund at Massachusetts General Hospital; Walter J. and Lille A. Berbecker Foundation FX We thank Dr. Nitin Damle in Wakefield, Rhode Island, and Dr. Vijay Sikand in East Lyme, Connecticut, for obtaining serum samples from patients with erythema migrans, Mr. Vincent Poszgay for making the synthetic preparation of ACG (BbGL-I), Dr. Rachel Schneerson for providing the preparation for our study, Ms. Gail McHugh for help in the processing and storage of serum samples, Ms. Colleen Squires for assistance with the preparation of this manuscript, and Dr. Shiv Pillai for helpful discussions. This work was supported by funding from the National Institutes of Health (RO1 AR-20358 to ACS and P41 RR10888 and S10 RR 15942 to CEC), the English, Bonter, Mitchell Foundation, the Eshe Fund, and the Lyme/Arthritis Research Fund at Massachusetts General Hospital. K.L.J. received support from a scholarship from the Walter J. and Lille A. Berbecker Foundation for the study of Lyme disease, and from the National Institutes of Health training grant AR-007258. NR 29 TC 11 Z9 12 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2009 VL 132 IS 1 BP 93 EP 102 DI 10.1016/j.clim.2009.03.510 PG 10 WC Immunology SC Immunology GA 457SY UT WOS:000266954900010 PM 19342303 ER PT J AU Palevsky, PM AF Palevsky, Paul M. TI Defining Contrast-Induced Nephropathy SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID RADIOCONTRAST-INDUCED NEPHROPATHY; ACUTE-RENAL-FAILURE; RANDOMIZED CONTROLLED-TRIAL; HIGH-RISK PATIENTS; SODIUM-BICARBONATE; CORONARY-ANGIOGRAPHY; PREVENTION; MEDIA; METAANALYSIS; NEPHROTOXICITY C1 [Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Renal Sect, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15240 USA. RP Palevsky, PM (reprint author), Univ Pittsburgh, Sch Med, Renal Sect, VA Pittsburgh Healthcare Syst, Room 7E123 111F-U,Univ Dr, Pittsburgh, PA 15240 USA. EM palevsky@pitt.edu OI Palevsky, Paul/0000-0002-7334-5400 NR 29 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL PY 2009 VL 4 IS 7 BP 1151 EP 1153 DI 10.2215/CJN.03410509 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 466WC UT WOS:000267693400001 PM 19541810 ER PT J AU Hinson, VK Goetz, CG Leurgans, S Fan, W Nguyen, T Hsu, A AF Hinson, Vanessa K. Goetz, Christopher G. Leurgans, Sue Fan, Wenqing Nguyen, Tiffany Hsu, Ann TI Reducing Dosing Frequency of Carbidopa/Levodopa: Double-Blind Crossover Study Comparing Twice-Daily Bilayer Formulation of Carbidopa/Levodopa (IPX054) Versus 4 Daily Doses of Standard Carbidopa/Levodopa in Stable Parkinson Disease Patients SO CLINICAL NEUROPHARMACOLOGY LA English DT Review DE Parkinson disease; levodopa; randomized clinical trials ID CAPTURE AB Objective: We compared IPX054, a bilayer tablet of immediate- and extended-release carbidop-/levodopa (CD/LD) given twice daily to standard CD/LD given 4 times daily in patients with stable Parkinson disease (PD). Methods: Twelve PD patients with no or mild fluctuations oil CD/LD 25/100 mg 4 times daily were randomized to a double-blind crossover comparison with IPX054 (50/200 mg) twice daily. At the end of each 2-week treatment, patients were video recorded while performing a modified Unified Parkinson's Disease Rating Scale motor examination and Rush Dyskinesia Rating Scale at 30-minute intervals over 8.5 hours. The primary Outcome measure was the number of videotape epochs rated as "ON" without troublesome dyskinesia by a blinded observer (Wilcoxon signed rank tests). Results: The 9 men and 3 women had a mean age of 69 years and mean PD duration of 6 years. IPX054 and CD/LD showed no significant differences in the primary outcome measure (mean number of video epochs rated as ON without troublesome dyskinesia; P = 0.14). The mean time to ON was improved with IPX054 (P = 0.014), and the mean modified Unified Parkinson's Disease Rating Scale scores slightly favored IPX054 (14.4 vs 16.9; P = 0.052.). Mean Rush Dyskinesia Rating Scale scores were not significantly different between IPX054 and CD/LD (0.45 vs 0.69; P = 0.25). No patient developed troublesome dyskinesias. Conclusions: in stable PD patients, no difference was detected between twice-daily treatment with IPX054 and CD/LD given 4 times daily In this group, substitution with IPX054 reduced closing frequency while maintaining CD/LD efficacy. In clinical practice, this case of administration may offer improved treatment compliance. C1 [Hinson, Vanessa K.] Med Univ S Carolina, Movement Disorders Program, Dept Neurosci, Charleston, SC 29425 USA. [Hinson, Vanessa K.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Goetz, Christopher G.; Leurgans, Sue; Fan, Wenqing] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Nguyen, Tiffany; Hsu, Ann] IMPAX Labs Inc, Hayward, CA USA. RP Hinson, VK (reprint author), Med Univ S Carolina, Movement Disorders Program, Dept Neurosci, 326 Calhoun St,Suite 308, Charleston, SC 29425 USA. EM hinsonvk@musc.edu NR 14 TC 3 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-5664 J9 CLIN NEUROPHARMACOL JI Clin. Neuropharmacol. PD JUL-AUG PY 2009 VL 32 IS 4 BP 189 EP 192 DI 10.1097/WNF.0b013e3181a27fae PG 4 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 481VX UT WOS:000268841600003 PM 19620848 ER PT J AU Huddleston, JI Scarborough, DM Goldvasser, D Freiberg, AA Malchau, H AF Huddleston, James I. Scarborough, Donna Moxley Goldvasser, Dov Freiberg, Andrew A. Malchau, Henrik TI How Often Do Patients with High-Flex Total Knee Arthroplasty Use High Flexion? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID IN-VIVO DETERMINATION; FOLLOW-UP; FUNCTIONAL-ACTIVITIES; FLUOROSCOPIC ANALYSIS; ENERGY-EXPENDITURE; OPTIMIZING FLEXION; CRUCIATE LIGAMENT; PHYSICAL-ACTIVITY; TOTAL CONDYLAR; DEEP FLEXION AB Although high-flexion TKA designs aim to safely accommodate deep flexion, it is unknown how often patients use deep flexion outside the laboratory. We used a validated smart-activity monitor to document the prevalence of knee flexion greater than 90 degrees in 20 consecutive patients (21 knees) who had high-flexion TKAs, at a minimum of 2 years' followup. Patients wore the device continuously for a mean of 35.7 +/- 0.5 hours. The 21 knees flexed more than 90 for an average of 10 +/- 3.8 minutes (0.5%). Activities performed with flexion greater than 90 degrees were, on average, 70% in single-limb stance, 12% moving from sitting to standing, 8% walking, 7% moving from standing to reclining, 2% stepping, 0.9% moving from lying to standing, and 0.1% running. Eight knees flexed greater than 120 for an average of 2.2 minutes (range, 0.2-15 minutes), or 0.1% of the testing time. Activities performed with flexion greater than 120 degrees were, on average, 90% in single-limb stance, 6% moving from sitting to standing, 3% walking, 0.6% moving from standing to reclining, 0.3% stepping, and 0.1% moving from lying to standing. Peak flexion used at any time during testing was, on average, 84% +/- 11% of maximum postoperative flexion (125 degrees +/- 12 degrees). These patients rarely used deep flexion. C1 [Huddleston, James I.] Stanford Univ, Med Ctr, Dept Orthopaed Surg, Stanford, CA 94305 USA. [Scarborough, Donna Moxley; Goldvasser, Dov; Freiberg, Andrew A.; Malchau, Henrik] Harvard Med Sch, Massachusetts Gen Hosp, Harris Orthopaed Biomech & Biomat Lab, Boston, MA USA. RP Huddleston, JI (reprint author), Stanford Univ, Med Ctr, Dept Orthopaed Surg, 300 Pasteur Dr,R 149, Stanford, CA 94305 USA. EM jhuddleston@stanford.edu FU Harris Orthopaedic Biomechanics and Biomaterials Laboratory; Stanford University Medical Center FX This work was performed at the Harris Orthopaedic Biomechanics and Biomaterials Laboratory and Stanford University Medical Center. NR 65 TC 15 Z9 20 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2009 VL 467 IS 7 BP 1898 EP 1906 DI 10.1007/s11999-009-0874-y PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 453ZS UT WOS:000266652000041 PM 19421828 ER PT J AU Lin, HW O'Neill, A Cunningham, MJ AF Lin, Harrison W. O'Neill, Allison Cunningham, Michael J. TI Ludwig's Angina in the Pediatric Population SO CLINICAL PEDIATRICS LA English DT Editorial Material DE Ludwig's angina; abscess; submental; submandibular; pediatric ID COMPLICATION; NECK AB As many as 1 in 3 of cases of Ludwig's angina Occur in children and adolescents, and pediatricians are therefore ideally Situated to detect these individuals at an early stage of their potentially life-threatening disease. The early identification and referral of children afflicted with Ludwig's angina to tertiary care centers allows for the rapid initiation of medical therapy and the consultation of those emergency services critical to providing such patients with optimal diagnostic and therapeutic interventions. This review provides an overview of the anatomical and pathophysiological considerations in Ludwig's angina and describes practical management principles to assist pediatricians in the diagnosis and treatment of this disease. Included in this review is an evidence-based algorithm for airway management. C1 [Lin, Harrison W.; Cunningham, Michael J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Lin, Harrison W.; Cunningham, Michael J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [O'Neill, Allison] Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Lin, HW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM harrison_lin@meei.harvard.edu NR 22 TC 4 Z9 4 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD JUL PY 2009 VL 48 IS 6 BP 583 EP 587 DI 10.1177/0009922809333095 PG 5 WC Pediatrics SC Pediatrics GA 456MP UT WOS:000266851100001 PM 19286617 ER PT J AU Oreskovic, NM Sawicki, GS Kinane, TB Winickoff, JP Perrin, JM AF Oreskovic, Nicolas M. Sawicki, Gregory S. Kinane, T. Bernard Winickoff, Jonathan P. Perrin, James M. TI Travel Patterns to School Among Children With Asthma SO CLINICAL PEDIATRICS LA English DT Article DE asthma; active commuting; physical activity; school; environment ID PHYSICAL-ACTIVITY; POLLUTANT EXPOSURE; CHILDHOOD; IMPACT; PREVALENCE; EXERCISE; WALKING; HEALTH AB Background. Active commuting to school provides regular exercise, which can improve asthma symptoms. Little is known about how children with asthma travel to school. Objective. To identify travel patterns and parental perceptions surrounding mode of travel to school among children with asthma. Methods. Cross-sectional study of 176 children with asthma aged 5 to 15 years. Parents completed questionnaires assessing mode of travel to school, physical activity, asthma control, physician counseling, and factors influencing parental decisions. Data analysis included descriptive and bivariate statistics. Results. Few (16%) children with asthma actively commute to school. Active travelers lived closer to school, and "distance" was the most frequently reported factor influencing a parent's decision regarding travel mode to school. Parents reported few concerns about pollution and little physician counseling on active travel. Conclusion. Few children with asthma actively travel to school. Asthma-specific concerns do not appear to guide parental decisions on travel mode to school. C1 [Oreskovic, Nicolas M.; Kinane, T. Bernard; Winickoff, Jonathan P.; Perrin, James M.] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Dept Pediat, Boston, MA 02114 USA. [Sawicki, Gregory S.] Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Oreskovic, NM (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Dept Pediat, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM noreskovic@partners.org OI Oreskovic, Nicolas/0000-0001-8702-8636 FU Deborah Munroe Noonan Memorial Fund FX The authors wish to thank Gabriel Malseptic and Nathan Demars for their excellent research assistance. This study was funded by the Deborah Munroe Noonan Memorial Fund. The Deborah Munroe Noonan Memorial Fund played no role in acquiring or analyzing the data, or in preparing the manuscript. Dr. Oreskcovic had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 25 TC 5 Z9 5 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD JUL PY 2009 VL 48 IS 6 BP 632 EP 640 DI 10.1177/0009922809335323 PG 9 WC Pediatrics SC Pediatrics GA 456MP UT WOS:000266851100008 PM 19420183 ER PT J AU Sawaya, HHB de Souza, RBC Carrasco, S Goldenstein-Schainberg, C AF Braga Sawaya, Heloisa Helena Christmann de Souza, Romy Beatriz Carrasco, Solange Goldenstein-Schainberg, Claudia TI Altered adhesion molecules expression on peripheral blood mononuclear cells from patients with systemic sclerosis and clinical correlations SO CLINICAL RHEUMATOLOGY LA English DT Article DE Adhesion molecules; ICAM-1; ICAM-3; Pathogenesis; Scleroderma; Systemic sclerosis ID L-SELECTIN; LOCALIZED SCLERODERMA; INVOLVEMENT; LYMPHOCYTES; RECEPTOR; SERA; SKIN AB The aim of the study was to evaluate the expressions of adhesion molecules (AM) on peripheral blood mononuclear cells (PBMNC) from systemic sclerosis (SSc) patients. Thirty-one SSc patients (ACR) and 20 normal subjects were selected for the study. PBMNC were analyzed for LFA-1 alpha, LFA-1 beta, ICAM-3, ICAM-1, and l-selectin expressions. ICAM-3 expression was decreased while ICAM-1 was increased on SSc PBMNC, compared to controls (p = 0.04 and 0.003, respectively). A positive association was found between LFA-1 alpha (r = 0.37, p = 0.03), LFA-1 beta (r = 0.38, p = 0.002), ICAM-3 (r = 0.42, p = 0.01), and l-selectin (r = 0.38, p = 0.03) expressions and greater number of immunosuppressive drugs taken by SSc patients. Also, anti-centromeric positive SSc patients had lower expressions of LFA-1 alpha, LFA-1 beta, ICAM-3, and l-selectin. Lower expression of ICAM-3 and higher expression of ICAM-1 suggest that AMs may be involved in the pathogenesis of scleroderma. C1 [Christmann de Souza, Romy Beatriz; Goldenstein-Schainberg, Claudia] Univ Sao Paulo, Div Rheumatol, BR-01246000 Sao Paulo, Brazil. [Braga Sawaya, Heloisa Helena] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP de Souza, RBC (reprint author), Univ Sao Paulo, Div Rheumatol, Av Dr Arnaldo,455-3 Andar Reumatol,Sala 3107, BR-01246000 Sao Paulo, Brazil. EM romy.souza@gmail.com RI Carrasco, Solange/G-5144-2012 NR 26 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0770-3198 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD JUL PY 2009 VL 28 IS 7 BP 847 EP 851 DI 10.1007/s10067-009-1124-0 PG 5 WC Rheumatology SC Rheumatology GA 451CI UT WOS:000266447900013 PM 19225705 ER PT J AU Nierenberg, AA AF Nierenberg, Andrew A. TI Distress: To Treat or Not to Treat? SO CNS SPECTRUMS LA English DT Editorial Material ID BORDERLINE PERSONALITY-DISORDER; THERAPY; MODEL C1 [Nierenberg, Andrew A.] Harvard Univ, Sch Med, Boston, MA 02163 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. RP Nierenberg, AA (reprint author), Harvard Univ, Sch Med, Boston, MA 02163 USA. NR 12 TC 1 Z9 1 U1 0 U2 0 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD JUL PY 2009 VL 14 IS 7 BP 344 EP 345 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 483JB UT WOS:000268959100001 PM 19773708 ER PT J AU Stedman, MR Gagnon, DR Lew, RA Solomon, DH Losina, E Brookhart, MA AF Stedman, Margaret R. Gagnon, David R. Lew, Robert A. Solomon, Daniel H. Losina, Elena Brookhart, M. Alan TI A SAS macro for a clustered permutation test SO COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE LA English DT Article DE Permutation test; Cluster randomized trial; Clustered permutation test; SAS macro ID COMMUNITY INTERVENTION TRIALS; DESIGN AB The clustered per-mutation test is a nonparametric method of significance testing for correlated data. It is often used in cluster randomized trials where groups of patients rather than individuals are randomized to either a treatment or control intervention. We describe a flexible and efficient SAS macro that implements the 2-sample clustered permutation test. We discuss the theory and applications behind this test as well as details of the SAS code. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Stedman, Margaret R.; Solomon, Daniel H.; Brookhart, M. Alan] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Stedman, Margaret R.; Gagnon, David R.; Lew, Robert A.; Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Gagnon, David R.; Lew, Robert A.] Boston VA Healthcare Syst, VA Cooperat Studies, MAVERIC, Boston, MA USA. [Solomon, Daniel H.; Brookhart, M. Alan] Harvard Univ, Sch Med, Boston, MA USA. [Solomon, Daniel H.; Losina, Elena] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA. RP Stedman, MR (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. EM mstedman2@partners.org OI Gagnon, David/0000-0002-6367-3179; Stedman, Margaret/0000-0001-9271-8332 FU National Institutes of Health [AG-027400] FX This work was supported by a grant from the National Institutes of Health (AG-027400) awarded to M. Alan Brookhart. NR 11 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-2607 J9 COMPUT METH PROG BIO JI Comput. Meth. Programs Biomed. PD JUL PY 2009 VL 95 IS 1 BP 89 EP 94 DI 10.1016/j.cmpb.2009.02.005 PG 6 WC Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 447JR UT WOS:000266187900008 PM 19321221 ER PT J AU Jurkunas, U Behlau, I Colby, K AF Jurkunas, Ula Behlau, Irmgard Colby, Kathryn TI Fungal Keratitis: Changing Pathogens and Risk Factors SO CORNEA LA English DT Article; Proceedings Paper CT 110th Annual Meeting of the American-Academy-of-Ophthalmology CY NOV 11-14, 2006 CL Las Vegas, NV SP Amer Acad Ophthalmol DE fungal keratitis; filamentous fungi; contact lens wear; voriconazole; corneal transplantation; keratoprosthesis; therapeutic keratoplasty; Fusarium; Candida ID CONTACT-LENS WEAR; FUSARIUM KERATITIS; TRIAZOLE ANTIFUNGAL; VORICONAZOLE; OUTBREAK; SPECTRUM AB Purpose: To describe changes in demographics and pathogens for fungal keratitis cases diagnosed at the Massachusetts Eye and Ear Infirmary. Methods: Patient demographics, clinical and laboratory findings, treatment and outcomes of 46 cases of culture-proven fungal keratitis diagnosed from January 2004 through November 2007 were compared with 23 cases of fungal keratitis previously collected over a similar period from January 1999 through November 2002. Results: During 2004-2007, the rate of fungal keratitis was 1.0 cases per month, an increase from the baseline rate of 0.5 cases per month during 1999-2002. The proportion of cases caused by filamentous fungi increased from 30% (1999-2002) to 65% (2004-2007) (P=0.01). Soft contact lens wear accounted for 41% of fungal keratitis cases in 2004-2007, as compared with 17% in 1999-2002. The majority of patients (70%) received oral antifungal treatment in addition to topical amphotericin B and natamycin. Seventeen patients (40%) required therapeutic keratoplasty. Patients with a history of conical transplant had the highest rate of therapeutic keratoplasties (67%) and had the poorest visual outcome (40% counting fingers or less). In the contact lens group, 94% of patients maintained vision of at least 20/40 and only 12% required surgery to control the infection. Conclusions: There has been an increase in fungal keratitis in the Boston area and a change in the causative pathogens and risk factors for infection. Filamentous fungi now account for the majority of fungal keratitis cases, whereas yeasts were the predominant pathogen in the past. Soft contact lens wear is currently the most common risk factor for development of fungal keratitis. C1 [Jurkunas, Ula; Behlau, Irmgard; Colby, Kathryn] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Jurkunas, Ula; Behlau, Irmgard; Colby, Kathryn] Schepens Eye Res Inst, Boston, MA USA. [Jurkunas, Ula; Colby, Kathryn] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Behlau, Irmgard] Harvard Univ, Sch Med, Dept Internal Med, Boston, MA USA. [Behlau, Irmgard] Mt Auburn Hosp, Div Infect Dis, Cambridge, MA USA. RP Colby, K (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St,Suite 727, Boston, MA 02114 USA. EM kacolby@meei.harvard.edu NR 19 TC 41 Z9 46 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD JUL PY 2009 VL 28 IS 6 BP 638 EP 643 PG 6 WC Ophthalmology SC Ophthalmology GA 463EP UT WOS:000267412500005 PM 19512908 ER PT J AU Kahn, JM Asch, RJ Iwashyna, TJ Haynes, K Rubenfeld, GD Angus, DC Asch, DA AF Kahn, Jeremy M. Asch, Rebecca J. Iwashyna, Theodore J. Haynes, Kevin Rubenfeld, Gordon D. Angus, Derek C. Asch, David A. TI Physician attitudes toward regionalization of adult critical care: A national survey SO CRITICAL CARE MEDICINE LA English DT Article DE patient transfer; triage; intensive care; mechanical ventilation; healthcare systems ID LUNG-PROTECTIVE VENTILATION; PEDIATRIC INTENSIVE-CARE; UNITED-STATES; HOSPITAL MORTALITY; FAMILY-MEMBERS; RESPONSE RATES; VOLUME; BARRIERS; ORGANIZATION; OUTCOMES AB Objective: Regionalization has been proposed as a method to improve outcomes for patients with critical illness. We sought to determine intensivist physician attitudes and potential barriers to the regionalization of adult critical care. Design: Mail survey. Setting. United States. Subjects: Actively practicing physicians specializing in adult critical care, emergency medicine, or internal medicine listed in the 2008 American Medical Association Physician Masterfile (n = 1200). Interventions: None. Measurements and Main Results: There were 569 eligible respondents (effective response rate = 53.0%). Respondents were similar to nonrespondents. Fifty-nine percent of respondents thought their hospital would mainly receive patients under a regionalized system, and 30% thought their hospital would mainly send patients. Opinions were split about whether regionalization would improve overall patient survival (52% agreed) and healthcare efficiency (66% agreed). Specialists in anesthesiology and surgery-critical care, academic physicians, and physicians who perceived that they would mainly receive patients were more likely to believe that regionalization would improve outcomes and efficiency (p < 0.001). The most commonly endorsed barriers to regionalization were personal strain on patient's families (66% agreed), current lack of a strong central authority (64% agreed), and the potential to overwhelm capacity at large hospitals (55% agreed). Commonly endorsed strategies to implement regionalization included using objective criteria to determine eligibility for transfer (87% agreed), developing common information technology platforms across hospitals (86% agreed), and demonstrating in a clinical trial that regionalization is beneficial (81% agreed). Conclusions: Intensivist physicians have mixed opinions about regionalization, with little consensus about whether regionalization will improve outcomes. Most felt that regionalization will improve patient outcomes, but many expressed concerns about unintended adverse consequences. Respondents identified several barriers and potential implementation strategies that can help policymakers design a regionalized system of critical care in the United States. (Crit Care Med 2009; 37:2149-2154) C1 [Kahn, Jeremy M.; Asch, Rebecca J.] Univ Penn, Sch Med, Div Pulm Allergy & Crit Care, Philadelphia, PA 19104 USA. [Kahn, Jeremy M.; Asch, David A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Kahn, Jeremy M.; Haynes, Kevin] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Iwashyna, Theodore J.] Univ Michigan, Div Pulm & Crit Care, Ann Arbor, MI 48109 USA. [Rubenfeld, Gordon D.] Sunnybrook Hlth Sci Ctr, Program Trauma Crit Care & Emergency Med, Toronto, ON M4N 3M5, Canada. [Angus, Derek C.] Univ Penn, Lab Clin Res Invest & Syst Modeling Acute Illness, Dept Crit Care Med, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ & Res & Promot, Philadelphia, PA USA. RP Kahn, JM (reprint author), Univ Penn, Sch Med, Div Pulm Allergy & Crit Care, Philadelphia, PA 19104 USA. EM jmkahn@mail.med.upenn.edu RI Angus, Derek/E-9671-2012; OI Asch, David/0000-0002-7970-286X; Iwashyna, Theodore/0000-0002-4226-9310 FU Society of Critical Care Medicine; National Institutes of Health [K23HL082650] FX This work was funded by a research grant from the Society of Critical Care Medicine. Dr. Kahn is supported by a career development award from the National Institutes of Health (K23HL082650). NR 32 TC 33 Z9 34 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2009 VL 37 IS 7 BP 2149 EP 2154 DI 10.1097/CCM.0b013e3181a009d0 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 461DQ UT WOS:000267245200001 PM 19455025 ER PT J AU Bellani, G Messa, C Guerra, L Spagnolli, E Foti, G Patroniti, N Fumagalli, R Musch, G Fazio, F Pesenti, A AF Bellani, Giacomo Messa, Cristina Guerra, Luca Spagnolli, Ester Foti, Giuseppe Patroniti, Nicolo Fumagalli, Roberto Musch, Guido Fazio, Ferruccio Pesenti, Antonio TI Lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: A [18F]-fluoro-2-deoxy-D-glucose PET/CT study SO CRITICAL CARE MEDICINE LA English DT Article DE artificial respiration; adult respiratory distress syndrome; positron-emission tomography; mechanical ventilators; x-ray computed tomography ID POSITRON-EMISSION-TOMOGRAPHY; BLOOD-FLOW; METABOLIC-ACTIVITY; GLUCOSE-UPTAKE; NEUTROPHIL SEQUESTRATION; VASCULAR-PERMEABILITY; SKELETAL-MUSCLE; FDG-PET; INJURY; VENTILATION AB Objective: Neutrophilic inflammation plays a key role in the pathogenesis of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Positron emission tomography (PET) with [(18)F]-fluoro-2-deoxy-D-glucose ((18)FDG) can be used to image cellular metabolism that, during lung inflammatory processes, likely reflects neutrophils activity. The aim of this study was to assess the magnitude and regional distribution of inflammatory metabolic activity in the lungs of patients with ALI/ARDS by PET with (18)FDG. Design: Prospective clinical investigation. Patients. Ten patients with ALI/ARDS; four spontaneously breathing and two mechanically ventilated subjects, without known lung disease, served as controls. Interventions. In each individual we performed an (18)FDG PET/computed tomography of the thorax. Measurements and Main Results. (18)FDG cellular influx rate constant (K(i)) was computed for the imaged lung field and for regions of interest, grouping voxels with similar density. In all patients with ALI/ARDS, K(i) was higher than in controls, also after accounting for the increased lung density. K(i) values differed greatly among patients, but in all patients K(i) of the normally aerated regions was much higher (2- to 24-fold) than in controls. Whereas in some patients the highest K(i) values corresponded to regions with the lowest aeration, in others these regions had lower K(i) than normally and mildly hypoaerated regions. Conclusion: In patents with ALI/ARDS, undergoing mechanical ventilation since days, the metabolic activity of the lungs is markedly increased across the entire lung density spectrum. The intensity of this activation and its regional distribution, however, vary widely within and between patents. (Crit Care Med 2009; 37:2216-2222) C1 [Bellani, Giacomo; Spagnolli, Ester; Fumagalli, Roberto; Pesenti, Antonio] Univ Milano Bicocca, Dept Expt Med, Monza, MI, Italy. [Messa, Cristina; Fazio, Ferruccio] Univ Milano Bicocca, Ctr Bioimmagini Mol, Monza, MI, Italy. [Bellani, Giacomo; Spagnolli, Ester; Foti, Giuseppe; Patroniti, Nicolo; Fumagalli, Roberto; Pesenti, Antonio] San Gerardo Hosp, Dept Perioperat Med & Intens Care, Monza, MI, Italy. [Guerra, Luca] San Gerardo Hosp, Nucl Med Unit, Monza, MI, Italy. [Messa, Cristina; Fazio, Ferruccio] CNR, Inst Mol Bioimaging & Physiol, Milan, Italy. [Musch, Guido] Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Boston, MA USA. RP Messa, C (reprint author), Univ Milano Bicocca, Dept Expt Med, Monza, MI, Italy. EM antonio.pesenti@unimib.it RI Bellani, Giacomo/D-2379-2010; Pesenti, Antonio/H-7483-2012; Foti, Giuseppe/K-8627-2016; Patroniti, Nicolo/K-6347-2016; OI Bellani, Giacomo/0000-0002-3089-205X; Patroniti, Nicolo/0000-0003-3600-193X; foti, giuseppe/0000-0002-8698-2046 FU European Society of Intensive Care Medicine; Italian Ministry of Education, University and Research FX Supported, in part, by a grant from the European Society of Intensive Care Medicine (ECCRN Young Investigator Award 2006) and by a national grant of the Italian Ministry of Education, University and Research (FIRB 2001 and Fondo di Internazionalizzazione 2005). NR 49 TC 63 Z9 64 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2009 VL 37 IS 7 BP 2216 EP 2222 DI 10.1097/CCM.0b013e3181aab31f PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 461DQ UT WOS:000267245200012 PM 19487931 ER PT J AU Fukudome, EY Alam, HB AF Fukudome, Eugene Y. Alam, Hasan B. TI Hypothermia in multisystem trauma SO CRITICAL CARE MEDICINE LA English DT Review DE trauma; hemorrhagic shock; lethal injury; exsanguination; cardiac arrest; resuscitation; therapeutic hypothermia; emergency preservation for resuscitation; suspended animation ID UNCONTROLLED HEMORRHAGIC-SHOCK; EXSANGUINATION CARDIAC-ARREST; EMERGENCY-DEPARTMENT THORACOTOMY; SPINAL-CORD-INJURY; MILD PERIOPERATIVE HYPOTHERMIA; CONVENTIONAL RINGERS SOLUTION; SECONDARY BRAIN-INJURY; PROLONGS SURVIVAL-TIME; PROFOUND HYPOTHERMIA; SWINE MODEL AB Exsanguinating hemorrhage is a common clinical feature of multisystem trauma that results in death or severe disability. Cardiovascular collapse resulting from hemorrhage is unresponsive to conventional methods of cardiopulmonary resuscitation. Even when bleeding is controlled rapidly, adequate circulation cannot be restored in time to avoid neurologic consequences that appear after only 5 mins of cerebral ischemia and hypoperfusion. Reperfusion adds further insult to injury. A novel solution to this problem would be to institute a therapy that makes cells and organs more resistant to ischemic injury, thereby extending the time they can tolerate such an insult. Hypothermia can attenuate some effects of ischemia and reperfusion. Accumulating preclinical data demonstrate that hypothermia can be induced safely and rapidly to achieve emergency preservation for resuscitation during lethal hemorrhage. Hypothermia may be an effective therapeutic approach for otherwise lethal traumatic hemorrhage, and a clinical trial to determine its utility is warranted. (Crit Care Med 2009; 37[Suppl.]:S265-S272) C1 [Alam, Hasan B.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Alam, HB (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. EM hbalam@partners.org NR 123 TC 20 Z9 24 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2009 VL 37 IS 7 BP S265 EP S272 DI 10.1097/CCM.0b013e3181aa60ac PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 461DT UT WOS:000267245500012 PM 19535957 ER PT J AU Rosendorff, C Black, HR AF Rosendorff, Clive Black, Henry R. TI Evidence for a lower target blood pressure for people with heart disease SO CURRENT OPINION IN CARDIOLOGY LA English DT Review DE blood pressure; cardiovascular risk; coronary artery disease; hypertension ID ISOLATED SYSTOLIC HYPERTENSION; RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR OUTCOMES; ACTIVE TREATMENT; PREVENTION; ATHEROSCLEROSIS; METAANALYSIS; HYPERTROPHY; MANAGEMENT; MORTALITY AB Purpose of review The review assesses the evidence for the benefit of lower blood pressure (BP) targets in hypertension management. Recent findings The current consensus target for the treatment of hypertension is a BP of below 140/90 mmHg for all patients, and a BP of below 130/80 mmHg for those with diabetes or chronic kidney disease. Recently added to the list of conditions warranting the lower BP target are coronary artery disease and coronary artery disease equivalents (stroke, carotid disease, aortic aneurysm, and peripheral vascular disease), as well as those individuals with a Framingham Risk Score of at least 10%. One theoretical issue with lower BP targets may be the existence of a J-shaped curve of BP versus cardiovascular event rate, implying a greater risk, especially of myocardial ischemia, of lowering diastolic BP, which is also the filling pressure of the coronary arteries, below the lower limit of coronary autoregulation. The evidence that this is not a compelling concern is provided by animal studies, clinical trials with both surrogate and hard endpoints, and epidemiologic data. Summary There is at present no proof that more aggressive treatment is harmful and much indirect evidence that it may be beneficial, although the clinical trials that specifically address this question are still in progress. C1 [Rosendorff, Clive] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Rosendorff, Clive] Mt Sinai Sch Med, New York, NY USA. [Black, Henry R.] NYU, Sch Med, New York, NY USA. RP Rosendorff, C (reprint author), James J Peters VA Med Ctr, Med 111,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM clive.rosendorff@va.gov NR 24 TC 8 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-4705 J9 CURR OPIN CARDIOL JI Curr. Opin. Cardiol. PD JUL PY 2009 VL 24 IS 4 BP 318 EP 324 DI 10.1097/HCO.0b013e32832bfb48 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 461PE UT WOS:000267279500008 PM 19395951 ER PT J AU Comper, WD Russo, LM AF Comper, Wayne D. Russo, Leileata M. TI The glomerular filter: an imperfect barrier is required for perfect renal function SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE albumin retrieval pathway; albuminuria; glomerular charge; proximal tubular cell ID DIABETIC-NEPHROPATHY; FILTRATION-RATE; FRACTIONAL CLEARANCE; ALBUMIN ABSORPTION; BASEMENT-MEMBRANE; MOLECULAR-SIZE; KIDNEY; PROTEINURIA; RAT; MECHANISMS AB Purpose of review There is currently a major debate on the mechanisms of albuminuria, and this review appraises recent studies in this area. Recent findings The traditional view of albuminuria is that it is the result of damage to an essentially impermeable glomerular barrier. However, over the years, critical evidence for this traditional model has been shown to be flawed. An alternative explanation has evolved in which the glomerular filter governs albumin permeability by size selectivity alone. This means that the filter offers a significant barrier to albumin, but it is imperfect - the barrier leaks albumin. The virtue of this leakage is that it endows the filter an in-built anticlogging mechanism. The filtered albumin, if not rescued, would be excreted at nephrotic levels in the urine. There is evidence that proximal tubular cells participate in retrieving most of this filtered albumin to return it back to the blood supply intact. A small amount of the filtered albumin is not retrieved but directed toward lysosomal degradation, and the peptide products are exocytosed into the tubular lumen and excreted. Summary In acquired and chemically induced kidney disease, albuminuria is the result of dysfunction in proximal tubular cell processing of albumin rather than alterations in glomerular permeability. C1 [Comper, Wayne D.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Comper, Wayne D.] Exosome Diagnost Inc, New York, NY USA. [Russo, Leileata M.] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Russo, Leileata M.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Russo, Leileata M.] Harvard Univ, Sch Med, Boston, MA USA. RP Comper, WD (reprint author), Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. EM wcomper@hotmail.com NR 57 TC 29 Z9 30 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2009 VL 18 IS 4 BP 336 EP 342 DI 10.1097/MNH.0b013e32832cb96a PG 7 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 464JL UT WOS:000267501100012 PM 19474730 ER PT J AU Fuller, BE Loftis, JM Rodriguez, VL McQuesten, MJ Hauser, P AF Fuller, Bret E. Loftis, Jennifer M. Rodriguez, Veronica L. McQuesten, Matthew J. Hauser, Peter TI Psychiatric and substance use disorders comorbidities in veterans with hepatitis C virus and HIV coinfection SO CURRENT OPINION IN PSYCHIATRY LA English DT Article DE coinfection; hepatitis C virus; HIV ID UNITED-STATES VETERANS; SEVERE MENTAL-ILLNESS; INFECTION; CARE; PREVALENCE; METHAMPHETAMINE; PERFORMANCE; DEPRESSION; DIAGNOSIS; THERAPY AB Purpose of review A growing number of veterans in the Veterans Health Administration are coinfected with HIV and hepatitis C virus. This review covers timely research relative to comorbid conditions that are common in this population including psychiatric diagnoses, substance use disorders and neurocognitive problems. Recent findings Current literature on the psychiatric, substance use disorders and cognitive problems of the coinfected population show that not only are rates of morbidity higher in the coinfected population but that this affects antiviral treatments as well. There is new evidence that brain injuries and infiltration of the virus into the central nervous system may be responsible for cognitive dysfunction. Cotesting, particularly in hepatitis C infected individuals, is not done routinely despite shared risk factors. Summary With this understanding of the comorbidities of the coinfected population, integrated healthcare models involving mental health, internal medicine, substance abuse treatment and internal medicine are crucial to work with these medically and psychologically complex patients. C1 [Fuller, Bret E.; Hauser, Peter] Portland VA Med Ctr, Div Mental Hlth, Portland, OR 97210 USA. [Fuller, Bret E.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Loftis, Jennifer M.] VA Med Ctr, Res Serv, Portland, OR USA. [Loftis, Jennifer M.; Hauser, Peter] JENS Lab, Portland, OR USA. [Hauser, Peter] Oregon Hlth & Sci Univ, Dept Internal Med, Dept Psychiat, Portland, OR 97201 USA. RP Fuller, BE (reprint author), Portland VA Med Ctr, Div Mental Hlth, 3170 SW US Vet Pk Rd,Mailcode P3MHDC, Portland, OR 97210 USA. EM bret.fuller@va.gov NR 46 TC 9 Z9 9 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD JUL PY 2009 VL 22 IS 4 BP 401 EP 408 DI 10.1097/YCO.0b013e32832cadb9 PG 8 WC Psychiatry SC Psychiatry GA 460LT UT WOS:000267189900012 PM 19436202 ER PT J AU Friedman, ES Wisniewski, SR Gilmer, W Nierenberg, AA Rush, AJ Fava, M Zisook, S Balasubramani, GK Trivedi, MH AF Friedman, Edward S. Wisniewski, Stephen R. Gilmer, William Nierenberg, Andrew A. Rush, A. John Fava, Maurizio Zisook, Sidney Balasubramani, G. K. Trivedi, Madhukar H. TI SOCIODEMOGRAPHIC, CLINICAL, AND TREATMENT CHARACTERISTICS ASSOCIATED WITH WORSENED DEPRESSION DURING TREATMENT WITH CITALOPRAM: RESULTS OF THE NIMH STAR*D TRIAL SO DEPRESSION AND ANXIETY LA English DT Article DE citalopram; SSRI; antidepressant treatment; worsened depression; intolerance ID SEQUENCED TREATMENT ALTERNATIVES; DIAGNOSTIC SCREENING QUESTIONNAIRE; POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; ILLNESS RATING-SCALE; REPORT QIDS-SR; RELIEVE DEPRESSION; MAJOR DEPRESSION; PSYCHOMETRIC EVALUATION; SERTRALINE TREATMENT AB Context: Outcomes of antidepressant medication treatment for major depressive disorder include remission, response, and nonresponse. But nonresponse can include depression that worsened over the course of treatment, an outcome that has received scant attention. Objective: To describe baseline sociodemographic, clinical, and treatment characteristics associated with worsened depression during a trial of citalopram. Design, participants, and settings: Open-label clinical trial of 2,876 adult outpatients seen in 18 primary and 23 psychiatric-care settings. Intervention: Citalopram was delivered using measurement-based care and flexible dosing with the aim of achieving symptom remission. Symptom and side effect ratings were obtained at each treatment visit. Main outcome measures: Worsened depression was defined as an exit score ! 3 points above the pretreatment (baseline) score on the 16-item QIDS-SR. Baseline sociodemographic, clinical, and treatment characteristics were examined for association with worsened depression. Results: Of 2,864 outpatients who returned for >= 2 post baseline visits, 150 (5.2%) had worsened depression at study exit. Baseline characteristics independently associated with increased worsened depression included African-American race (OR = 2.02), having less than a college education (OR = 2.36), posttraumatic stress disorder (OR = 1.78), drug abuse (OR = 1.97), hypochondriasis (OR = 2.74). Participants with worsened depression spent less time in treatment; had fewer treatment visits; exited the study sooner; bad more frequent, intense, and burdensome adverse effects; and were more intolerant of medication. Conclusions: The presence of certain baseline characteristics indicated a greater likelibood of worsened depression during antidepressant treatment. Patients with these characteristics should be monitored closely during treatment and may be candidates for more aggressive treatment. Depression and Anxiety 26:612-621, 2009. Published 2009 Wiley-Liss, Inc. C1 [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. [Wisniewski, Stephen R.; Balasubramani, G. K.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA 15213 USA. [Gilmer, William] Northwestern Univ, Dept Psychiat, Chicago, IL 60611 USA. [Nierenberg, Andrew A.; Fava, Maurizio] Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. [Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Zisook, Sidney] Univ Calif San Diego, VA San Diego Healthcare Syst, San Diego, CA 92103 USA. [Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Div Mood Disorders, Dallas, TX 75390 USA. RP Friedman, ES (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. EM friedmane@upmc.edu OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382; Goundappa K, Balasubramani/0000-0001-7221-1825 FU National Institute of Mental Health; National Institutes of Health [N01MH90003]; NIMH [1UO1MH61562-01A2 MHT, R01MH064062-01A2 MHT] FX Contract grant sponsors: National Institute of Mental Health; National Institutes of Health; Contract grant number: N01MH90003; Contract grant sponsors: NIMH; Contract grant number: 1UO1MH61562-01A2 MHT; R01MH064062-01A2 MHT; NR 44 TC 16 Z9 17 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUL PY 2009 VL 26 IS 7 BP 612 EP 621 DI 10.1002/da.20568 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 467KQ UT WOS:000267738000004 PM 19382183 ER PT J AU Warden, D Rush, AJ Wisniewski, SR Lesser, IM Thase, ME Balasubramani, GK Shores-Wilson, K Nierenberg, AA Trivedi, MH AF Warden, Diane Rush, A. John Wisniewski, Stephen R. Lesser, Ira M. Thase, Michael E. Balasubramani, G. K. Shores-Wilson, Kathy Nierenberg, Andrew A. Trivedi, Madhukar H. TI INCOME AND ATTRITION IN THE TREATMENT OF DEPRESSION: A STAR*D REPORT SO DEPRESSION AND ANXIETY LA English DT Article DE attrition; adherence; depression; antidepressant; predictors ID SEQUENCED TREATMENT ALTERNATIVES; DIAGNOSTIC SCREENING QUESTIONNAIRE; ILLNESS RATING-SCALE; REPORT QIDS-SR; SOCIOECONOMIC-STATUS; QUICK INVENTORY; SOCIODEMOGRAPHIC PREDICTORS; ANTIDEPRESSANT TREATMENT; PSYCHOMETRIC EVALUATION; MAJOR DEPRESSION AB Background: Attrition, or dropping out of treatment, remains a major issue in the care of depressed outpatients. Whether different factors are associated with attrition for different socioeconomic groups is not known. This report assessed whether attrition rates and predictors of attrition differed among depressed outpatients with different income levels. Methods: Outpatients with non-psychotic major depressive disorder treated for up to 14 weeks with citalopram in the first step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were divided by household incomes of <$20,000, $20,000-<$40,000, and >=$40,000. Attrition rates and sociodemographic and clinical correlates of attrition were identified for each group. Results: Regardless of income level, remission rates were lower for participants who dropped out of treatment. Attrition rates increased as income decreased. For all income levels, younger age was independently associated with attrition. For the lowest income level, less education, better mental health functioning, being oil public insurance, and having more concurrent Axis I conditions were associated with a greater likelihood of attrition. For the middle income group, less education, better mental health functioning, being Black or of another non-White race, and treatment in a psychiatric versus primary-care setting predicted greater attrition. For the highest income group, being Hispanic, having a family history of drug abuse, and melancholic features predicted attrition. Atypical symptom features (middle income group) and recurrent depression (highest income group) were associated with retention. Conclusions: Efforts to retain patients in antidepressant treatment should focus especially on less educated patients with lower household incomes and younger patients. Depression and Anxiety 26:622-633, 2009. Publisbed 2009 Wiley-Liss, Inc. C1 [Warden, Diane; Rush, A. John; Shores-Wilson, Kathy; Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Rush, A. John] Duke Natl Univ Singapore, Singapore, Singapore. [Wisniewski, Stephen R.; Balasubramani, G. K.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA USA. [Lesser, Ira M.] Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst, Dept Psychiat, Torrance, CA 90509 USA. [Thase, Michael E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. RP Warden, D (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. EM Diane.Warden@UTSouthwestern.edu OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382; Goundappa K, Balasubramani/0000-0001-7221-1825 FU National Institute of Mental Health, National Institutes of Health [N01MH90003]; National Alliance for Research on Schizophrenia and Depression FX Contract/grant sponsor: National Institute of Mental Health, National Institutes of Health, contract grant number: N01MH90003; National Alliance for Research on Schizophrenia and Depression. NR 58 TC 24 Z9 25 U1 3 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUL PY 2009 VL 26 IS 7 BP 622 EP 633 DI 10.1002/da.20541 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 467KQ UT WOS:000267738000005 PM 19582825 ER PT J AU Asgari, MM Bertenthal, D Sen, S Sahay, A Chren, MM AF Asgari, Maryam M. Bertenthal, Daniel Sen, Saunak Sahay, Anju Chren, Mary-Margaret TI Patient Satisfaction After Treatment of Nonmelanoma Skin Cancer SO DERMATOLOGIC SURGERY LA English DT Article ID MOHS MICROGRAPHIC SURGERY; SQUAMOUS-CELL CARCINOMA; CARE; BASAL; MORBIDITY; VETERANS AB BACKGROUND Patient satisfaction is an important aspect of patient-centered care but has not been systematically studied after treatment of nonmelanoma skin cancer (NMSC), the most prevalent cancer. OBJECTIVE To compare patient satisfaction after treatment for NMSC and to determine factors associated with better satisfaction. METHODS We prospectively measured patient, tumor, and care characteristics in 834 consecutive patients at two centers before and after destruction, excision, and Mohs surgery. We evaluated factors associated with short-term and long-term satisfaction. RESULTS In all treatment groups, patients were more satisfied with the interpersonal manners of the staff, communication, and financial aspects of their care than with the technical quality, time with the clinician, and accessibility of their care (p<.05). Short-term satisfaction did not differ across treatment groups. In multivariable regression models adjusting for patient, tumor, and care characteristics, higher long-term satisfaction was independently associated with younger age, better pretreatment mental health and skin-related quality of life, and treatment with Mohs surgery (p<.05). CONCLUSIONS Long-term patient satisfaction after treatment of NMSC is related to pretreatment patient characteristics (mental health, skin-related quality of life) and treatment type (Mohs) but not tumor characteristics. These results can guide informed decision-making for treatment of NMSC. C1 [Chren, Mary-Margaret] Univ Calif San Francisco, San Francisco VAMC, Dept Dermatol, San Francisco, CA 94121 USA. [Asgari, Maryam M.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Bertenthal, Daniel; Sen, Saunak; Sahay, Anju; Chren, Mary-Margaret] San Francisco VA Med Ctr, Hlth Serv Res Enhancement Award Program, San Francisco, CA USA. [Sen, Saunak] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. RP Chren, MM (reprint author), Univ Calif San Francisco, San Francisco VAMC, Dept Dermatol, 4150 Clement St,151 R, San Francisco, CA 94121 USA. EM chrenm@derm.ucsf.edu RI Asgari, Maryam/O-4947-2016 FU NIAMS NIH HHS [K24 AR052667, K24 AR052667-01, K23 AR051037-03, K23 AR051037] NR 27 TC 24 Z9 24 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1076-0512 J9 DERMATOL SURG JI Dermatol. Surg. PD JUL PY 2009 VL 35 IS 7 BP 1041 EP 1049 DI 10.1111/j.1524-4725.2009.01181.x PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 466JT UT WOS:000267658700004 PM 19438672 ER PT J AU Seale, P Lazar, MA AF Seale, Patrick Lazar, Mitchell A. TI Brown Fat in Humans: Turning up the Heat on Obesity SO DIABETES LA English DT Editorial Material ID ADIPOSE-TISSUE; TRANSCRIPTIONAL CONTROL; ADULT HUMANS; THERMOGENESIS; PRDM16; MUSCLE; MICE; MEN C1 [Seale, Patrick] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Seale, Patrick] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Lazar, Mitchell A.] Univ Penn, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Lazar, Mitchell A.] Inst Diabet Obes & Metab, Philadelphia, PA USA. RP Seale, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM patrick_seale@dfci.harvard.edu; lazar@mail.med.upenn.edu FU NIDDK NIH HHS [DK-49210, DK-081605, DK-49780, K99 DK081605, P01 DK049210, R00 DK081605, R01 DK049780] NR 17 TC 54 Z9 56 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2009 VL 58 IS 7 BP 1482 EP 1484 DI 10.2337/db09-0622 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 466VF UT WOS:000267690700004 PM 19564460 ER PT J AU Estall, JL Kahn, M Cooper, MP Fisher, FM Wu, MK Laznik, D Qu, LS Cohen, DE Shulman, GI Spiegelman, BM AF Estall, Jennifer L. Kahn, Mario Cooper, Marcus P. Fisher, Ffolliott Martin Wu, Michele K. Laznik, Dina Qu, Lishu Cohen, David E. Shulman, Gerald I. Spiegelman, Bruce M. TI Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator-Activated Receptor-gamma Coactivator-1 alpha Expression SO DIABETES LA English DT Article ID COA DEHYDROGENASE-DEFICIENCY; FATTY-ACID OXIDATION; ENERGY-METABOLISM; NUCLEAR RECEPTORS; SKELETAL-MUSCLE; KNOCKOUT MICE; LIVER-DISEASE; RESISTANCE; PGC-1-ALPHA; PGC-1 AB OBJECTIVE-The peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1 alpha show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1 alpha activity affect metabolism and energy homeostasis has yet to be determined. RESEARCH DESIGN AND METHODS-To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1 alpha levels, we used the Cre/Lox system to create mice heterozygous for PGC-1 alpha specifically within the liver (LH mice). RESULTS-These mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial beta-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes. CONCLUSIONS-These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1 alpha levels, underlining the importance of tightly regulated PGC-1 alpha expression in the maintenance of lipid homeostasis and glucose metabolism. Diabetes 58:1499-1508, 2009 C1 [Estall, Jennifer L.; Cooper, Marcus P.; Laznik, Dina; Qu, Lishu; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Estall, Jennifer L.; Cooper, Marcus P.; Laznik, Dina; Qu, Lishu; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kahn, Mario; Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Kahn, Mario; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Kahn, Mario; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Fisher, Ffolliott Martin] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Endocrinol, Boston, MA 02115 USA. [Wu, Michele K.; Cohen, David E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol,Dept Med, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu FU National Research Council of Canada; National Institutes of Health [DK061562] FX J.L.E. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and the H.L. Holmes Award for Postdoctoral Studies from the National Research Council of Canada. National Institutes of Health Grant DK061562 (to B.M.S.) supported the work described in this report. NR 41 TC 62 Z9 62 U1 1 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD JUL PY 2009 VL 58 IS 7 BP 1499 EP 1508 DI 10.2337/db08-1571 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 466VF UT WOS:000267690700007 PM 19366863 ER PT J AU Prokopenko, I Zeggini, E Hanson, RL Mitchell, BD Rayner, NW Akan, P Baier, L Das, SK Elliott, KS Fu, M Frayling, TM Groves, CJ Gwilliam, R Scott, LJ Voight, BF Hattersley, AT Hu, C Morris, AD Ng, M Palmer, CNA Tello-Ruiz, M Vaxillaire, M Wang, CR Stein, L Chan, J Jia, WP Froguel, P Elbein, SC Deloukas, P Bogardus, C Shuldiner, AR McCarthy, MI AF Prokopenko, Inga Zeggini, Eleftheria Hanson, Robert L. Mitchell, Braxton D. Rayner, N. William Akan, Pelin Baier, Leslie Das, Swapan K. Elliott, Katherine S. Fu, Mao Frayling, Timothy M. Groves, Christopher J. Gwilliam, Rhian Scott, Laura J. Voight, Benjamin F. Hattersley, Andrew T. Hu, Cheng Morris, Andrew D. Ng, Maggie Palmer, Colin N. A. Tello-Ruiz, Marcela Vaxillaire, Martine Wang, Cong-rong Stein, Lincoln Chan, Juliana Jia, Weiping Froguel, Philippe Elbein, Steven C. Deloukas, Panos Bogardus, Clifton Shuldiner, Alan R. McCarthy, Mark I. CA Int Type 2 Diabet 1q Consortium TI Linkage Disequilibrium Mapping of the Replicated Type 2 Diabetes Linkage Signal on Chromosome 1q SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; NUCLEAR FACTOR-4-ALPHA GENE; GK RAT; SUSCEPTIBILITY; LOCI; VARIANTS; RISK; POPULATION; DISEASES; SAMPLES AB OBJECTIVE-Linkage of the chromosome 1q21-25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal. RESEARCH DESIGN AND METHODS-In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate similar to 80% coverage of common variation across the region (r(2) > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in similar to 8,500 case subjects and 12,400 control subjects. RESULTS-Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21-1.571, P = 1.4 x 10(-6), in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18-1.761, P = 1.0 x 10(-5), under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status. CONCLUSIONS-Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance. Diabetes 58:1704-1709, 2009 C1 [Prokopenko, Inga; Zeggini, Eleftheria; Rayner, N. William; Elliott, Katherine S.; Groves, Christopher J.; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Prokopenko, Inga; Rayner, N. William; Groves, Christopher J.; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Zeggini, Eleftheria; Akan, Pelin; Gwilliam, Rhian; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Hanson, Robert L.; Baier, Leslie; Bogardus, Clifton] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Mitchell, Braxton D.; Fu, Mao; Shuldiner, Alan R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Das, Swapan K.; Elbein, Steven C.] Cent Arkansas Vet Healthcare Syst, Endocrinol Sect, Med Serv, Little Rock, AR USA. [Das, Swapan K.] Univ Arkansas Med Sci, Div Endocrinol & Metab, Dept Internal Med, Coll Med, Little Rock, AR 72205 USA. [Frayling, Timothy M.; Hattersley, Andrew T.] Peninsula Med Sch, Inst Clin & Biomed Sci, Exeter, Devon, England. [Scott, Laura J.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Scott, Laura J.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Voight, Benjamin F.] Broad Inst Harvard, Cambridge, MA USA. [Voight, Benjamin F.] MIT, Cambridge, MA 02139 USA. [Voight, Benjamin F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Voight, Benjamin F.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Voight, Benjamin F.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hu, Cheng; Wang, Cong-rong; Jia, Weiping] Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Dept Endocrinol & Metab, Peoples Hosp 6, Shanghai 200030, Peoples R China. [Morris, Andrew D.] Univ Dundee, Diabet Res Grp, Biomed Res Inst, Dundee, Scotland. [Ng, Maggie; Chan, Juliana] Chinese Univ Hong Kong, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland. [Tello-Ruiz, Marcela; Stein, Lincoln] Cold Spring Harbor Lab, New York, NY USA. [Vaxillaire, Martine; Froguel, Philippe] Univ Lille 2, CNRS, Inst Biol, UMR 8090, Lille, France. [Vaxillaire, Martine; Froguel, Philippe] Univ Lille 2, Inst Pasteur, Lille, France. [Stein, Lincoln] Ontario Inst Canc Res, Toronto, ON, Canada. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7LJ, England. RP McCarthy, MI (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM mark.mccarthy@drl.ox.ac.uk RI Study, GoDARTS/K-9448-2016; Hu, Cheng/C-3346-2008; Palmer, Colin/C-7053-2008; Morris, Andrew/C-2837-2009; Voight, Benjamin/F-1775-2011; Hossain, Sarah /C-7332-2009; Jia, Weiping/B-7483-2012; Deloukas, Panos/B-2922-2013; Hanson, Robert/O-3238-2015; Prokopenko, Inga/H-3241-2014; Chan, Juliana /B-7918-2016; OI Palmer, Colin/0000-0002-6415-6560; Hossain, Sarah /0000-0003-1355-0979; Deloukas, Panos/0000-0001-9251-070X; Hanson, Robert/0000-0002-4252-7068; Prokopenko, Inga/0000-0003-1624-7457; Chan, Juliana /0000-0003-1325-1194; Zeggini, Eleftheria/0000-0003-4238-659X; Mitchell, Braxton/0000-0003-4920-4744 FU Intramural NIH HHS; Medical Research Council [G0601201(79675), G0600331, G0601201, G0601261]; NCI NIH HHS [K07-CA67960]; NCRR NIH HHS [M01 RR014288, M01 RR14288]; NIA NIH HHS [T32 AG000219, T32-AG00219]; NIDDK NIH HHS [K24-DK02673, P30 DK079637, R01 DK039311, R01 DK054261, R01 DK073490, R01-DK073490, R01-DK39311, R01-DK54261, U01 DK058026, U01-DK58026]; Wellcome Trust [072960, 077011, 079557, 088885, GR072960] NR 24 TC 18 Z9 20 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2009 VL 58 IS 7 BP 1704 EP 1709 DI 10.2337/db09-0081 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 466VF UT WOS:000267690700032 PM 19389826 ER PT J AU Meigs, JB AF Meigs, James B. TI Multiple Biomarker Prediction of Type 2 Diabetes SO DIABETES CARE LA English DT Editorial Material ID METABOLIC SYNDROME; GLUCOSE-TOLERANCE; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; MELLITUS; MARKERS; METAANALYSIS; ADIPONECTIN; COMMUNITIES C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA 02115 USA. RP Meigs, JB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA 02115 USA. EM jmeigs@partners.org FU NIDDK NIH HHS [K24 DK080140] NR 25 TC 14 Z9 14 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2009 VL 32 IS 7 BP 1346 EP 1348 DI 10.2337/dc09-0754 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 469EK UT WOS:000267878300044 PM 19564478 ER PT J AU Zrebiec, J AF Zrebiec, John TI A National Study of the Diabetes Educator Report on a Practice Analysis Conducted by the National Certification Board for Diabetes Educators SO DIABETES EDUCATOR LA English DT Article AB Purpose The practice analysis described in this report was conducted by the National Certification Board for Diabetes Educators (NCBDE) to (1) provide a basis for documenting the continuing validity of the Certification Examination for Diabetes Educators, (2) define new areas that should be assessed in future certification examinations, and (3) ensure that the content of certification examinations is related to practice. Methods The study involved developing a diabetes educator job task list and survey, distributing 4103 surveys, and analyzing survey responses from a multidisciplinary and geographically representative sample of certified diabetes educators. Results Eight hundred thirty-six surveys were suitable for analysis, with relevant demographic subgroups adequately represented. Based on survey data, an examination matrix and detailed content outline was constructed that will be used by NCBDE to assemble future test forms. Conclusions Certification examination specifications were developed directly related to the important activities that diabetes educators perform. Future forms of the certification examination will continue to be matched to job-related, criterion-referenced test specifications and will have strong evidence of content validity. Future forms of the exam will contain 200 items at specified cognitive levels with a representative sampling of tasks within 3 core areas from the detailed content outline. C1 [Zrebiec, John] Natl Certificat Board Diabet Educators, Arlington Hts, IL USA. RP Zrebiec, J (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM zrebiec@joslin.harvard.edu FU National Certification Board for Diabetes Educators FX NCBDE appreciated the psychometric expertise of Steven Nettles, EdD, and Christopher Traynor, MS, from Applied Measurement Professionals, Inc., and the managerial skill of Joyce Bohren, retired CEO of NCBDE. In particular, NCBDE is grateful to the members of the Practice Analysis Advisory Committee for contributing their time and sharing their professional experience while guiding this complex project. The committee included Stephen Ponder, MD, CDE, Co-Chairperson; Joni Beck, PharmD, BC-ADM, CDE; Karen Bolderman, RD, LDN, CDE; Renea Bradley, RN, CDE; Ned Crockett, MD, CDE; Marjorie Cypress, PhD, C-ANP, CDE; Wendy Kushion, MSN, APRN-BC, CDE; Sandy Muchnick, MEd, CDE; Claudia Shwide-Slavin, MS, RD, BC-ADM, CDE; Phyllis Secraw, RN, CDE; Carrie Swift, MS, RD, BC-ADM, CDE. Funding was provided by the National Certification Board for Diabetes Educators. NR 3 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 J9 DIABETES EDUCATOR JI Diabetes Educ. PD JUL PY 2009 VL 35 IS 4 BP 657 EP 663 DI 10.1177/0145721709336300 PG 7 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA 474TK UT WOS:000268306800011 PM 19448043 ER PT J AU Cadena, J Thompson, GR Ho, TT Medina, E Hughes, DW Patterson, TF AF Cadena, Jose Thompson, George R., III Ho, Tony T. Medina, Edward Hughes, Darrel W. Patterson, Thomas F. TI Immune reconstitution inflammatory syndrome after cessation of the tumor necrosis factor alpha blocker adalimumab in cryptococcal pneumonia SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article DE Cryptococcus; TNF-alpha inhibitors; Adalimumab; Immune reconstitution ID PARADOXICAL RESPONSE; THERAPY; TUBERCULOSIS AB Tumor necrosis factor a antagonists have proven efficacious for a variety of autoimmune-mediated diseases. However, recent data have highlighted the risk of invasive fungal infections with their use. These agents are typically discontinued when infectious complications occur during therapy; however, the immune reconstitution inflammatory syndrome (IRIS) tray be seen after drug cessation. We describe the 1st case of IRIS secondary to cryptococcal pneumonia after cessation of adalimumab. Published by Elsevier Inc. C1 [Cadena, Jose; Thompson, George R., III; Ho, Tony T.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, Dept Med, San Antonio, TX 78229 USA. [Medina, Edward] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Cadena, Jose; Thompson, George R., III; Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Hughes, Darrel W.] Univ Hlth Syst, Dept Pharm, San Antonio, TX 78229 USA. RP Thompson, GR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, Dept Med, San Antonio, TX 78229 USA. EM thompsong2@uthscsa.edu NR 11 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0732-8893 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD JUL PY 2009 VL 64 IS 3 BP 327 EP 330 DI 10.1016/j.diagmicrobio.2009.03.019 PG 4 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 461OL UT WOS:000267277300014 PM 19501793 ER PT J AU Vincent, RK Odorico, JS AF Vincent, Robert K. Odorico, Jon S. TI Reduced serum concentration is permissive for increased in vitro endocrine differentiation from murine embryonic stem cells SO DIFFERENTIATION LA English DT Article DE Embryonic stem cells; Endocrine differentiation; Fetal calf serum; Serum replacement; Pancreatic duodenal homeobox 1; Neurogenin 3; Tetracycline-inducible ID INSULIN-PRODUCING CELLS; PANCREATIC BETA-CELLS; DIRECTED DIFFERENTIATION; ISLET DIFFERENTIATION; TARGETED EXPRESSION; GENE-TRANSCRIPTION; EXOCRINE PANCREAS; PROGENITORS; MAFA; PDX-1 AB Embryonic stem cells (ESCs) have been shown to be capable of differentiating into pancreatic progenitors and insulin-producing cells in vitro. However, before ESC derivatives can be used in clinical settings, efficient selective differentiation needs to be achieved. Essential to improving ESC differentiation to islet endocrine cells is an understanding of the influences of extrinsic signals and transcription factors on cell specification. Herein, we investigate the influence of serum-supplemented growth conditions on the differentiation of murine ESCs to endocrine lineages in the context of over-expression of two pancreatic transcription factors, Pdx1 and Ngn3. To study the effect of different serum formulations and concentrations on the ability of murine ESCs to differentiate into endocrine cells in vitro, cells were grown into embryoid bodies and then differentiated in various serum replacement (SR), fetal calf serum (FCS) and serum-free conditions. Using immunohistochemistry and quantitative real-time RT-PCR (QPCR), we found that, of the conditions tested, 1% SR differentiation medium resulted in the highest levels of insulin-1 mRNA and significantly increased the total number of insulin-expressing cells. Applying this knowledge to cell lines in which Pdx1 or Ngn3 transgene expression could be induced by exposure to doxycycline we differentiated TetPDX1 and TetNgn3 ESCs under conditions of either 10% FCS or 1% SR medium. In the presence of 10% serum, induced expression of either Pdx1 or Ngn3 in differentiating ESCs resulted in modest increases in hormone transcripts and cell counts. However, changing the serum formulation from 10% FCS to 1% SR significantly enhanced the number of insulin+/C-peptide+ cells in parallel with increased insulin-1 transcript levels in both inducible cell lines. In summary, these data demonstrate that induced expression of key pancreatic transcription factors in combination with low serum/SR concentrations increases endocrine cell differentiation from murine ESCs. (C) 2009 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved. C1 [Vincent, Robert K.; Odorico, Jon S.] Univ Wisconsin, Sch Med & Publ Hlth, Div Transplantat, Dept Surg, Madison, WI 53792 USA. [Vincent, Robert K.; Odorico, Jon S.] WiCell Res Inst, Madison, WI 53792 USA. [Vincent, Robert K.; Odorico, Jon S.] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. RP Odorico, JS (reprint author), Univ Wisconsin Hosp, Dept Surg, Div Transplantat, H4-756 Clin Sci Ctr,600 Highland Ave, Madison, WI 53792 USA. EM jon@surgery.wisc.edu NR 59 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 J9 DIFFERENTIATION JI Differentiation PD JUL PY 2009 VL 78 IS 1 BP 24 EP 34 DI 10.1016/j.diff.2009.03.006 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 555RP UT WOS:000274532000003 PM 19446949 ER PT J AU Yermilov, I Jain, S Sekeris, E Bentrem, DJ Hines, OJ Reber, HA Ko, CY Tomlinson, JS AF Yermilov, Irina Jain, Sushma Sekeris, Evan Bentrem, David J. Hines, Oscar J. Reber, Howard A. Ko, Clifford Y. Tomlinson, James S. TI Utilization of Parenteral Nutrition Following Pancreaticoduodenectomy: Is Routine Jejunostomy Tube Placement Warranted? SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Pancreaticoduodenectomy; Parenteral nutrition; Enterostomy tube; Postoperative nutrition ID SINGLE-INSTITUTION EXPERIENCE; PANCREATIC-CANCER; MORBIDITY; MORTALITY; RESECTION; LENGTH; TRIAL; COSTS AB Introduction Complications following pancreaticoduodenectomy (PD) often necessitate nutritional support. This study analyzes the utilization of parenteral nutrition (TPN) during the surgical admission as evidence for or against routine jejunostomy placement. Methods The California Cancer Registry (1994-2003) was linked to the California Inpatient File; PD for adenocarcinoma was performed in 1,873 patients. TPN use and enterostomy tube placement were determined and preoperative characteristics predictive of TPN use during the surgical admission were identified. Results Fourteen percent of patients received TPN, 23% underwent enterostomy tube placement, and 63% received no supplemental nutritional support. TPN was associated with longer hospital stay (18 vs. 13 days, P < 0.0001). The Charlson Comorbidity Index (CCI) a parts per thousand yen 3 had nearly two-fold greater odds of receiving TPN (odds ratio [OR] = 1.85, P < 0.005). Conclusion Approximately 1 in 6 patients undergoing PD received TPN, which was associated with prolonged hospital stay. CCI a parts per thousand yen 3 was associated with increased odds of TPN utilization. Selected jejunostomy placement in patients with high CCI is worthy of consideration. C1 [Yermilov, Irina; Ko, Clifford Y.; Tomlinson, James S.] VA Greater Angeles Healthcare Syst, Dept Surg, Los Angeles, CA 90073 USA. [Yermilov, Irina; Jain, Sushma; Sekeris, Evan; Hines, Oscar J.; Reber, Howard A.; Ko, Clifford Y.; Tomlinson, James S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Bentrem, David J.] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Hines, Oscar J.; Reber, Howard A.; Tomlinson, James S.] Univ Calif Los Angeles, Ctr Pancreat Dis, Los Angeles, CA USA. RP Tomlinson, JS (reprint author), VA Greater Angeles Healthcare Syst, Dept Surg, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM James.Tomlinson@va.gov NR 24 TC 13 Z9 16 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUL PY 2009 VL 54 IS 7 BP 1582 EP 1588 DI 10.1007/s10620-008-0526-1 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 454AV UT WOS:000266654900030 PM 18958617 ER PT J AU Iezzoni, LI AF Iezzoni, Lisa I. TI Public Health Goals for Persons With Disabilities: Looking Ahead to 2020 SO DISABILITY AND HEALTH JOURNAL LA English DT Editorial Material DE disability; public health; Healthy People ID DISPARITIES AB Much of this article first appeared as testimony of Dr. Iezzoni before the U.S. Senate Health, Education, Labor, and Pensions Committee, Washington, DC, January 27, 2009. Dr. Iezzoni serves on the Secretary's Advisory Committee on National Health Promotion and Disease Prevention Objectives for 2020. This article represents her personal views and not the views of the committee. (C) 2009 Elsevier Inc. All rights reserved. C1 [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. EM liezzoni@partners.org NR 16 TC 16 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 J9 DISABIL HEALTH J JI Disabil. Health J. PD JUL PY 2009 VL 2 IS 3 BP 111 EP 115 DI 10.1016/j.dhjo.2009.03.002 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA 668QM UT WOS:000283284700001 PM 21122749 ER PT J AU Kahn, R Biswas, K Childress, AR Shoptaw, S Fudala, PJ Gorgon, L Montoya, I Collins, J McSherry, F Li, SH Chiang, N Alathari, H Watson, D Liberto, J Beresford, T Stock, C Wallace, C Gruber, V Elkashef, A AF Kahn, Roberta Biswas, Kousick Childress, Anna-Rose Shoptaw, Steve Fudala, Paul J. Gorgon, Liza Montoya, Ivan Collins, Joseph McSherry, Frances Li, Shou-Hua Chiang, Nora Alathari, Husam Watson, Donnie Liberto, Joseph Beresford, Thomas Stock, Christopher Wallace, Christopher Gruber, Valerie Elkashef, Ahmed TI Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cocaine; Dependence; Baclofen ID RECEPTOR AGONISTS BACLOFEN; LONGITUDINAL DATA-ANALYSIS; HIGH-DOSE BACLOFEN; GABA(B) RECEPTOR; ALCOHOL-DEPENDENCE; SEEKING BEHAVIOR; RATS; SYMPTOMS; NICOTINE; REINSTATEMENT AB Background: Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABA(B) receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) vs placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary Outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60 mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Kahn, Roberta; Gorgon, Liza; Montoya, Ivan; Li, Shou-Hua; Chiang, Nora; Elkashef, Ahmed] NIDA, DPMCDA, Bethesda, MD 20892 USA. [Biswas, Kousick; Collins, Joseph; McSherry, Frances] Cooperat Studies Program Coordinating Ctr 151E, DVA, Perry Point, MD 21902 USA. [Fudala, Paul J.] Reckitt Benckiser Pharmaceut Inc, Richmond, VA 23235 USA. [Shoptaw, Steve; Watson, Donnie] Friends Res Inst Inc, Los Angeles, CA USA. [Childress, Anna-Rose] Univ Penn, Sch Med, Dept Psychiat, Addict Treatment Res Ctr, Philadelphia, PA 19104 USA. [Alathari, Husam] Inova Ctr Addict Treatment Serv, Falls Church, VA 22042 USA. [Watson, Donnie] Univ Calif Los Angeles, Integrated Substance Abuse Program, Torrance, CA 90502 USA. [Liberto, Joseph] VA Maryland Hlth Care Syst MH 116, Baltimore, MD 21201 USA. [Beresford, Thomas] Eastern Colorado Vet Affairs Healthcare Syst, Psychiat Serv 116, Denver, CO 80220 USA. [Stock, Christopher] Vet Affairs Salt Lake City Healthcare Syst, Salt Lake City, UT 84148 USA. [Wallace, Christopher] S Texas Vet Healthcare Syst, Vet Affairs Med Ctr Psychiat Serv 116A, San Antonio, TX 78229 USA. [Gruber, Valerie] San Francisco Gen Hosp, San Francisco, CA 94110 USA. RP Kahn, R (reprint author), NIDA, DPMCDA, 6001 Execut Blvd,Rm 4123,MSC 9551, Bethesda, MD 20892 USA. EM rkan@nida.nih.gov FU National Institute on Drug Abuse [Y1-DA4006] FX This study was Supported by the National Institute on Drug Abuse through the Department of Veterans Affairs Cooperative Studies Program (Interagency Agreement No. Y1-DA4006). NR 35 TC 42 Z9 42 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2009 VL 103 IS 1-2 BP 59 EP 64 DI 10.1016/j.drugalcdep.2009.03.011 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 455LG UT WOS:000266760700009 PM 19414226 ER PT J AU Russom, A Irimia, D Toner, M AF Russom, Aman Irimia, Daniel Toner, Mehmet TI Chemical gradient-mediated melting curve analysis for genotyping of SNPs SO ELECTROPHORESIS LA English DT Article DE Chemical gradient; Formamide; Melting curve analysis; SNP; Urea ID SINGLE-NUCLEOTIDE POLYMORPHISMS; ALLELE-SPECIFIC HYBRIDIZATION; FLOW-THROUGH DEVICE; MONOLAYERED BEADS; DNA HYBRIDIZATION; LOW-TEMPERATURE; REAL-TIME; ARRAYS; UREA; FORMAMIDE AB This report describes a microfluidic solid-phase chemical gradient-mediated melting curve analysis method for SNP analysis. The method is based on allele-specific denaturation to discriminate mismatched (MM) from perfectly matched (PM) DNA duplexes upon exposure to linear chemical gradient. PM and MM DNA duplexes conjugated on beads are captured in a microfluidic gradient generator device designed with dams, keeping the beads trapped perpendicular to a gradient generating channel. Two denaturants, formamide and urea, were tested for their ability to destabilize the DNA duplex by competing with Watson-Crick pairing. Upon exposure to the chemical gradient, rapid denaturing profile was monitored in real time using fluorescence microscopy. The results show that the two duplexes exhibit different kinetics of denaturation profiles, enabling discrimination of MM from PM DNA duplexes to score SNP. C1 [Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA USA. RP Toner, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. EM mtoner@hms.harvard.edu RI Russom, Aman/B-1675-2012; OI Irimia, Daniel/0000-0001-7347-2082; Russom, Aman/0000-0002-0242-358X FU National Institute of Health BioMEMS Resource Center [P41 grant, P41 EB-002503] FX This work was supported by the National Institute of Health BioMEMS Resource Center (P41 grant, P41 EB-002503). The authors thank Octavio Hurtado and White Will for assistance. NR 38 TC 4 Z9 4 U1 0 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUL PY 2009 VL 30 IS 14 BP 2536 EP 2543 DI 10.1002/elps.200800729 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 484JV UT WOS:000269041500017 PM 19593749 ER PT J AU Miller, SJ Jessen, WJ Mehta, T Hardiman, A Sites, E Kaiser, S Jegga, AG Li, H Upadhyaya, M Giovannini, M Muir, D Wallace, MR Lopez, E Serra, E Nielsen, GP Lazaro, C Stemmer-Rachamimov, A Page, G Aronow, BJ Ratner, N AF Miller, Shyra J. Jessen, Walter J. Mehta, Tapan Hardiman, Atira Sites, Emily Kaiser, Sergio Jegga, Anil G. Li, Hua Upadhyaya, Meena Giovannini, Marco Muir, David Wallace, Margaret R. Lopez, Eva Serra, Eduard Nielsen, G. Petur Lazaro, Conxi Stemmer-Rachamimov, Anat Page, Grier Aronow, Bruce J. Ratner, Nancy TI Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene SO EMBO MOLECULAR MEDICINE LA English DT Article DE MPNST; neurofibroma; NF1; Schwann cell; Sox9 ID NERVE SHEATH TUMORS; TRANSCRIPTION FACTOR SOX10; CREST STEM-CELLS; SCHWANN-CELLS; DERMAL NEUROFIBROMAS; NF1 MUTATION; GLIAL-CELLS; EXPRESSION; PROTEIN; IDENTIFICATION AB Understanding the biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumours is essential, as there is a lack of tumour biomarkers, prognostic factors and therapeutics. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n - 10), NF1-derived primary benign neurofibroma Schwann cells (NFSCs) (n = 22), malignant peripheral nerve sheath tumour (MPNST) cell lines (n = 13), benign neurofibromas (NF) (n = 26) and MPNST (n = 6). Dermal and plexiform NFs were indistinguishable. A prominent theme in the analysis was aberrant differentiation. NFs repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes up-regulated in sarcomas were significantly enriched for genes activated in neural crest cells. We validated the differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in NF and MPSNT tissue sections and targeting SOX9 - strongly expressed in NF1-related tumours - caused MPNST cell death. SOX9 is a biomarker of NF and MPNST, and possibly a therapeutic target in NF1. C1 [Miller, Shyra J.; Hardiman, Atira; Sites, Emily; Ratner, Nancy] Univ Cincinnati, Coll Med, Div Expt Hematol, Cincinnati, OH 45221 USA. [Miller, Shyra J.; Hardiman, Atira; Sites, Emily; Ratner, Nancy] Univ Cincinnati, Coll Med, Div Canc Biol, Cincinnati Childrens Hosp, Cincinnati, OH USA. [Jessen, Walter J.; Kaiser, Sergio; Jegga, Anil G.; Aronow, Bruce J.] Univ Cincinnati, Coll Med, Div Biomed Informat, Cincinnati Childrens Hosp,Res Fdn, Cincinnati, OH USA. [Mehta, Tapan; Page, Grier] Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. [Li, Hua; Wallace, Margaret R.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Upadhyaya, Meena] Univ Wales Coll Cardiff, Coll Med, Inst Med Genet, Cardiff CF1 3NS, S Glam, Wales. [Giovannini, Marco] Fdn Jean Dausset CEPH, INSERM, U434, Paris, France. [Muir, David] Univ Florida, Dept Pediat, Gainesville, FL USA. [Muir, David] Univ Florida, Dept Neurosci, Gainesville, FL 32610 USA. [Lopez, Eva; Serra, Eduard] Inst Catala Oncol, Ctr Genet Med & Mol, Barcelona, Spain. [Lopez, Eva; Serra, Eduard; Lazaro, Conxi] IDIBELL, Barcelona, Spain. [Lazaro, Conxi] Inst Catala Oncol, Lab Recerca Translac, Barcelona, Spain. [Nielsen, G. Petur; Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Nielsen, G. Petur; Stemmer-Rachamimov, Anat] Harvard Univ, Sch Med, Boston, MA USA. RP Ratner, N (reprint author), Univ Cincinnati, Coll Med, Div Expt Hematol, Cincinnati, OH 45221 USA. EM nancy.ratner@cchmc.org RI Serra, Eduard/K-1332-2013; OI Serra, Eduard/0000-0003-2895-9857; Jegga, Anil/0000-0002-4881-7752; Jessen, Walter/0000-0003-3840-4337 FU DAMD [DOD W81XWH-04-1-0273]; Hayward Foundation; NINDS [K01-NS049191]; [T32 CA 59268] FX We gratefully acknowledge Dr Patrick Wood of the Miami Project to Cure Paralysis for providing human Schwann cells obtained from the cauda equina of organ donors. The cauda equine were provided by the University of Miami Life Alliance Organ Procurement Agency (Dr David Levi, Director). Cincinnati Children's Hospital Affymetrix GeneChip Core (Dr Steve Potter, Sean Smith and Hung-Chi Liang) performed microarray hybridization. We thank Drs Larry Gelbert (Eli Lilly) and Chris Roberts (Rosetta) for extensive input into the development and progress of the NF1 microarray consortium. This study was supported by the DAMD (DOD W81XWH-04-1-0273). MRW was supported by the Hayward Foundation. SM was the recipient of NINDS Translational Neuroscience Award K01-NS049191 and ES was supported by T32 CA 59268. NR 52 TC 52 Z9 52 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-4676 J9 EMBO MOL MED JI EMBO Mol. Med. PD JUL PY 2009 VL 1 IS 4 BP 236 EP 248 DI 10.1002/emmm.200900027 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 543GY UT WOS:000273563200007 PM 20049725 ER PT J AU Loyola, A Tagami, H Bonaldi, T Roche, D Quivy, JP Imhof, A Nakatani, Y Dent, SYR Almouzni, G AF Loyola, Alejandra Tagami, Hideaki Bonaldi, Tiziana Roche, Daniele Quivy, Jean Pierre Imhof, Axel Nakatani, Yoshihiro Dent, Sharon Y. R. Almouzni, Genevieve TI The HP1 alpha-CAF1-SetDB1-containing complex provides H3K9me1 for Suv39-mediated K9me3 in pericentric heterochromatin SO EMBO REPORTS LA English DT Article DE CAF1; H3K9 methylation; HP1 alpha; pericentric heterochromatin; SetDB1 ID ZINC-FINGER PROTEINS; HISTONE H3; DROSOPHILA SU(VAR)3-9; DNA-REPLICATION; HP1; METHYLTRANSFERASE; METHYLATION; LYSINE-9; PROGRESSION; REPRESSION AB Trimethylation of lysine 9 in histone H3 (H3K9me3) enrichment is a characteristic of pericentric heterochromatin. The hypothesis of a stepwise mechanism to establish and maintain this mark during DNA replication suggests that newly synthesized histone H3 goes through an intermediate methylation state to become a substrate for the histone methyltransferase Suppressor of variegation 39 (Suv39H1/H2). How this intermediate methylation state is achieved and how it is targeted to the correct place at the right time is not yet known. Here, we show that the histone H3K9 methyltransferase SetDB1 associates with the specific heterochromatin protein 1 alpha (HP1 alpha)-chromatin assembly factor 1 (CAF1) chaperone complex. This complex monomethylates K9 on non-nucleosomal histone H3. Therefore, the heterochromatic HP1 alpha-CAF1-SetDB1 complex probably provides H3K9me1 for subsequent trimethylation by Suv39H1/H2 in pericentric regions. The connection of CAF1 with DNA replication, HP1 alpha with heterochromatin formation and SetDB1 for H3K9me1 suggests a highly coordinated mechanism to ensure the propagation of H3K9me3 in pericentric heterochromatin during DNA replication. C1 [Loyola, Alejandra; Roche, Daniele; Quivy, Jean Pierre; Almouzni, Genevieve] Inst Curie, UPMC, CNRS, UMR218, F-75248 Paris 05, France. [Loyola, Alejandra] Fdn Ciencia Vida, Santiago, Chile. [Loyola, Alejandra] Univ San Sebastian, Santiago, Chile. [Loyola, Alejandra; Dent, Sharon Y. R.] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Unit 1000, Houston, TX 77030 USA. [Tagami, Hideaki; Nakatani, Yoshihiro] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Tagami, Hideaki; Nakatani, Yoshihiro] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bonaldi, Tiziana] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy. [Imhof, Axel] Histone Modificat Grp, D-80336 Munich, Germany. [Imhof, Axel] Munich Ctr Integrated Prot Sci, D-80336 Munich, Germany. RP Almouzni, G (reprint author), Inst Curie, UPMC, CNRS, UMR218, 26 Rue Ulm, F-75248 Paris 05, France. EM genevieve.almouzni@curie.fr RI Bonaldi, Tiziana/K-5075-2016 OI Bonaldi, Tiziana/0000-0003-3556-1265 FU Odyssey Scholarship; CONICYT [CCTE-PFB16] FX A. L. is supported by an Odyssey Scholarship and CONICYT Program CCTE-PFB16. NR 22 TC 95 Z9 97 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD JUL PY 2009 VL 10 IS 7 BP 769 EP 775 DI 10.1038/embor.2009.90 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 465PQ UT WOS:000267599700021 PM 19498464 ER PT J AU Khan, AA Bilezikian, JP Potts, JT AF Khan, Aliya A. Bilezikian, John P. Potts, John T., Jr. TI ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM: A COMMENTARY ON THE REVISED GUIDELINES SO ENDOCRINE PRACTICE LA English DT Editorial Material ID 3RD INTERNATIONAL WORKSHOP; MILD PRIMARY HYPERPARATHYROIDISM; CLINICAL-TRIAL; SURGERY; MANAGEMENT; DIAGNOSIS C1 [Bilezikian, John P.] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Khan, Aliya A.] McMaster Univ, Div Endocrinol, Hamilton, ON, Canada. [Khan, Aliya A.] McMaster Univ, Div Geriatr, Hamilton, ON, Canada. [Potts, John T., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Bilezikian, JP (reprint author), Columbia Univ, Coll Phys & Surg, Dept Med, 630 W 168th St,Ph 8 W 864, New York, NY 10032 USA. EM jpb2@columbia.edu FU NIDDK NIH HHS [R01 DK032333-26, R01 DK032333, R01 DK032333-27] NR 22 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC CLIN ENDOCRINOL PI JACKSONVILLE PA 1000 RIVERSIDE AVE, STE 205, JACKSONVILLE, FL 32204 USA SN 1530-891X J9 ENDOCR PRACT JI Endocr. Pract. PD JUL-AUG PY 2009 VL 15 IS 5 BP 494 EP 498 DI 10.4158/EP09162.CO PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 482XJ UT WOS:000268923600014 PM 19546049 ER PT J AU Barnwell, LFS Lugo, JN Lee, WL Willis, SE Gertz, SJ Hrachovy, RA Anderson, AE AF Barnwell, L. Forbes S. Lugo, Joaquin N. Lee, Wai L. Willis, Sarah E. Gertz, Shira J. Hrachovy, Richard A. Anderson, Anne E. TI Kv4.2 knockout mice demonstrate increased susceptibility to convulsant stimulation SO EPILEPSIA LA English DT Article DE A-type K channel; Channelopathies; Seizures; Status epilepticus; Mouse ID CA1 PYRAMIDAL NEURONS; POTASSIUM CHANNEL GENE; RAT HIPPOCAMPAL SLICE; EPILEPTIFORM ACTIVITY; DOWN-REGULATION; HUMAN EPILEPSY; K+ CURRENT; CURRENTS; SEIZURE; REPOLARIZATION AB P>Purpose: Kv4.2 subunits contribute to the pore-forming region of channels that express a transient, A-type K(+) current (A-current) in hippocampal CA1 pyramidal cell dendrites. Here, the A-current plays an important role in signal processing and synaptic integration. Kv4.2 knockout mice show a near elimination of the A-current in area CA1 dendrites, producing increased excitability in this region. In these studies, we evaluated young adult Kv4.2 knockout mice for spontaneous seizures and the response to convulsant stimulation in the whole animal in vivo and in hippocampal slices in vitro. Methods: Electroencephalogram electrode-implanted Kv4.2 knockout and wild-type mice were observed for spontaneous behavioral and electrographic seizures. The latency to seizure and status epilepticus onset in Kv4.2 knockout and wild-type mice was assessed following intraperitoneal injection of kainate. Extracellular field potential recordings were performed in hippocampal slices from Kv4.2 knockout and wild-type mice following the bath application of bicuculline. Results: No spontaneous behavioral or electrographic seizures were observed in Kv4.2 knockout mice. Following kainate, Kv4.2 knockout mice demonstrated a decreased seizure and status epilepticus latency as well as increased mortality compared to wild-type littermates. The background strain modified the seizure susceptibility phenotype in Kv4.2 knockout mice. In response to bicuculline, slices from Kv4.2 knockout mice exhibited an increase in epileptiform bursting in area CA1 as compared to wild-type littermates. Discussion: These studies show that loss of Kv4.2 channels is associated with enhanced susceptibility to convulsant stimulation, supporting the concept that Kv4.2 deficiency may contribute to aberrant network excitability and regulate seizure threshold. C1 [Anderson, Anne E.] Baylor Coll Med, Feigin Ctr 955, Dept Neurol, Houston, TX 77030 USA. [Lugo, Joaquin N.; Lee, Wai L.; Anderson, Anne E.] Baylor Coll Med, Dept Pediat, Neurol Sect, Cain Fdn Labs, Houston, TX 77030 USA. [Gertz, Shira J.] Baylor Coll Med, Dept Pediat, Sect Pediat Crit Care Med, Houston, TX 77030 USA. [Anderson, Anne E.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Hrachovy, Richard A.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Anderson, AE (reprint author), Baylor Coll Med, Feigin Ctr 955, Dept Neurol, 1102 Bates St,MC 3-6365, Houston, TX 77030 USA. EM annea@bcm.tmc.edu FU NIH/NINDS [NS049427, NS039943, K01-NS046328, F32NS056664]; Epilepsy Foundation Postdoctoral Fellowship; Partnership for Pediatric Research in Epilepsy/Epilepsy Foundation; Citizens United for Research in Epilepsy FX Disclosures: None of the authors has any conflict of interest to disclose. NR 42 TC 28 Z9 29 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JUL PY 2009 VL 50 IS 7 BP 1741 EP 1751 DI 10.1111/j.1528-1167.2009.02086.x PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 466KJ UT WOS:000267660800008 PM 19453702 ER PT J AU Evans, CH Liu, FJ Glatt, V Hoyland, JA Kirker-Head, C Walsh, A Betz, O Wells, JW Betz, V Porter, RM Saad, FA Gerstenfeld, LC Einhorn, TA Harris, MB Vrahas, MS AF Evans, C. H. Liu, F. -J. Glatt, V. Hoyland, J. A. Kirker-Head, C. Walsh, A. Betz, O. Wells, J. W. Betz, V. Porter, R. M. Saad, F. A. Gerstenfeld, L. C. Einhorn, T. A. Harris, M. B. Vrahas, M. S. TI USE OF GENETICALLY MODIFIED MUSCLE AND FAT GRAFTS TO REPAIR DEFECTS IN BONE AND CARTILAGE SO EUROPEAN CELLS & MATERIALS LA English DT Article DE Adenovirus; bone morphogenetic protein; large segmental defects; cartilage repair; bone healing; gene therapy; animal models; facilitated endogenous repair; tissue engineering; fibrodysplasia ossificans progressiva AB We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad. BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified ("gene activated") tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible. C1 [Evans, C. H.; Liu, F. -J.; Glatt, V.; Wells, J. W.; Porter, R. M.] Harvard Univ, Ctr Adv Orthopaed Studies, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Evans, C. H.; Liu, F. -J.; Betz, O.; Wells, J. W.; Betz, V.; Porter, R. M.] Harvard Univ, Brigham & Womens Hosp, Ctr Mol Orthopaed, Sch Med, Boston, MA 02115 USA. [Hoyland, J. A.] Univ Manchester, Tissue Injury & Repair Res Grp, Manchester, Lancs, England. [Kirker-Head, C.; Walsh, A.] Tufts Cummings Sch Vet Med, Orthopaed Res Lab, Grafton, MA USA. [Betz, V.; Vrahas, M. S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Saad, F. A.] Childrens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Gerstenfeld, L. C.; Einhorn, T. A.] Boston Univ, Med Ctr, Dept Orthoped Surg, Boston, MA USA. [Harris, M. B.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Evans, CH (reprint author), Harvard Univ, Ctr Adv Orthopaed Studies, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave,RN-115, Boston, MA 02215 USA. EM cevans@bidmc.harvard.edu RI Liu, Fangjun/B-1012-2012; Hoyland, Judith/P-5168-2014; Wells, James/C-7480-2011; OI Hoyland, Judith/0000-0003-4876-5208; Wells, James/0000-0002-9618-6940; /0000-0002-0477-1211 FU NIAMS, NIH [R01 AR 050243]; AO Foundation FX This research was funded by NIH grant R01 AR 050243 from NIAMS (to CHE) and the AO Foundation (to MSV and CHE). The authors thank Thomas J. Gill III, MD, Department of Orthopaedic Surgery, Massachusetts General Hospital, for his advice to use Fischer rats. NR 40 TC 50 Z9 50 U1 0 U2 3 PU AO RESEARCH INSTITUTE DAVOS-ARI PI DAVOS PA CLAVADELERSTRASSE 8, DAVOS, CH 7270, SWITZERLAND SN 1473-2262 J9 EUR CELLS MATER JI Eur. Cells Mater. PD JUL-DEC PY 2009 VL 18 BP 96 EP 111 PG 16 WC Cell & Tissue Engineering; Engineering, Biomedical; Materials Science, Biomaterials SC Cell Biology; Engineering; Materials Science GA V20CC UT WOS:000208117100009 PM 20073015 ER PT J AU Muehlschlegel, JD Perry, TE Liu, KY Nascimben, L Fox, AA Collard, CD Avery, EG Aranki, SF D'Ambra, MN Shernan, SK Body, SC AF Muehlschlegel, Jochen D. Perry, Tjoervi E. Liu, Kuang-Yu Nascimben, Luigino Fox, Amanda A. Collard, Charles D. Avery, Edwin G. Aranki, Sary F. D'Ambra, Michael N. Shernan, Stanton K. Body, Simon C. CA CABG Genomics Investigators TI Troponin is superior to electrocardiogram and creatinine kinase MB for predicting clinically significant myocardial injury after coronary artery bypass grafting SO EUROPEAN HEART JOURNAL LA English DT Article DE Cardiopulmonary bypass; Electrocardiography; Surgery; Mortality; Enzymes; Troponin ID UNIVERSAL DEFINITION; CARDIAC-SURGERY; HEART-SURGERY; Q-WAVES; INFARCTION; ASSAY; MULTICENTER; PERFORMANCE; MORTALITY; SURVIVAL AB Cardiac biomarkers are routinely elevated after uncomplicated cardiac surgery to levels considered diagnostic of myocardial infarction in ambulatory populations. We investigated the diagnostic power of electrocardiogram (ECG) and cardiac biomarker criteria to predict clinically relevant myocardial injury using benchmarks of mortality and increased hospital length of stay (HLOS) in patients undergoing coronary artery bypass graft (CABG) surgery. Perioperative ECGs, creatinine kinase MB fraction, and cardiac troponin I (cTnI) were assessed in 545 primary CABG patients. None of the ECG criteria for myocardial injury predicted mortality or HLOS. However, post-operative day (POD) 1 cTnI levels independently predicted 5-year mortality (hazard ratio = 1.42; 95% CI 1.14-1.76 for each 10 mu g/L increase; P = 0.009), while adjusting for baseline demographic characteristics and perioperative risk factors. Moreover, cTnI was the only biomarker that significantly improved the prediction of 5-year mortality estimated by the logistic Euroscore (P = 0.02). Furthermore, the predictive value of cTnI for 5-year mortality was replicated in a separately collected cohort of 1031 CABG patients using cardiac troponin T. Electrocardiogram diagnosis of post-operative myocardial injury after CABG does not independently predict an increased risk of 5-year mortality or HLOS. Conversely, cTnI is independently associated with an increased risk of mortality and prolonged HLOS. C1 [Muehlschlegel, Jochen D.; Perry, Tjoervi E.; Liu, Kuang-Yu; Nascimben, Luigino; Fox, Amanda A.; D'Ambra, Michael N.; Shernan, Stanton K.; Body, Simon C.] Harvard Univ, Brigham & Womens Hosp, Dept Anaesthesiol Perioperat & Pain Med, Sch Med, Boston, MA 02115 USA. [Collard, Charles D.] St Lukes Episcopal Hosp, Texas Heart Inst, Baylor Coll Med, Div Cardiovasc Anaesthesia, Houston, TX USA. [Avery, Edwin G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Anaesthesia & Crit Care, Div Cardiac Anaesthesia,Heart Ctr, Boston, MA USA. [Aranki, Sary F.] Harvard Univ, Brigham & Womens Hosp, Div Cardiac Surg, Sch Med, Boston, MA 02115 USA. RP Muehlschlegel, JD (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Anaesthesiol Perioperat & Pain Med, Sch Med, CWN L1,75 Francis St, Boston, MA 02115 USA. EM jmuehlschlegel@partners.org FU Bayerw Fellowship in Blood Conservation, Biosite Inc., San Diego, CA, USA; NIH [HL-068774]; NCRR [M01 02558]; Society of Cardiovascular Anaesthesiologists Research Starter Grant; Siemens Medical Solutions Diagnostics, Tarrytown, NY FX This work was supported by the Bayerw Fellowship in Blood Conservation, Biosite Inc., San Diego, CA, USA (J.D.M.); NIH (HL-068774 to S. C. B., NCRR M01 02558 to C. D. C. and A. A. F.); Society of Cardiovascular Anaesthesiologists Research Starter Grant; and Siemens Medical Solutions Diagnostics, Tarrytown, NY (J.D.M.). NR 33 TC 25 Z9 26 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2009 VL 30 IS 13 BP 1574 EP 1583 DI 10.1093/eurheartj/ehp134 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 466MM UT WOS:000267666300015 PM 19406870 ER PT J AU Michelson, AD Frelinger, AL Braunwald, E Downey, WE Angiolillo, DJ Xenopoulos, NP Jakubowski, JA Li, YF Murphy, SA Qin, J McCabe, CH Antman, EM Wiviott, SD AF Michelson, Alan D. Frelinger, Andrew L., III Braunwald, Eugene Downey, William E. Angiolillo, Dominick J. Xenopoulos, Nicholas P. Jakubowski, Joseph A. Li, Youfu Murphy, Sabina A. Qin, Jie McCabe, Carolyn H. Antman, Elliott M. Wiviott, Stephen D. CA TRITON-TIMI 38 Investigators TI Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial SO EUROPEAN HEART JOURNAL LA English DT Article DE Platelets; Prasugrel; Clopidogrel; Clinical trials; Platelet function ID PERCUTANEOUS CORONARY INTERVENTION; STIMULATED PHOSPHOPROTEIN PHOSPHORYLATION; ASPIRIN-TREATED PATIENTS; HIGH-DOSE CLOPIDOGREL; RESPONSE VARIABILITY; ACTIVE METABOLITE; ARTERY-DISEASE; EFFICIENT GENERATION; ACHIEVES GREATER; RESISTANCE AB To examine the extent of platelet inhibition by prasugrel vs. clopidogrel in a TRITON-TIMI 38 substudy. TRITON-TIMI 38 randomized acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) to prasugrel or standard dose clopidogrel. Selected sites prospectively enrolled TRITON-TIMI 38 patients to evaluate adenosine diphosphate (ADP)-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) (n = 125 patients) and, in a subset (n = 31 patients), ADP-stimulated platelet aggregation. VASP platelet reactivity index (PRI) was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1-2 h post-PCI (>= 1 h after loading dose) (P < 0.001) and at 30 days (P < 0.001). Maximal platelet aggregation to 20 mu M ADP was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1-2 h (P = 0.004) and 30 days (P = 0.03). Results were similar with 5 mu M ADP. Thienopyridine hyporesponsiveness, prespecified as VASP PRI > 50%, was more frequent in clopidogrel-treated patients than in prasugrel-treated patients at 1-2 h (P < 0.001) and 30 days (P = 0.03). The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI. C1 [Michelson, Alan D.; Frelinger, Andrew L., III] Childrens Hosp, Dept Med, Div Hematol Oncol, Ctr Platelet Res Studies, Boston, MA 02115 USA. [Michelson, Alan D.; Frelinger, Andrew L., III] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Michelson, Alan D.; Frelinger, Andrew L., III; Li, Youfu] Univ Massachusetts, Sch Med, Dept Pediat, Ctr Platelet Funct Studies, Worcester, MA 01655 USA. [Michelson, Alan D.; Frelinger, Andrew L., III; Li, Youfu] Univ Massachusetts, Sch Med, Dept Med, Ctr Platelet Funct Studies, Worcester, MA USA. [Michelson, Alan D.; Li, Youfu] Univ Massachusetts, Sch Med, Dept Pathol, Ctr Platelet Funct Studies, Worcester, MA 01605 USA. [Braunwald, Eugene; Murphy, Sabina A.; Qin, Jie; McCabe, Carolyn H.; Antman, Elliott M.; Wiviott, Stephen D.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Downey, William E.] LeBauer Cardio Res, Greensboro, NC USA. [Angiolillo, Dominick J.] Univ Florida, Coll Med, Jacksonville, FL USA. [Jakubowski, Joseph A.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Frelinger, Andrew L., III] Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01655 USA. RP Michelson, AD (reprint author), Childrens Hosp, Dept Med, Div Hematol Oncol, Ctr Platelet Res Studies, 300 Longwood Ave,Karp 08213, Boston, MA 02115 USA. EM michelson@platelets.org FU Daiichi Sankyo Company, Limited (Tokyo, Japan); Eli Lilly and Company (Indianapolis, IN, USA) FX This work was supported by Daiichi Sankyo Company, Limited (Tokyo, Japan) and Eli Lilly and Company (Indianapolis, IN, USA). NR 27 TC 139 Z9 143 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2009 VL 30 IS 14 BP 1753 EP 1763 DI 10.1093/eurheartj/ehp159 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 472DO UT WOS:000268109600019 PM 19435740 ER PT J AU George, S Blay, JY Casali, PG Le Cesne, A Stephenson, P DePrimo, SE Harmon, CS Law, CNJ Morgan, JA Ray-Coquard, I Tassell, V Cohen, DP Demetri, GD AF George, S. Blay, J. Y. Casali, P. G. Le Cesne, A. Stephenson, P. DePrimo, S. E. Harmon, C. S. Law, C. N. J. Morgan, J. A. Ray-Coquard, I. Tassell, V. Cohen, D. P. Demetri, G. D. TI Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Sunitinib; GIST; Receptor tyrosine kinases; Targeted therapy; Continuous daily dosing ID TYROSINE KINASE INHIBITOR; RENAL-CELL CARCINOMA; GROWTH-FACTOR; IN-VITRO; SU11248; HYPOTHYROIDISM; CANCER; BIOMARKERS; MUTATIONS; VIVO AB Aims: To assess the antitumour activity, safety, pharmacokinetics and pharmacodynamics of continuous daily sunitinib dosing in patients with imatinib-resistant/intolerant gastrointestinal stromal tumour (GIST) and to assess morning dosing versus evening dosing. Patients and methods: In this open-label phase II study, patients were randomised to receive morning or evening dosing of sunitinib 37.5 mg/day. The primary end-point was clinical benefit rate (CBR; percent complete responses + partial responses [PRs] + stable disease [SD] >= 24 weeks). Secondary end-points included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters and plasma biomarker levels. Results: Sixty of 61 planned patients received treatment (30 per dosing group); 26 completed the study. overall, the CBR was 53% (95% exact CI, 40-66): eight patients (13%) achieved objective PRs; 24 (40%) achieved SD >= 24 weeks. Median PFS was 34 weeks (95% CI, 24-49); median OS was 107 weeks (95% CI, 72 - not yet calculable). Most adverse events (AEs) were of grade 1 or 2 in severity, and were manageable through dose modification or standard interventions. No new AEs were apparent compared with the approved intermittent dosing schedule. Antitumour activity and safety were generally similar with morning and evening dosing. Continuous daily sunitinib dosing achieved and sustained effective drug concentrations without additional accumulation across cycles. Decreases from baseline in plasma levels of soluble KIT after 20 and 24 weeks of dosing correlated with longer OS. Conclusion: For patients with imatinib-resistant/intolerant GIST, continuous daily sunitinib dosing appears to be an active alternative dosing strategy with acceptable safety. (c) 2009 Published by Elsevier Ltd. C1 [George, S.; Morgan, J. A.; Demetri, G. D.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Blay, J. Y.] UJOMM HEH & Conticanet FP6 018806, Ctr Leon Berard, F-69373 Lyon, France. [Blay, J. Y.] Univ Lyon 1, F-69622 Lyon, France. [Casali, P. G.] Ist Nazl Tumori, I-20133 Milan, Italy. [Le Cesne, A.] Inst Gustave Roussy, F-94805 Villejuif, France. [Stephenson, P.] Rho Inc, Chapel Hill, NC 27517 USA. [DePrimo, S. E.; Harmon, C. S.; Law, C. N. J.; Tassell, V.; Cohen, D. P.] Pfizer Oncol, San Diego, CA 92121 USA. [Ray-Coquard, I.] Hosp Civils Lyon, Ctr Leon Berard, Dept Med Oncol, F-69008 Lyon, France. [Ray-Coquard, I.] Hosp Civils Lyon, EA SIS 4128, F-69008 Lyon, France. RP George, S (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. EM suzanne_george@dfci.harvard.edu RI Blay, Jean-Yves/N-3966-2016; casali, Paolo Giovanni/D-1524-2017 OI Blay, Jean-Yves/0000-0001-7190-120X; casali, Paolo Giovanni/0000-0003-4056-8023 FU Pfizer Inc FX This study was supported in part by funding from Pfizer Inc. The study was designed by P.G. Casali, J.Y Blay and G.D. Demetri in collaboration with Pfizer, who managed the logistical aspects of this study. Data were collected and analysed by Pfizer in collaboration with the team of academic investigators. The manuscript was written by S. George with substantive input from all authors and with medical writing services provided by ACUMED (Tytherington, UK), with funding from Pfizer. The decision to submit the manuscript for publication was made by the authors. NR 25 TC 172 Z9 181 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2009 VL 45 IS 11 BP 1959 EP 1968 DI 10.1016/j.ejca.2009.02.011 PG 10 WC Oncology SC Oncology GA 476UX UT WOS:000268472700009 PM 19282169 ER PT J AU Horst, D Kriegl, L Engel, J Jung, A Kirchner, T AF Horst, David Kriegl, Lydia Engel, Jutta Jung, Andreas Kirchner, Thomas TI CD133 and nuclear beta-catenin: The marker combination to detect high risk cases of low stage colorectal cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Colon cancer; CD133; Nuclear beta-catenin; Cancer stem cells; Survival; Progression ID COLON-CANCER; STEM-CELLS; ADJUVANT CHEMOTHERAPY; EXPRESSION; SURVIVAL; CARCINOMA; ACTIVATION; TUMORS; TRIAL; APC AB Nuclear beta-catenin and CD133 are linked with two hallmarks of colon cancer, wingless-type mouse mammary tumour virus integration site (WNT)-pathway dysregulation and colon cancer stem cells (Co-CSCs), respectively Both molecules may be related, as Co-CSCs were proposed to require activated WNT-signalling and as CD133 was postulated as a WNT/beta-catenin target gene. Herein, we investigated the expression of these markers on serial sections of 162 stage IIA colonic adenocarcinomas. We found that the expression of these molecules is statistically independent and that they mark distinct but overlapping subpopulations of the tumour cells. Moreover, we show that their combined evaluation can identify colon cancer cases with vastly reduced survival (hazard ratio (HR) 13.4, 95% confidence interval (CI): 4.7-38.2) and a high risk of tumour progression (HR 6.8, 95%CI: 3.1-15.0). In conclusion, the independence of these markers may on the one hand have implications for their presumed value to identify Co-CSCs; on the other hand it allows their combined analysis to become a powerful tool to identify high risk cases of stage IIA colon cancer. (c) 2009 Elsevier Ltd. All rights reserved. C1 [Horst, David; Kriegl, Lydia; Jung, Andreas; Kirchner, Thomas] Univ Munich, Inst Pathol, Munich, Germany. [Engel, Jutta] Univ Munich, Tumorregister Munchen, Inst Med Informat Verabeitung Biometrie & Epidemi, Munich, Germany. RP Horst, D (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM davidn_horst@dfci.harvard.edu NR 24 TC 51 Z9 53 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2009 VL 45 IS 11 BP 2034 EP 2040 DI 10.1016/j.ejca.2009.04.004 PG 7 WC Oncology SC Oncology GA 476UX UT WOS:000268472700019 PM 19403300 ER PT J AU Chua, S Levine, RA Yosefy, C Handschumacher, MD Chu, J Qureshi, A Neary, J Ton-Nu, TT Fu, M Wu, CJ Hung, J AF Chua, Sarah Levine, Robert A. Yosefy, Chaim Handschumacher, Mark D. Chu, John Qureshi, Anwer Neary, Jennifer Ton-Nu, Thanh-Thao Fu, Morgan Wu, Chiung Jen Hung, Judy TI Assessment of right ventricular function by real-time three-dimensional echocardiography improves accuracy and decreases interobserver variability compared with conventional two-dimensional views SO EUROPEAN JOURNAL OF ECHOCARDIOGRAPHY LA English DT Article DE Right ventricle function; Three-dimensional echocardiography ID IN-VITRO VALIDATION; MAGNETIC-RESONANCE; GREAT-ARTERIES; PULMONARY-HYPERTENSION; EJECTION FRACTION; VOLUME; TRANSPOSITION; RECONSTRUCTION; OPERATION; MASS AB Aims Two-dimensional echocardiographic (2DE) assessment of right ventricular ( RV) function is difficult, often resulting in inconsistent RV evaluation. Real-time three-dimensional echocardiography (RT3DE) allows the RV to be viewed in multiple planes, which can potentially improve RV assessment and limit interobserver variability when compared with 2DE. Methods and results Twenty-five patients underwent 2DE and RT3DE. Views of 2DE ( RV inflow, RV short axis, and apical four-chamber) were compared with RT3DE views by four readers. RT3DE data sets were sliced from anterior-posterior ( apical view) and from base to apex ( short axis) to obtain six standardized planes. Readers recorded the RV ejection fraction (RVEF) from 2DE and RT3DE images. RVEF recorded by RT3DE (RVEF(3D)) and 2D (RVEF(2D)) were compared with RVEF by disc summation (RVEF(DS)), which was used as a reference. Interobserver variability among readers of RVEF3D and RVEF2D was then compared. Overall, mean RVEF(DS), RVEF(3D), and RVEF(2D) were 37 +/- 11%, 38 +/- 10%, 41 +/- 10%, respectively. The mean difference of RVEF(3D) - RVEF(DS) was significantly less than RVEF(2D)-RVEF(DS) (3.7 +/- 4% vs. 7.1 +/- 5%, P = 0.0066, F-test). RVEF(3D) correlated better with RVEF(DS) (r = 0.875 vs. r = 0.69, P = 0.028, t-test). RVEF(3D) was associated with a 39% decrease in interobserver variability when compared with RVEF(2D) [standard deviation of mean difference: 3.7 vs. 5.1, (RT3DE vs. 2DE), P = 0.018, t-test]. Conclusions RT3DE provides improved accuracy of RV function assessment and decreases interobserver variability when compared with 2D views. C1 [Chua, Sarah; Levine, Robert A.; Yosefy, Chaim; Handschumacher, Mark D.; Chu, John; Qureshi, Anwer; Neary, Jennifer; Ton-Nu, Thanh-Thao; Hung, Judy] Harvard Univ, Cardiac Ultrasound Lab, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Chua, Sarah; Fu, Morgan; Wu, Chiung Jen] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Kaohsiung Med Ctr, Kaohsiung, Taiwan. RP Hung, J (reprint author), Harvard Univ, Cardiac Ultrasound Lab, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,VBK 508, Boston, MA 02114 USA. EM jhung@partners.org FU NHLBI NIH HHS [R01 HL038176, R01 HL072265, K24 HL067434]; NIBIB NIH HHS [R21 EB005294, R21 EB005294-02]; NIMHD NIH HHS [L32 MD000722, L32 MD000722-03] NR 27 TC 15 Z9 23 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1525-2167 J9 EUR J ECHOCARDIOGR JI Eur. J. Echocardiogr. PD JUL PY 2009 VL 10 IS 5 BP 619 EP 624 DI 10.1093/ejechocard/jep013 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 466ML UT WOS:000267666200007 PM 19258335 ER PT J AU Goodwin, G Fleischhacker, W Arango, C Baumann, P Davidson, M de Hert, M Falkai, P Kapur, S Leucht, S Licht, R Naber, D O'Keane, V Papakostas, G Vieta, E Zohar, J AF Goodwin, Guy Fleischhacker, Wolfgang Arango, Celso Baumann, Pierre Davidson, Michael de Hert, Marc Falkai, Peter Kapur, Shitij Leucht, Stefan Licht, Rasmus Naber, Dieter O'Keane, Veronica Papakostas, George Vieta, Eduard Zohar, Joseph TI Advantages and disadvantages of combination treatment with antipsychotics ECNP Consensus Meeting, March 2008, Nice SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Mania; Schizophrenia; Major depression; Obsessive-compulsive disorder (OCD); Antipsychotics; Antidepressants; Mood stabilizers; Anticonvulsants; Polypharmacy ID OBSESSIVE-COMPULSIVE DISORDER; BIPOLAR-I-DISORDER; HOSPITALIZED SCHIZOPHRENIC-PATIENTS; PLACEBO-CONTROLLED TRIAL; BONE-MINERAL DENSITY; DOUBLE-BLIND; PHARMACOLOGICAL-TREATMENT; P-GLYCOPROTEIN; ATYPICAL ANTIPSYCHOTICS; SUBJECTIVE EXPERIENCE AB Terminology and principles of combining antipsychotics with a second medication. The term "combination" includes virtually all the ways in which one medication may be added to another. The other commonly used terms are "augmentation" which implies an additive effect from adding a second medicine to that obtained from prescribing a first, an "add on" which implies adding on to existing, possibly effective treatment which, for one reason or another, cannot or should not be stopped. The issues that arise in all potential indications are: a) how long it is reasonable to wait to prove insufficiency of response to monotherapy; b) by what criteria that response should be defined; c) how optimal is the dose of the first monotherapy and, therefore, how confident can one be that its tack of effect is due to a truly inadequate response? Before one considers combination treatment, one or more of the following criteria should be met; a) monotherapy has been only partially effective on core symptoms; b) monotherapy has been effective on some concurrent symptoms but not others, for which a further medicine is believed to be required; c) a particular combination might be indicated de novo in some indications; d) The combination could improve tolerability because two compounds may be employed below their individual dose thresholds for side effects. Regulators have been concerned primarily with a and, in principle at least, c above. In clinical practice, the use of combination treatment reflects the often unsatisfactory outcome of treatment with single agents. Antipsychotics in mania. There is good evidence that most antipsychotics tested show efficacy in acute mania when added to lithium or valproate for patients showing no or a partial response to lithium or valproate alone. Conventional 2-armed trial designs could benefit from a third antipsychotic monotherapy arm. In the long term treatment of bipolar disorder, in patients responding acutely to the addition of quetiapine to lithium or valproate, this combination reduces the subsequent risk of relapse to depression, mania or mixed states compared to monotherapy with lithium or valproate. Comparable data is not available for combination with other antipsychotics. Antipsychotics in major depression. Some atypical antipsychotics have been shown to induce remission when added to an antidepressant (usually a SSRI or SNRI) in unipolar patients in a major depressive episode unresponsive to the antidepressant monotherapy. Refractoriness is defined as at least 6 weeks without meeting an adequate pre-defined treatment response. Long term data is not yet available to support continuing efficacy. Schizophrenia. There is only limited evidence to support the combination of two or more antipsychotics in schizophrenia. Any monotherapy should be given at the maximal tolerated dose and at least two antipsychotics of different action/tolerability and clozapine should be given as a monotherapy before a combination is considered. The addition of a high potency D2/3 antagonist to a low potency antagonist like clozapine or quetiapine is the logical combination to treat positive symptoms, although further evidence from well conducted clinical trials is needed. Other mechanisms of action than D2/3 blockade, and hence other combinations might be more relevant for negative, cognitive or affective symptoms. Obsessive-compulsive disorder. SSRI monotherapy has moderate overall average benefit in OCD and can take as long as 3 months for benefit to be decided. Antipsychotic addition may be considered in OCD with tic disorder and in refractory OCD. For OCD with poor insight (OCD with "psychotic features"), treatment of choice should be medium to high dose of SSRI, and only in refractory cases, augmentation with antipsychotics might be considered. Augmentation with hatoperidol and risperidone was found to be effective (symptom reduction of more than 35%) for patients with tics. For refractory OCD, there is data suggesting a specific role for hatoperidol and risperidone as well, and some data with regard to potential therapeutic benefit with olanzapine and quetiapine. Antipsychotics and adverse effects in severe mental illness. Cardio-metabotic risk in patients with severe mental illness and especially when treated with antipsychotic agents are now much better recognized and efforts to ensure improved physical health screening and prevention are becoming established. (C) 2009 Elsevier B.V. and ECNP. All rights reserved. C1 [Goodwin, Guy] Warneford Hosp, Univ Dept Psychiat, Oxford OX3 7JX, England. [Fleischhacker, Wolfgang] Med Univ Innsbruck, Biol Psychiat Div, A-6020 Innsbruck, Austria. [Arango, Celso] Univ Gregorio Maranon, Gen Hosp, Ctr Invest Biomed Red Salud Mental, Dept Psychiat,CIBERSAM, Madrid, Spain. [Baumann, Pierre] Dept Univ Psychiat Adulte, Unite Biochim & Psychopharmacol Clin, Prilly, Switzerland. [Davidson, Michael] Tel Aviv Univ, Dept Psychiat, Tel Aviv, Israel. [de Hert, Marc] UPC KU Leuven, B-3070 Kortenberg, Belgium. [Falkai, Peter] Univ Gottingen, Dept Psychiat, D-37075 Gottingen, Germany. [Kapur, Shitij] Kings Coll London, Inst Psychiat, London SE5 8AF, England. [Leucht, Stefan] Tech Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany. [Licht, Rasmus] Aarhus Univ, Hosp Psychiat, Mood Disorders Res & Clin Unit, DK-8240 Risskov, Denmark. [Naber, Dieter] Univ Med Ctr Hamburg Eppendorf, Dept Psychiat & Psychotherapy, D-20246 Hamburg, Germany. [O'Keane, Veronica] St James Hosp, Jonathan Swift Clin, Dublin 8, Ireland. [Papakostas, George] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Papakostas, George] Harvard Univ, Sch Med, Boston, MA USA. [Vieta, Eduard] Univ Barcelona, IDIBAPS, CIBERSAM, Hosp Clin,Bipolar Disorders Programme, Barcelona, Catalonia, Spain. [Zohar, Joseph] Chaim Sheba Med Ctr, Dept Psychiat, IL-52621 Tel Hashomer, Israel. RP Goodwin, G (reprint author), Warneford Hosp, Univ Dept Psychiat, Oxford OX3 7JX, England. EM guy.goodwin@psych.ox.ac.uk RI Vieta, Eduard/I-6330-2013; Papakostas, George/I-6905-2013; Arango Lopez, Celso/H-6433-2015; OI Vieta, Eduard/0000-0002-0548-0053; Papakostas, George/0000-0002-2465-5103; Arango Lopez, Celso/0000-0003-3382-4754; o'keane, veronica/0000-0002-1519-099X; Kapur, Shitij/0000-0002-2231-2924 FU ECNP Office FX We wish to thank the ECNP Office for their support of the consensus meeting. NR 82 TC 81 Z9 86 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD JUL PY 2009 VL 19 IS 7 BP 520 EP 532 DI 10.1016/j.euroneuro.2009.04.003 PG 13 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 463GG UT WOS:000267417600009 PM 19411165 ER PT J AU Li, GA Wang, SB Passias, P Xia, Q Li, G Wood, K AF Li, Guoan Wang, Shaobai Passias, Peter Xia, Qun Li, Gang Wood, Kirkham TI Segmental in vivo vertebral motion during functional human lumbar spine activities SO EUROPEAN SPINE JOURNAL LA English DT Article DE In vivo spine motion; Vertebral kinematics; Spine biomechanics; Lumbar spine; Dual fluoroscopes ID LOW-BACK-PAIN; INTERVERTEBRAL DISC REPLACEMENT; IMAGE MATCHING METHOD; AXIAL ROTATION; KINEMATICS; MRI; DEFORMATION; FLUOROSCOPY; EXTENSION; SYSTEM AB Quantitative data on the range of in vivo vertebral motion is critical to enhance our understanding of spinal pathology and to improve the current surgical treatment methods for spinal diseases. Little data have been reported on the range of lumbar vertebral motion during functional body activities. In this study, we measured in vivo 6 degrees-of-freedom (DOF) vertebral motion during unrestricted weightbearing functional body activities using a combined MR and dual fluoroscopic imaging technique. Eight asymptomatic living subjects were recruited and underwent MRI scans in order to create 3D vertebral models from L2 to L5 for each subject. The lumbar spine was then imaged using two fluoroscopes while the subject performed primary flexion-extension, left-right bending, and left-right twisting. The range of vertebral motion during each activity was determined through a previously described imaging-model matching technique at L2-3, L3-4, and L4-5 levels. Our data revealed that the upper vertebrae had a higher range of flexion than the lower vertebrae during flexion-extension of the body (L2-3, 5.4 +/- A 3.8A degrees; L3-4, 4.3 +/- A 3.4A degrees; L4-5, 1.9 +/- A 1.1A degrees, respectively). During bending activity, the L4-5 had a higher (but not significant) range of left-right bending motion (4.7 +/- A 2.4A degrees) than both L2-3 (2.9 +/- A 2.4A degrees) and L3-4 (3.4 +/- A 2.1A degrees), while no statistical difference was observed in left-right twisting among the three vertebral levels (L2-3, 2.5 +/- A 2.3A degrees; L3-4, 2.4 +/- A 2.6A degrees; and L4-5, 2.9 +/- A 2.1A degrees, respectively). Besides the primary rotations reported, coupled motions were quantified in all DOFs. The coupled translation in left-right and anterior-posterior directions, on average, reached greater than 1 mm, while in the proximal-distal direction this was less than 1 mm. Overall, each vertebral level responds differently to flexion-extension and left-right bending, but similarly to the left-right twisting. This data may provide new insight into the in vivo function of human spines and can be used as baseline data for investigation of pathological spine kinematics. C1 [Li, Guoan; Wang, Shaobai; Passias, Peter; Xia, Qun; Li, Gang; Wood, Kirkham] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Wang, Shaobai] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Xia, Qun] Tianjin Orthopaed Hosp, Tianjin, Peoples R China. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU NASS; Massachusetts General Hospital; Tianjin Orthopaedic Hospital FX The financial support from a NASS research grant and Department of Orthopaedic Surgery of Massachusetts General Hospital was greatly appreciated. This research was also supported by the Orthopaedic Department at Tianjin Orthopaedic Hospital. We also thank Drs. Brian Grottkau and Michael Kozanek for technical assistance. NR 37 TC 52 Z9 59 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6719 J9 EUR SPINE J JI Eur. Spine J. PD JUL PY 2009 VL 18 IS 7 BP 1013 EP 1021 DI 10.1007/s00586-009-0936-6 PG 9 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 469KE UT WOS:000267895900012 PM 19301040 ER PT J AU Sung, KF Odinokova, IV Mareninova, OA Rakonczay, Z Hegyi, P Pandol, SJ Gukovsky, I Gukovskaya, AS AF Sung, Kai-Feng Odinokova, Irina V. Mareninova, Olga A. Rakonczay, Zoltan, Jr. Hegyi, Peter Pandol, Stephen J. Gukovsky, Ilya Gukovskaya, Anna S. TI Prosurvival Bcl-2 proteins stabilize pancreatic mitochondria and protect against necrosis in experimental pancreatitis SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Pancreatic acinar cell; Bcl-xL; CCK; Mitochondrial membrane potential; Cytochrome c release; Caspase-3 ID MEMBRANE PERMEABILITY TRANSITION; SMALL-MOLECULE INHIBITORS; CELL-DEATH; ACINAR-CELLS; X-L; CASPASE ACTIVATION; TARGETING BCL-2; KAPPA-B; APOPTOSIS; CANCER AB Acinar cells in pancreatitis die through apoptosis and necrosis, the roles of which are different. The severity of experimental pancreatitis correlates directly with the extent of necrosis and inversely, with apoptosis. Apoptosis is mediated by the release of cytochrome c into the cytosol followed by caspase activation, whereas necrosis is associated with the mitochondrial membrane potential (Delta Psi m) loss leading to ATP depletion. Here, we investigate the role of Bcl-2 proteins in apoptosis and necrosis in pancreatitis. We found tip-regulation of prosurvival Bcl-2 proteins in pancreas in various experimental models of acute pancreatitis, most pronounced for Bcl-xL. This up-regulation translated into increased levels of Bcl-xL and Bcl-2 in pancreatic mitochondria. Bcl-xL/Bcl-2 inhibitors induced Delta Psi m loss and cytochrome c release in isolated mitochondria. Corroborating the results On mitochondria, Bcl-xL/Bcl-2 inhibitors induced Delta Psi m loss, NIT depletion and necrosis in pancreatic acinar cells, both untreated and hyperstimulated with CCK-8 (in vitro pancreatitis model). Together Bcl-xL/Bcl-2 inhibitors and CCK induced more necrosis than either treatment alone. Bcl-xL/Bcl-2 inhibitors also stimulated cytochrome c release in acinar cells leading to caspase-3 activation and apoptosis. However, different from their effect on pronecrotic signals, the Stimulation by Bcl-xL/Bcl-2 inhibitors of apoptotic responses was less in CCK-treated than control cells. Therefore, Bcl-xL/Bcl-2 inhibitors potentiated CCK-induced necrosis but not apoptosis. Correspondingly, transfection with Bcl-xL siRNA stimulated necrosis but not apoptosis in the in vitro pancreatitis model. Further, in animal models of pancreatitis Bcl-xL up-regulation inversely correlated with necrosis, but not apoptosis. Results indicate that Bcl-xL and Bcl-2 protect acinar cells from necrosis in pancreatitis by stabilizing mitochondria against death signals. We conclude that Bcl-xL/Bcl-2 inhibition would aggravate acute pancreatitis, whereas Bcl-xL/Bcl-2 up-regulation presents a strategy to prevent or attenuate necrosis in pancreatitis. (C) 2009 Elsevier Inc. All rights reserved. C1 [Gukovskaya, Anna S.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, W Los Angeles VA Healthcare Ctr, Los Angeles, CA 90073 USA. [Sung, Kai-Feng; Odinokova, Irina V.; Mareninova, Olga A.; Pandol, Stephen J.; Gukovsky, Ilya; Gukovskaya, Anna S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Sung, Kai-Feng] Chang Gung Mem Hosp, Dept Hepatogastroenterol, Taipei 10591, Taiwan. [Odinokova, Irina V.] Russian Acad Sci, Inst Theoret & Expt Biophys, Pushchino 142292, Moscow Region, Russia. [Rakonczay, Zoltan, Jr.; Hegyi, Peter] Univ Szeged, Szeged, Hungary. RP Gukovskaya, AS (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, W Los Angeles VA Healthcare Ctr, 11301 Wilshire Blvd,Blg 258,Rm 340, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu FU NIH [DK59936]; American Gastroenterology Association Foundation Designated Research Scholar Award in Pancreatitis; Department of Veteran Affairs FX This study was supported by NIH Grant DK59936 (to A.S.G.), by the American Gastroenterology Association Foundation Designated Research Scholar Award in Pancreatitis (to O.A.M.) and by the Department of Veteran Affairs (to S.J.P.). We thank Dr. A. Lugea for help with animal models of pancreatitis, and Drs. G. Eibl and E. Angst for help with using iQ5 real-time PCR detection system. NR 54 TC 39 Z9 40 U1 0 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUL 1 PY 2009 VL 315 IS 11 BP 1975 EP 1989 DI 10.1016/j.yexcr.2009.01.009 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 454BG UT WOS:000266656000018 PM 19331832 ER PT J AU Samuel, DP Wen, PY Kieran, MW AF Samuel, David P. Wen, Patrick Y. Kieran, Mark W. TI Antiangiogenic (metronomic) chemotherapy for brain tumors: current and future perspectives SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE adult; antiangiogenic; brain tumor; chemotherapy; glioblastoma multiforme; low-dose; metronomic; pediatric ID METASTATIC BREAST-CANCER; ENDOTHELIAL GROWTH-FACTOR; NERVOUS-SYSTEM TUMORS; LOW-DOSE CHEMOTHERAPY; CELL-LUNG-CANCER; RECURRENT MALIGNANT GLIOMA; DAILY ORAL ETOPOSIDE; II CLINICAL-TRIAL; PHASE-II; SOLID TUMORS AB Significant advances in the diagnosis and treatment of brain tumors have been made through better imaging, surgical techniques and advances in radiation therapy. However, the cure rate for most adult and pediatric brain tumor patients has not mirrored this success. Angiogenesis, the development of neovascularization, provides the required nutrients and oxygen to an expanding tumor and is controlled by a complex balance of proangiogenic cytokines and antiangiogenic factors. A series of new inhibitors of angiogenesis are now in clinical trials. Most of these rely on inhibiting tumor cell-mediated cytokines or blocking the activation of their cognate receptors. Cytotoxic chemotherapy, by contrast, targets dividing cells but can be modulated to attack dividing endothelial cells. This review will focus on the use of low-dose antiangiogenic (also called metronomic) chemotherapy to inhibit endothelial cell function and resultant neovascularization in the treatment of adult and pediatric brain tumors. By examining the biology and preclinical findings that led to the development of antiangiogenid metronomic chemotherapy, clinical studies have been undertaken that support the role of this approach in the clinic, and have led to the introduction of a number of markers being used to better predict active combinations and appropriate patient populations. C1 [Samuel, David P.; Kieran, Mark W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Samuel, David P.; Kieran, Mark W.] Childrens Hosp, Boston, MA 02115 USA. [Wen, Patrick Y.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. RP Kieran, MW (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Room SW331, Boston, MA 02115 USA. EM mark_kieran@dfci.harvard.edu OI Kieran, Mark/0000-0003-2184-7692 NR 119 TC 10 Z9 10 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD JUL PY 2009 VL 18 IS 7 BP 973 EP 983 DI 10.1517/13543780903025752 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 467GL UT WOS:000267726200007 PM 19548852 ER PT J AU McCann, AB Jaff, MR AF McCann, Andrew B. Jaff, Michael R. TI Treatment strategies for peripheral artery disease SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE atherosclerosis; atherosclerotic risk factor intervention; intermittent claudication; peripheral artery disease ID RANDOMIZED CONTROLLED-TRIAL; PROPIONYL-L-CARNITINE; SUSTAINED-RELEASE BUPROPION; ENDOTHELIAL PROGENITOR CELLS; L-ARGININE SUPPLEMENTATION; RECEPTOR PARTIAL AGONIST; CRITICAL LIMB ISCHEMIA; C-REACTIVE PROTEIN; DOUBLE-BLIND TRIAL; HIGH-RISK PATIENTS AB Peripheral arterial disease is an underecognized manifestation of systemic atherosclerosis associated with high rates of cardiovascular morbidity and mortality. The rationale of therapy is to reduce cardiovascular risk, improve symptoms of intermittent claudication, and prevent the development of critical limb ischemia and amputation. Exercise therapy and several pharmacologic agents have been shown to improve walking distance in patients with intermittent claudication. Patients with lifestyle-interfering symptoms despite exercise, or those who progress to critical limb ischemia, frequently undergo revascularization. Endovascular techniques are commonly used in these patients. Combined pharmacological and endovascular strategies will play an increasing role in management of these patients in the future. C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, Vasc Ctr, 55 Fruit St, Boston, MA 02114 USA. EM mjaff@partners.org NR 138 TC 6 Z9 9 U1 1 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD JUL PY 2009 VL 10 IS 10 BP 1571 EP 1586 DI 10.1517/14656560902988502 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 466CI UT WOS:000267637800005 PM 19527186 ER PT J AU Saless, N Litscher, SJ Franco, GEL Houlihan, MJ Sudhakaran, S Raheem, KA O'Neil, TK Vanderby, R Demant, P Blank, RD AF Saless, Neema Litscher, Suzanne J. Franco, Gloria E. Lopez Houlihan, Meghan J. Sudhakaran, Shaan Raheem, Khalid Abdul O'Neil, Tyriina K. Vanderby, Ray Demant, Peter Blank, Robert D. TI Quantitative trait loci for biomechanical performance and femoral geometry in an intercross of recombinant congenic mice: restriction of the Bmd7 candidate interval SO FASEB JOURNAL LA English DT Article DE osteoporosis; Wnt; modeling and remodeling; linkage; endothelin ID RECEPTOR-RELATED PROTEIN-5; BONE-MINERAL DENSITY; HETEROGENEOUS MOUSE-POPULATION; MECHANICAL-PROPERTIES; GENETIC DISSECTION; INBRED STRAINS; UTAH PARADIGM; MASS; STRENGTH; LRP5 AB Despite steady progress in identifying quantitative trait loci (QTLs) for bone phenotypes, relatively little progress has been made in moving from QTLs to identifying the relevant gene. We exploited the genetic structure of recombinant congenic mouse strains by performing a reciprocal intercross of the strains HcB-8 and HcB-23, phenotyped for body size, femoral biomechanical performance, and femoral diaphyseal geometry and mapped with R/qtl and QTL Cartographer. Significant QTLs are present on chromosomes 1, 2, 3, 4, 6, and 10. We found significant sex x QTL and cross-direction x QTL interactions. The chromosome 4 QTL affects multiple femoral anatomic features and biomechanical properties. The known segregating segment of chromosome 4 contains only 18 genes, among which Ece1, encoding endothelin-converting enzyme 1, stands out as a candidate. Endothelin signaling has been shown to promote the growth of osteoblastic metastases and to potentiate signaling via the Wnt pathway. The colocalizing chromosome 4 QTL Bmd7 (for bone mineral density 7) increases responsiveness to mechanical loading. By exploiting the short informative segment of chromosome 4 and the known biology, we propose that Ece1 is the gene responsible for Bmd7 and that it acts by increasing responsiveness to mechanical loading through modulation of Wnt signaling. Saless, N., Litscher, S. J., Lopez Franco, G. E., Houlihan, M. J., Sudhakaran, S., Raheem, K. A., O'Neil, T. K., Vanderby, R., Demant, P., Blank, R. D. Quantitative trait loci for biomechanical performance and femoral geometry in an intercross of recombinant congenic mice: restriction of the Bmd7 candidate interval. FASEB J. 23, 2142-2154 (2009) C1 [Saless, Neema; Litscher, Suzanne J.; Franco, Gloria E. Lopez; Houlihan, Meghan J.; Sudhakaran, Shaan; Raheem, Khalid Abdul; O'Neil, Tyriina K.; Vanderby, Ray; Blank, Robert D.] Univ Wisconsin, Madison, WI USA. [Demant, Peter] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Blank, Robert D.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Blank, RD (reprint author), H4-556 CSC 5148,600 Highland Ave, Madison, WI 53705 USA. EM rdb@medicine.wisc.edu OI Blank, Robert Daniel/0000-0003-2950-1944 FU Office of Research and Development, Biomedical Laboratory Research and Development Service, Department of Veterans Affairs FX We thank Anath Shalev, Marc Drezner, Theresa Guise, and Charles Turner for helpful discussions. This material is based on work supported by the Office of Research and Development, Biomedical Laboratory Research and Development Service, Department of Veterans Affairs, and performed in the Geriatrics Research, Education, and Clinical Center at the William S. Middleton Memorial Veterans Hospital. This report is Madison GRECC manuscript 2008-13. NR 64 TC 22 Z9 22 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2009 VL 23 IS 7 BP 2142 EP 2154 DI 10.1096/fj.08-118679 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 481UC UT WOS:000268836500014 PM 19261723 ER PT J AU Jindal, R Nahmias, Y Tilles, AW Berthiaume, F Yarmush, ML AF Jindal, Rohit Nahmias, Yaakov Tilles, Arno W. Berthiaume, Francois Yarmush, Martin L. TI Amino acid-mediated heterotypic interaction governs performance of a hepatic tissue model SO FASEB JOURNAL LA English DT Article DE acute phase proteins; coculture; extracellular matrix; liver ID CELL-CELL INTERACTIONS; EXTRACELLULAR-MATRIX; SANDWICH CONFIGURATION; HEPATOCYTE FUNCTION; ENDOTHELIAL-CELLS; RAT-LIVER; IN-VITRO; NONPARENCHYMAL CELLS; CULTURED-HEPATOCYTES; COCULTURE AB Tissue-engineered models that mimic in vivo tissue organization offer the potential of capturing complex signaling pathways in vitro. In the liver, hepatocytes and endothelial cells are closely associated but separated by the extracellular matrix of the space of Disse. This unique configuration was mimicked by embedding primary hepatocytes in collagen gel and overlaying the matrix with endothelial cells. We demonstrate that during the first few days of culture, the secretion of albumin and fibrinogen was 2-fold higher in cocultures compared to hepatocytes alone. Hepatocyte function in both cultures stabilized to a similar level during the second week, suggesting that endothelial cells can induce the early recovery of hepatocytes after isolation and seeding. Endothelial cell-conditioned medium reproduced the effect of coculture in a dose-dependent fashion, suggesting a role for endothelial cell-derived soluble factors. Endothelial cell-conditioned medium increased mRNA levels of various acute-phase proteins such as albumin, fibrinogen, transferrin, and alpha-macroglobulin in hepatocytes. Surprisingly, the effect of endothelial cell-conditioned medium was not mediated by growth factors or cytokines, or by secreted extracellular matrix, but by the release of the amino acid proline, which mediates endogenous collagen synthesis by hepatocytes. These findings suggest an important role for proline secretion by endothelial cells as a paracrine factor regulating hepatocyte function.-Jindal, R., Nahmias, Y., Tilles, A. W., Berthiaume, F., Yarmush, M. L. Amino acid-mediated heterotypic interaction governs performance of a hepatic tissue model. FASEB J. 23, 2288-2298 (2009) C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA USA. Shriners Hosp Children, Boston, MA USA. RP Yarmush, ML (reprint author), 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org RI Nahmias, Yaakov/H-4725-2013; OI Nahmias, Yaakov/0000-0002-6051-616X FU NIH BioMEMS Resource Center [P41 EB-002503, RO1AI063795] FX We thank Chris Pohun Chen, Avrum Leeder, Luke Selby, and Carley Shulman for the isolation of cells from rat livers. We appreciate the help of Dr. David Yarmush in conducting collagen measurement studies. This work was supported by NIH BioMEMS Resource Center grant P41 EB-002503 and NIH grant RO1AI063795. Microscopic imaging studies were made possible by a core morphology facility, and gene expression measurements were carried out at the Genomic and Proteomic Facility at Boston's Shriners Burns Hospital. NR 32 TC 29 Z9 30 U1 0 U2 9 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2009 VL 23 IS 7 BP 2288 EP 2298 DI 10.1096/fj.08-114934 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 481UC UT WOS:000268836500028 PM 19246486 ER PT J AU Salmon, AB Leonard, S Masamsetti, V Pierce, A Podlutsky, AJ Podlutskaya, N Richardson, A Austad, SN Chaudhuri, AR AF Salmon, Adam B. Leonard, Shanique Masamsetti, Venkata Pierce, Anson Podlutsky, Andrej J. Podlutskaya, Natalia Richardson, Arlan Austad, Steven N. Chaudhuri, Asish R. TI The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis SO FASEB JOURNAL LA English DT Article DE longevity; comparative biology; oxidative stress; ubiquitin-proteasome; Chiroptera ID NAKED MOLE-RAT; FREE-RADICAL PRODUCTION; LIVING RODENT; ANTIOXIDANT DEFENSES; CELLULAR-RESISTANCE; HEART-MITOCHONDRIA; STRESS RESISTANCE; H2O2 PRODUCTION; MULTIPLE FORMS; METABOLIC-RATE AB Altered structure, and hence function, of cellular macromolecules caused by oxidation can contribute to loss of physiological function with age. Here, we tested whether the lifespan of bats, which generally live far longer than predicted by their size, could be explained by reduced protein damage relative to short-lived mice. We show significantly lower protein oxidation (carbonylation) in Mexican free-tailed bats (Tadarida brasiliensis) relative to mice, and a trend for lower oxidation in samples from cave myotis bats (Myotis velifer) relative to mice. Both species of bat show in vivo and in vitro resistance to protein oxidation under conditions of acute oxidative stress. These bat species also show low levels of protein ubiquitination in total protein lysates along with reduced proteasome activity, suggesting diminished protein damage and removal in bats. Lastly, we show that bat-derived protein fractions are resistant to urea-induced protein unfolding relative to the level of unfolding detected in fractions from mice. Together, these data suggest that long lifespan in some bat species might be regulated by very efficient maintenance of protein homeostasis.-Salmon, A. B., Leonard, S., Masamsetti, V., Pierce, A., Podlutsky, A. J., Podlutskaya, N., Richardson, A., Austad, S. N., Chaudhuri, A. R. The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis. FASEB J. 23, 2317-2326 (2009) C1 [Chaudhuri, Asish R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Pierce, Anson; Richardson, Arlan; Chaudhuri, Asish R.] S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. [Pierce, Anson; Richardson, Arlan; Austad, Steven N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78245 USA. RP Chaudhuri, AR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, Sam & Ann Barshop Inst Longev & Aging Studies, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM chaudhuria@uthscsa.edu RI Pierce, Anson/D-1079-2012; Podlutsky, Andrej/F-5421-2015 OI Pierce, Anson/0000-0002-1383-0180; FU NIH [T32 AG021890-05, AG23843, R37 AG26557, AG022873]; [K07 AG025063 04] FX The authors thank Bertran Friguet (Universite Paris, Paris, France) for providing 20S proteasome antibody. We also thank Tom Kunz and Louise Allen for help in obtaining our bat samples. This work was supported by K07 AG025063 04 (A. R. C., A. R., S.N.A.); NIH training grant T32 AG021890-05 (A. B. S.); and NIH grants AG23843, R37 AG26557 (A. R.), and AG022873 (S.N.A.). NR 48 TC 54 Z9 55 U1 3 U2 16 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2009 VL 23 IS 7 BP 2317 EP 2326 DI 10.1096/fj.08-122523 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 481UC UT WOS:000268836500031 PM 19244163 ER PT J AU Duke-Cohan, J AF Duke-Cohan, J. TI Regulation of extracellular proteolysis by CUB-domain containing proteins SO FEBS JOURNAL LA English DT Meeting Abstract CT 34th Congress of the Federation-of-European-Biochemical-Societies CY JUL 04-09, 2009 CL Prague, CZECH REPUBLIC SP Federat European Biochem Soc C1 [Duke-Cohan, J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUL PY 2009 VL 276 BP 18 EP 18 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 458ZS UT WOS:000267069900047 ER PT J AU Wall, C Wrisley, DM Statler, KD AF Wall, Conrad, III Wrisley, Diane M. Statler, Kennyn D. TI Vibrotactile tilt feedback improves dynamic gait index: A fall risk indicator in older adults SO GAIT & POSTURE LA English DT Article DE Prostheses and implants; Postural balance; Falls; Accidental; Biofeedback ID VESTIBULAR DISORDERS ACTIVITIES; DAILY LIVING SCALE; ELDERLY POPULATION; POSTURAL CONTROL; BALANCE; PREVENTION; COMMUNITY; TRIAL AB The purpose of this study was to determine the effectiveness of vibrotactile feedback of body tilt in improving dynamic gait index (DGI) a fall risk indicator in community dwelling older adults. Twelve healthy elderly subjects (three males and nine females, age 79.7 +/- 5.4 yrs) were tested in an institutional balance rehabilitation laboratory to investigate changes between the feedback off and on conditions. Subjects were acutely exposed to a vibrotactile display that indicated the magnitude and direction of their body tilt from the vertical. DGI and mediolateral (ML) sway were determined during locomotion with, and without, vibrotactile tilt feedback (VTTF). All subjects were at risk for falls based on their initial DGI Score (range: 1519, mean 17.4 +/- 1.56), which was taken with the vibratory stimulus turned off. Subjects learned to use the trunk tilt information from the vibrotactile feedback vest through 20-30 min of gait and balance training consisting of activities that challenged their balance. Subjects were then retested on the DGI. Statistically significant changes were demonstrated for the DGI total score while using the vibrotactile tilt feedback. DGI total scores improved from 17.1 +/- 0.4 to 20.8 +/- 0.3 (p < 0.05). We conclude that vibrotactile tilt feedback improves both control of mediolateral sway during gait and dynamic gait index. Both are fall risk indicators for this population. (C) 2009 Elsevier B.V. All rights reserved. C1 [Wall, Conrad, III] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Jenks Vestibular Diagnost Lab,Dept Otol & Laryngo, Boston, MA 02114 USA. [Wrisley, Diane M.] SUNY Buffalo, Dept Rehabil Sci, Buffalo, NY 14260 USA. RP Wall, C (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Jenks Vestibular Diagnost Lab,Dept Otol & Laryngo, Boston, MA 02114 USA. EM cwall@mit.edu FU NIH NICDC [R01DC0006210]; New York Physical Therapy Association (NYPTA) Research Designated Funds FX Some of this material was presented at the American Speech and Hearing Association, November 15, 2007, in Boston, MA, the American Neurotology Society September 15,2007 in Washington, DC, and at the American Physical Therapy Association February 16, 2007 in Boston, MA. Honoraria were received for 2 of these presentations (ASHA and ANS). NR 31 TC 30 Z9 32 U1 5 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD JUL PY 2009 VL 30 IS 1 BP 16 EP 21 DI 10.1016/j.gaitpost.2009.02.019 PG 6 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 457DC UT WOS:000266905000004 PM 19345107 ER PT J AU Podolsky, DK Gerken, G Eyking, A Cario, E AF Podolsky, Daniel K. Gerken, Guido Eyking, Annette Cario, Elke TI Colitis-Associated Variant of TLR2 Causes Impaired Mucosal Repair Because of TFF3 Deficiency SO GASTROENTEROLOGY LA English DT Article ID INTESTINAL TREFOIL FACTOR; INFLAMMATORY-BOWEL-DISEASE; TOLL-LIKE RECEPTOR-2; SILENCER INHIBITOR; EPITHELIAL-CELLS; BARRIER FUNCTION; GOBLET CELLS; DIFFERENTIATION; EXPRESSION; GROWTH AB BACKGROUND & AIMS: Goblet cells (GC) facilitate mucosal protection and epithelial barrier repair, yet the innate immune mechanisms that selectively drive GC functions have not been defined. The aim of this study was to determine whether Toll-like receptor (TLR) 2 and modulation of GC-derived trefoil factor (TFF) 3 are functionally linked in the intestine. METHODS: GC modulation was assessed using quantitative real-rime polymerase chain reaction analysis (qRT-PCR), Western blotting, and confocal microscopy Dextran sulfate sodium (DSS) colitis was induced in wild-type, TFF3(-/-), and TLR2(-/-) mice. Recombinant TLR2 ligand or TFF3 peptide were orally administered after DSS termination. Caco-2 cells overexpressing full-length TLR2 or mutant TLR2-R7S3Q were tested for TFF3 synthesis and functional-related effects in a Wounding assay. RESULTS: Data from in vitro (Ls174T) and ex vivo models of murine and human GC reveal that TLR2 activation selectively induces synthesis of TFF3. In vivo studies using TFF3-/- or TLR2-/- mice demonstrate the ability for oral treatment with a TLR2 agonist to confer antiapoptotic protection of the intestinal mucosa against inflammatory stress-induced damage through TFF3. Recombinant TFF3 rescues TLR2-deficient mice from increased morbidity and mortality during acute colonic injury. Severe ulcerative colitis (UC) has recently been found to be associated with the R753Q polymorphism of the TLR2 gene. The relevance of the observed functional effect of TLR2 in regulating GC is confirmed by the finding that the UC-associated TLR2R753Q variant is functionally deficient in the ability to induce TFF3 synthesis, thus leading to impaired wound healing. CONCLUSIONS: These data demonstrate a novel function of TLR2 in intestinal GC that links products of commensal bacteria to innate immune protection of the host via TFF3. C1 [Cario, Elke] Univ Hosp Essen, Div Gastroenterol & Hepatol, Inst Grp 1, D-45147 Essen, Germany. [Podolsky, Daniel K.] UT SW Med Ctr, Dept Internal Med, Dallas, TX USA. [Podolsky, Daniel K.] Massachusetts Gen Hosp, Gastrointestinal Unit, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Podolsky, Daniel K.] Harvard Univ, Sch Med, Boston, MA USA. [Gerken, Guido; Eyking, Annette; Cario, Elke] Univ Duisburg Essen, Sch Med, Essen, Germany. RP Cario, E (reprint author), Univ Hosp Essen, Div Gastroenterol & Hepatol, Inst Grp 1, Virchowstr 171, D-45147 Essen, Germany. EM elke.cario@uni-duisburg-essen.de OI Gerken, Guido/0000-0001-6734-5001 FU NIDDK NIH HHS [P30 DK043351-17, DK60049, DK43351, R01 DK060049-07, P30 DK043351, R01 DK060049] NR 37 TC 100 Z9 103 U1 2 U2 20 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2009 VL 137 IS 1 BP 209 EP 220 DI 10.1053/j.gastro.2009.03.007 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 463DU UT WOS:000267410100031 PM 19303021 ER PT J AU Eksteen, B Mora, JR Haughton, EL Henderson, NC Lee-Turner, L Villablanca, EJ Curbishley, SM Aspinall, AI von Andrian, UH Adams, DH AF Eksteen, Bertus Mora, J. Rodrigo Haughton, Emma L. Henderson, Neil C. Lee-Turner, Laura Villablanca, Eduardo J. Curbishley, Stuart M. Aspinall, Alex I. von Andrian, Ulrich H. Adams, David H. TI Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells SO GASTROENTEROLOGY LA English DT Article ID THYMUS-EXPRESSED CHEMOKINE; INTEGRIN ALPHA-4-BETA-7; HEPATIC EXPRESSION; LYMPHOID-TISSUE; SMALL-INTESTINE; CROHNS-DISEASE; BETA 7; LYMPHOCYTES; MADCAM-1; CCL25 AB BACKGROUND & AIMS: Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and alpha 4 beta 7, which recognize CCL25 and mucosal addressin cell-adhesion molecule-1 in the intestine promoting the development of regional immunity. In mice, imprinting of CCR9 and alpha 4 beta 7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extra-intestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+alpha 4 beta 7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and alpha 4 beta 7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC. METHODS: Human and murine DCs from gut, liver, or portal lymph nodes and hepatic stellate cells were used to activate CD8 T cells. Imprinting of CCR9 and alpha 4 beta 7 and functional migration responses were determined. Crossover activation protocols assessed plasticity of gut homing. RESULTS: Activation by gut DCs imprinted high levels of functional CCR9 and alpha 4 beta 7 on naive CD8 T cells, whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA dependent and demonstrated plasticity. CONCLUSIONS: Imprinting and plasticity of gut-homing human CD8 T cells requires primary activation or reactivation by gut DCs and is retinoic acid dependent. The inability of liver DCs to imprint gut tropism implies that alpha 4 beta 7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut. C1 [Eksteen, Bertus; Haughton, Emma L.; Lee-Turner, Laura; Curbishley, Stuart M.; Adams, David H.] Univ Birmingham, Liver Res Ctr, MRC Ctr Immune Regulat, Inst Biomed Res,Med Sch, Birmingham B15 2TT, W Midlands, England. [Mora, J. Rodrigo; Villablanca, Eduardo J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Henderson, Neil C.] Univ Edinburgh, Ctr Inflammat Res, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. [Aspinall, Alex I.] Univ Calgary, Foothills Hosp, Calgary, AB, Canada. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. RP Adams, DH (reprint author), Univ Birmingham, Liver Res Ctr, MRC Ctr Immune Regulat, Inst Biomed Res,Med Sch, 5th Floor,Wolfson Dr, Birmingham B15 2TT, W Midlands, England. EM d.h.adams@bham.ac.uk RI Adams, David/C-9092-2009; von Andrian, Ulrich/A-5775-2008; Villablanca, Eduardo/E-1380-2016; OI Villablanca, Eduardo/0000-0001-9522-9729; ADAMS, David/0000-0001-6776-0336; Aspinall, Alexander/0000-0001-5534-6146 FU Medical Research Council [G0601816, ]; NIAID NIH HHS [R01 AI061663, R01 AI069259] NR 33 TC 61 Z9 63 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2009 VL 137 IS 1 BP 320 EP 329 DI 10.1053/j.gastro.2009.02.046 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 463DU UT WOS:000267410100041 PM 19233184 ER PT J AU Leung, FW AF Leung, Felix W. TI Search for premalignant mucosal lesions: does endoscopic measurement of oxygen saturation by differential path-length spectroscopy help? SO GASTROINTESTINAL ENDOSCOPY LA English DT Editorial Material ID IN-VIVO; BARRETTS-ESOPHAGUS; TECHNOLOGY; DYSPLASIA C1 [Leung, Felix W.] Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, North Hills, CA USA. [Leung, Felix W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gastroenterol, Los Angeles, CA 90095 USA. RP Leung, FW (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, North Hills, CA USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JUL PY 2009 VL 70 IS 1 BP 7 EP 8 DI 10.1016/j.gie.2008.11.015 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 464RI UT WOS:000267523200002 PM 19559830 ER PT J AU Shergill, AK McQuaid, KR Rempel, D AF Shergill, Amandeep K. McQuaid, Kenneth R. Rempel, David TI Ergonomics and GI endoscopy SO GASTROINTESTINAL ENDOSCOPY LA English DT Review ID CUMULATIVE TRAUMA DISORDERS; CARPAL-TUNNEL-SYNDROME; LAPAROSCOPIC SURGERY; INTERVENTIONAL CARDIOLOGISTS; COLONOSCOPY; PREVALENCE; INJURIES; OVERUSE; MONITOR; HEIGHT C1 [Shergill, Amandeep K.; McQuaid, Kenneth R.] Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA USA. [Shergill, Amandeep K.; McQuaid, Kenneth R.] San Francisco VA Med Ctr, Med Serv, Gastroenterol Sect, San Francisco, CA 94121 USA. [Rempel, David] Univ Calif San Francisco, Dept Med, Div Occupat Med, San Francisco, CA USA. [Rempel, David] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. RP Shergill, AK (reprint author), San Francisco VA Med Ctr, GI Sect, 4150 Clement St,Bldg 203 111B1, San Francisco, CA 94121 USA. RI Rempel, David/E-8424-2013 NR 48 TC 24 Z9 24 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JUL PY 2009 VL 70 IS 1 BP 145 EP 153 DI 10.1016/j.gie.2008.12.235 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 464RI UT WOS:000267523200022 PM 19559836 ER PT J AU Kolodkin-Gal, D Edden, Y Hartshtark, Z Ilan, L Khalaileh, A Pikarsky, AJ Pikarsky, E Rabkin, SD Panet, A Zamir, G AF Kolodkin-Gal, D. Edden, Y. Hartshtark, Z. Ilan, L. Khalaileh, A. Pikarsky, A. J. Pikarsky, E. Rabkin, S. D. Panet, A. Zamir, G. TI Herpes simplex virus delivery to orthotopic rectal carcinoma results in an efficient and selective antitumor effect SO GENE THERAPY LA English DT Article DE HSV-1; colon carcinoma; oncolysis; PKR; 2-aminopurine ID DEPENDENT-PROTEIN-KINASE; GENE-THERAPY; IN-VIVO; CELL-PROLIFERATION; BREAST-CANCER; COLON-CANCER; TYPE-1 G207; PKR; EXPRESSION; VECTORS AB Cancer of the rectum poses a complex therapeutic challenge because of its proximity to adjacent organs and anal sphincters. The addition of radiotherapy before surgical resection has been shown to confer good survival rates while preserving sphincter function. Nevertheless, radiation is associated with significant side effects. On the basis of our previous work showing that herpes simplex virus type-1 (HSV-1) preferentially infects human colon cancer, we set out to examine the oncolytic effect of HSV-1 on orthotopic rectal tumors in mice. Two vectors were compared for oncolytic activity, HSV-1(G beta) with wild-type replication and an attenuated HSV-1 vector (HSV-G47 Delta). Intratumoral injection of HSV-1(G beta) and HSV-G47 Delta resulted in a significant reduction or disappearance of the tumors and increased survival of mice. Although the use of HSV-1(G beta) was associated with systemic toxicity, HSV-G47 Delta appears to possess a selective oncolytic activity. Moreover, infection with HSV-G47 Delta resulted in the activation of the double-stranded RNA-dependent protein kinase (PKR) pathway. A significant improvement in viral replication and the antitumor effect was observed when the PKR inhibitor 2-aminopurine was coadministered with HSV-G47 Delta to the tumor. In conclusion, the efficacy of local delivery of HSV-G47 Delta combined with a specific chemical inhibitor of antiviral activity points to a novel therapeutic modality for rectal cancer and other solid tumors. Gene Therapy (2009) 16, 905-915; doi:10.1038/gt.2009.44; published online 14 May 2009 C1 [Kolodkin-Gal, D.; Panet, A.] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Virol, IL-91120 Jerusalem, Israel. [Edden, Y.; Pikarsky, A. J.] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Gen Surg, IL-91120 Jerusalem, Israel. [Hartshtark, Z.; Khalaileh, A.; Zamir, G.] Hebrew Univ Jerusalem, Hadassah Med Sch, Expt Surg Lab, IL-91120 Jerusalem, Israel. [Ilan, L.] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Expt Med & Canc Res, IL-91120 Jerusalem, Israel. [Pikarsky, E.] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pathol, IL-91120 Jerusalem, Israel. [Rabkin, S. D.] Massachusetts Gen Hosp, Dept Neurosurg, Mol Neurosurg Lab, Boston, MA 02114 USA. [Rabkin, S. D.] Harvard Univ, Sch Med, Boston, MA USA. RP Panet, A (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Virol, IL-91120 Jerusalem, Israel. EM amospa@ekmd.huji.ac.il RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 FU European Community FX This work was supported by a grant from the European Community, program 6, The Cinigene Network of Excellence, and by a grant from Philip-Morris US and the international external research program. We especially thank Professor Zichria Zakay-Rones, The Hebrew University, Hadassah Medical School, for her valuable contribution to our work and we also thank Ms Evelyn Zeira for her contribution. NR 29 TC 11 Z9 11 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD JUL PY 2009 VL 16 IS 7 BP 905 EP 915 DI 10.1038/gt.2009.44 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 468HB UT WOS:000267806600009 PM 19440231 ER PT J AU Scherrer, JF Virgo, KS Zeringue, A Bucholz, KK Jacob, T Johnson, RG True, WR Carney, RM Freedland, KE Xian, H Caplan, L McDonald, J Eisen, SA AF Scherrer, Jeffrey F. Virgo, Katherine S. Zeringue, Angelique Bucholz, Kathleen K. Jacob, Theodore Johnson, Robert G. True, William R. Carney, Robert M. Freedland, Kenneth E. Xian, Hong Caplan, Liron McDonald, Jay Eisen, Seth A. TI Depression increases risk of incident myocardial infarction among Veterans Administration patients with rheumatoid arthritis SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Depression; Myocardial infarction; Rheumatoid arthritis; Veterans ID CORONARY-HEART-DISEASE; PSYCHIATRIC-DISORDERS; MORTALITY; MEN; AFFAIRS; COMORBIDITY; POPULATION; PREVALENCE; DIAGNOSIS; SYMPTOMS AB Objective: This study evaluates whether depression is a risk factor for incident myocardial infarction (MI) in Department of Veterans Affairs (VA) patients with rheumatoid arthritis (RA) between 30 and 79 years of age. Methods: We used a retrospective cohort study of 15,634 patients with RA. Diagnoses and sociodemographic data were obtained from VA administrative and pharmacy databases between fiscal years 1999 and 2006. Entry into the cohort required 2 years of patient time with no evidence of cardiovascular disease. Cox proportional hazard models with time-dependent covariates were computed to determine whether RA patients with depression as compared to RA patients without depression were at increased risk for MI during the maximum 6-year follow-up period. Results: Unadjusted analyses indicated depressed RA patients were 1.4 times more likely than nondepressed RA patients to have an MI during follow-up. These results remained significant (HR=1.4; 95% CI: in the adjusted Cox proportional hazards model which included the effects of sociodemographics and known physical risks (e.g., diabetes) for MI. Conclusions: Depressed RA patients, without a history of cardiovascular disease, are 40% more likely to have a heart attack as compared to those without depression. These data demonstrate a rapid (within 6 years) transition to MI following onset of depression in RA patients. Increased monitoring of depression and heart disease status in this patient population may be warranted which in turn may result in longer duration of life. Published by Elsevier Inc. C1 [Scherrer, Jeffrey F.; Virgo, Katherine S.; Zeringue, Angelique; Bucholz, Kathleen K.; True, William R.; Xian, Hong; McDonald, Jay] St Louis Vet Affairs Med Ctr, Res Serv, St Louis, MO 63106 USA. [Scherrer, Jeffrey F.; Bucholz, Kathleen K.] Washington Univ, Dept Psychiat, Midwest Alcoholism Res Ctr, Sch Med, St Louis, MO 63108 USA. [Virgo, Katherine S.; Johnson, Robert G.] St Louis Univ, Med Ctr, Dept Surg, St Louis, MO 63110 USA. [Zeringue, Angelique; Xian, Hong; McDonald, Jay] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63108 USA. [Jacob, Theodore] Vet Affairs Palo Alto Hlth Care Syst, Menlo Pk, CA 94025 USA. [True, William R.] Washington Univ, George Warren Brown Sch Social Work, St Louis, MO 63110 USA. [Caplan, Liron] Univ Colorado, Dept Med Rheumatol, Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Eisen, Seth A.] Dept Vet Affairs, Hlth Serv Res & Dev Serv, Washington, DC USA. RP Scherrer, JF (reprint author), St Louis VAMC 151JC, St Louis, MO 63106 USA. EM scherrej@psychiatry.wustl.edu RI Zeringue, Angelique/I-1755-2012 FU VA; CSCP [458]; Career Development Award FX This study was supported by VA grants, CSCP #458 and Career Development Award to Jeffrey F. Scherrer. NR 36 TC 29 Z9 31 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2009 VL 31 IS 4 BP 353 EP 359 DI 10.1016/j.genhosppsych.2009.04.001 PG 7 WC Psychiatry SC Psychiatry GA 468DN UT WOS:000267794500009 PM 19555796 ER PT J AU Moser, KL Kelly, JA Lessard, CJ Harley, JB AF Moser, K. L. Kelly, J. A. Lessard, C. J. Harley, J. B. TI Recent insights into the genetic basis of systemic lupus erythematosus SO GENES AND IMMUNITY LA English DT Review DE lupus; genetics; autoimmunity ID COMPLEMENT DEFICIENCY; RHEUMATOID-ARTHRITIS; FAMILIAL AGGREGATION; FUNCTIONAL VARIANTS; AFRICAN-AMERICANS; NULL ALLELES; RISK-FACTORS; ASSOCIATION; SUSCEPTIBILITY; DISEASE AB Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region ( multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fc gamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease. Genes and Immunity (2009) 10, 373-379; doi: 10.1038/gene.2009.39; published online 14 May 2009 C1 [Moser, K. L.; Kelly, J. A.; Lessard, C. J.; Harley, J. B.] Oklahoma Med Res Fdn, Arthrit & Immunol Program, Oklahoma City, OK 73104 USA. [Moser, K. L.; Lessard, C. J.; Harley, J. B.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Harley, J. B.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. RP Moser, KL (reprint author), Oklahoma Med Res Fdn, Arthrit & Immunol Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM moserk@omrf.org FU NIH [AR043274, AI24717, AR62277, AR42460, AI31584, DE015223, RR015577, RR020143, AR48940, AR049084]; Mary Kirkland Scholarship; Barrett Scholarship Fund; Alliance for Lupus Research; US Department of Veterans Affairs FX This work has been supported by the NIH (AR043274, AI24717, AR62277, AR42460, AI31584, DE015223, RR015577, RR020143, AR48940 and AR049084), the Mary Kirkland Scholarship, the Barrett Scholarship Fund, the Alliance for Lupus Research and the US Department of Veterans Affairs. NR 56 TC 177 Z9 184 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL PY 2009 VL 10 IS 5 BP 373 EP 379 DI 10.1038/gene.2009.39 PG 7 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 472YH UT WOS:000268168800001 PM 19440199 ER PT J AU Lu, R Vidal, GS Kelly, JA Delgado-Vega, AM Howard, XK Macwana, SR Dominguez, N Klein, W Burrell, C Harley, IT Kaufman, KM Bruner, GR Moser, KL Gaffney, PM Gilkeson, GS Wakeland, EK Li, QZ Langefeld, CD Marion, MC Divers, J Alarcon, GS Brown, EE Kimberly, RP Edberg, JC Ramsey-Goldman, R Reveille, JD McGwin, G Vila, LM Petri, MA Bae, SC Cho, SK Bang, SY Kim, I Choi, CB Martin, J Vyse, TJ Merrill, JT Harley, JB Alarcon-Riquelme, ME Nath, SK James, JA Guthridge, JM AF Lu, R. Vidal, G. S. Kelly, J. A. Delgado-Vega, A. M. Howard, X. K. Macwana, S. R. Dominguez, N. Klein, W. Burrell, C. Harley, I. T. Kaufman, K. M. Bruner, G. R. Moser, K. L. Gaffney, P. M. Gilkeson, G. S. Wakeland, E. K. Li, Q-Z Langefeld, C. D. Marion, M. C. Divers, J. Alarcon, G. S. Brown, E. E. Kimberly, R. P. Edberg, J. C. Ramsey-Goldman, R. Reveille, J. D. McGwin, G., Jr. Vila, L. M. Petri, M. A. Bae, S-C Cho, S-K Bang, S-Y Kim, I. Choi, C-B Martin, J. Vyse, T. J. Merrill, J. T. Harley, J. B. Alarcon-Riquelme, M. E. Nath, S. K. James, J. A. Guthridge, J. M. CA BIOLUPUS Multictr Collaborations GENLES Multictr Collaboration TI Genetic associations of LYN with systemic lupus erythematosus SO GENES AND IMMUNITY LA English DT Article DE systemic lupus erythematosus; association; LYN; SNP ID GENOME-WIDE ASSOCIATION; B-CELLS; DEFICIENT MICE; AUTOIMMUNE-DISEASE; KINASE LYN; VARIANTS; PROLIFERATION; LYMPHOCYTES; PREVALENCE; ACTIVATION AB We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P = 1.1 x 10(-4), odds ratio (OR) = 0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism ( SNP) is located in the 50 untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P = 1.5 x 10(-3), OR = 0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets. Genes and Immunity (2009) 10, 397-403; doi: 10.1038/gene.2009.19; published online 16 April 2009 C1 [Lu, R.; Vidal, G. S.; Macwana, S. R.; Dominguez, N.; Klein, W.; James, J. A.; Guthridge, J. M.] Oklahoma Med Res Fdn, Clin Immunol Program, Oklahoma City, OK 73104 USA. [Kelly, J. A.; Howard, X. K.; Burrell, C.; Harley, I. T.; Kaufman, K. M.; Bruner, G. R.; Moser, K. L.; Gaffney, P. M.; Harley, J. B.; Alarcon-Riquelme, M. E.; Nath, S. K.] Oklahoma Med Res Fdn, Arthrit & Immunol Program, Oklahoma City, OK 73104 USA. [Delgado-Vega, A. M.; Alarcon-Riquelme, M. E.] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. [Kaufman, K. M.; Harley, J. B.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Gilkeson, G. S.] Med Univ S Carolina, Dept Med, Div Rheumatol, Charleston, SC 29425 USA. [Wakeland, E. K.; Li, Q-Z] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA. [Langefeld, C. D.; Marion, M. C.; Divers, J.] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Alarcon, G. S.; Brown, E. E.; Kimberly, R. P.; Edberg, J. C.; McGwin, G., Jr.] Univ Alabama, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Ramsey-Goldman, R.] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Dept Med, Chicago, IL 60611 USA. [Reveille, J. D.] Univ Texas Houston Hlth Sci Ctr, Div Rheumatol & Clin Immunogenet, Dept Internal Med, Houston, TX USA. [Vila, L. M.] Univ Puerto Rico, Div Rheumatol, Dept Med, San Juan, PR 00936 USA. [Petri, M. A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21205 USA. [Bae, S-C; Cho, S-K; Bang, S-Y; Kim, I.; Choi, C-B] Hanyang Univ, Hosp Rheumat Dis, Dept Rheumatol, Seoul 133791, South Korea. [Martin, J.] CSIC, Inst Biomed & Parasitol Lopez Neyra, Granada, Spain. [Vyse, T. J.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Rheumatol Sect, London, England. [Merrill, J. T.] Oklahoma Med Res Fdn, Dept Clin Pharmacol, Oklahoma City, OK 73104 USA. [Harley, J. B.; James, J. A.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Harley, J. B.; James, J. A.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. RP Guthridge, JM (reprint author), 825 NE 13th St,MS 53, Oklahoma City, OK 73104 USA. EM guthridgej@omrf.org RI Delgado-Vega, Angelica Maria/A-4318-2009; Vyse, Tim/G-3887-2011; Martin, Javier/B-8141-2008; D'Alfonso, Sandra/K-7295-2014; Witte, Torsten/B-5783-2016; OI Delgado-Vega, Angelica Maria/0000-0002-9865-0591; D'Alfonso, Sandra/0000-0002-3983-9925; Silva, Berta/0000-0001-6579-5068; Kimberly, Robert/0000-0002-5330-3086; Alarcon Riquelme, Marta Eugenia/0000-0002-7632-4154 FU National Institutes of Health [RR020143, RR015577, NIAID-HHSN266200500026C, AI031584, AR053483, AR48940, AI063622, AR049084, AR42460, AR12253, AR62277, AI24717, AI063274, AR052125, AR043247, DEO15223]; Kirkland Scholar awards; Alliance for Lupus Research; US Department of Veterans Affairs; Swedish Research Council; Korea Healthcare technology RD Project; Ministry for Health, Welfare and Family Affairs, Republic of Korea; Torsten & Ragnar Soderbergs Foundation; Swedish Foundation Against Rheumatism; Gustaf Vth-80th-Year Foundation; Plan Nacional de I+D, Spain [SAF06-00398]; Junta de Andalucia [CTS-180]; OHRS [HR08-037]; Oklahoma Center for the Advancement of Science Technology; [A010252]; [A080588] FX We thank the participants, both patients and controls, who graciously agreed to take part in these studies by donating samples to the various collections, including the Lupus Family Registry and Repository (http://lupus.omrf.org), PROFILE, BIOLUPUS and many other individual or multicenter collaborator initiated collections. We also thank the recruitment and technical teams at each of the sample procurement sites for their important contributions. We thank the Wake Forest University Health Sciences Center for Public Health Genomics for support of the data analysis efforts of our Wake Forest University collaborators. Finally, we thank the various funding sources as outlined on the title page for their continued support for the collection of samples and the conduct of this research.; Members of BIOLUPUS who have provided samples to this study are: Peter Junker, Ann Voss and Helle Laustrup (Odense, Denmark), Bernard Lawerys and Fredric Houssieau (Louvain, Belgium), Carlos Vasconcelos and Berta Martins Da Silva (Porto, Portugal), Carmen Gutierrez and Ana Suarez (Oviedo, Spain), Torsten Witte (Hannover, Germany), Sandra D'Alfonso, Sergio Migliaresi, Mauro Galeazzi and Gian Domenico Sebastiani (Novara, Naples, Siena and Rome, Italy), Bernardo Pons-Estel and the members of GENLES (Rosario, Argentina) and Emoke Endreffy (Szeged, Hungary). Peter K Gregersen from the Feinstein Institute of Medical Research and Jorge R Oksenberg from the University of California at San Francisco graciously provided controls used in this study. Members of PROFILE who have provided samples to this study are Graciela S Alarcon, Elizabeth E Brown, Robert P Kimberly, Jeffery C Edberg and Gerald McGwin, Jr (University of Alabama Birmingham, Birmingham, AL, USA), Rosalind Ramsey-Goldman (Northwestern University Feinberg School of Medicine, Chicago, IL, USA), John D Reveille (University Texas Health Science Center, Houston, TX, USA), Luis M Vila (University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA) and Michelle A Petri (Johns Hopkins Hospital, Baltimore, MD, USA). This project was funded by National Institutes of Health RR020143 (JMG and JBH), RR015577 (JMG, JBH, JAJ), NIAID-HHSN266200500026C (JMG and JAJ), AI031584 (JBH, JMG, JAJ), AR053483 (JMG, SKN and JAJ), AR48940 (JBH, JAJ), AI063622 (SKN), Kirkland Scholar awards (JBH and JAJ), AR049084 (SKN, JBH, RPK, RRG, JDR, MAP, LMV, GSA, JCE, GMcG Jr), AR42460 (JBH), AR12253 (JBH), AR62277 (JBH), AI24717 (JBH), AI063274 (PMG), AR052125 (PMG), AR043247 (KLM), DEO15223 (JBH), Alliance for Lupus Research (JBH), the US Department of Veterans Affairs (JBH), Swedish Research Council (MEAR), the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea. (A010252, A080588) (SCB), the Torsten & Ragnar Soderbergs Foundation (MEAR), the Swedish Foundation Against Rheumatism (MEAR), the Gustaf Vth-80th-Year Foundation (MEAR), Plan Nacional de I+D, Spain (SAF06-00398) (JM), the Junta de Andalucia, grupo CTS-180 (JM) and OHRS award # HR08-037 from the Oklahoma Center for the Advancement of Science & Technology (JMG). Dr Harley has received consulting fees, speaking fees and/or director's fees from Bio-Rad Laboratories, Merck, UCB Inc., ImmunoVision Inc., IVAX Diagnostics and JK Autoimmunity and owns stock or stock options in IVAX Diagnostics. NR 29 TC 50 Z9 51 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL PY 2009 VL 10 IS 5 BP 397 EP 403 DI 10.1038/gene.2009.19 PG 7 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 472YH UT WOS:000268168800004 PM 19369946 ER PT J AU Douglas, KB Windels, DC Zhao, J Gadeliya, AV Wu, H Kaufman, KM Harley, JB Merrill, J Kimberly, RP Alarcon, GS Brown, EE Edberg, JC Ramsey-Goldman, R Petri, M Reveille, JD Vila, LM Gaffney, PM James, JA Moser, KL Alarcon-Riquelme, ME Vyse, TJ Gilkeson, GS Jacob, CO Ziegler, JT Langefeld, CD Ulgiati, D Tsao, BP Boackle, SA AF Douglas, K. B. Windels, D. C. Zhao, J. Gadeliya, A. V. Wu, H. Kaufman, K. M. Harley, J. B. Merrill, J. Kimberly, R. P. Alarcon, G. S. Brown, E. E. Edberg, J. C. Ramsey-Goldman, R. Petri, M. Reveille, J. D. Vila, L. M. Gaffney, P. M. James, J. A. Moser, K. L. Alarcon-Riquelme, M. E. Vyse, T. J. Gilkeson, G. S. Jacob, C. O. Ziegler, J. T. Langefeld, C. D. Ulgiati, D. Tsao, B. P. Boackle, S. A. TI Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing SO GENES AND IMMUNITY LA English DT Article DE alternative splicing; systemic lupus erythematosus; complement receptors; single-nucleotide polymorphisms; B cells; follicular dendritic cells ID EPSTEIN-BARR-VIRUS; B-LYMPHOCYTES; C3D RECEPTOR; EXON RECOGNITION; EXPRESSION; CR-2; GENE; CELL; SUSCEPTIBILITY; CD21 AB Genetic factors influence susceptibility to systemic lupus erythematosus (SLE). A recent family-based analysis in Caucasian and Chinese populations provided evidence for association of single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene with SLE. Here we confirmed this result in a case-control analysis of an independent European-derived population including 2084 patients with SLE and 2853 healthy controls. A haplotype formed by the minor alleles of three CR2 SNPs (rs1048971, rs17615, rs4308977) showed significant association with decreased risk of SLE (30.4% in cases vs 32.6% in controls, P = 0.016, OR = 0.90 (0.82-0.98)). Two of these SNPs are in exon 10, directly 50 of an alternatively spliced exon preferentially expressed in follicular dendritic cells (FDC), and the third is in the alternatively spliced exon. Effects of these SNPs and a fourth SNP in exon 11 (rs17616) on alternative splicing were evaluated. We found that the minor alleles of these SNPs decreased splicing efficiency of exon 11 both in vitro and ex vivo. These findings further implicate CR2 in the pathogenesis of SLE and suggest that CR2 variants alter the maintenance of tolerance and autoantibody production in the secondary lymphoid tissues where B cells and FDCs interact. Genes and Immunity (2009) 10, 457-469; doi: 10.1038/gene.2009.27; published online 23 April 2009 C1 [Boackle, S. A.] Univ Colorado, Denver Sch Med, Div Rheumatol, Aurora, CO 80045 USA. [Zhao, J.; Wu, H.; Tsao, B. P.] Univ Calif Los Angeles, Los Angeles, CA USA. [Kaufman, K. M.; Harley, J. B.; Merrill, J.; Gaffney, P. M.; James, J. A.; Moser, K. L.; Alarcon-Riquelme, M. E.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Kaufman, K. M.; Harley, J. B.; Merrill, J.; James, J. A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Kaufman, K. M.; Harley, J. B.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Kimberly, R. P.; Alarcon, G. S.; Brown, E. E.; Edberg, J. C.] Univ Alabama, Birmingham, AL USA. [Ramsey-Goldman, R.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Petri, M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Reveille, J. D.] Univ Texas Houston Hlth Sci Ctr, Houston, TX USA. [Vila, L. M.] Univ Puerto Rico, San Juan, PR 00936 USA. [Alarcon-Riquelme, M. E.] Uppsala Univ, Uppsala, Sweden. [Vyse, T. J.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [Gilkeson, G. S.] Med Univ S Carolina, Charleston, SC 29425 USA. [Jacob, C. O.] Univ So Calif, Los Angeles, CA USA. [Ziegler, J. T.; Langefeld, C. D.] Wake Forest Univ Hlth Sci, Sect Stat Genet & Bioinformat, Winston Salem, NC USA. [Ulgiati, D.] Univ Western Australia, Sch Biomed Biomol & Chem Sci, Crawley, WA, Australia. RP Boackle, SA (reprint author), Univ Colorado, Denver Sch Med, Div Rheumatol, Mail Stop B-115,1775 Aurora Court, Aurora, CO 80045 USA. EM susan.boackle@ucdenver.edu RI Vyse, Tim/G-3887-2011; Zhao, Jian/E-6292-2012; OI Kimberly, Robert/0000-0002-5330-3086; Alarcon Riquelme, Marta Eugenia/0000-0002-7632-4154 FU NIH/NCI Cancer Core [P30 CA046934]; National Institutes of Health (NIH) [P30 DK57516]; American College of Rheumatology Research and Education Foundation; Alliance for Lupus Research; US Department of Veterans Affairs; Kirkland Scholar/Hospital for Special Surgery and Rheuminations; NIH [NIAID-DAIT-B AA-05-11, N01 AR12253, N01 AR62277, P01 AR049084, P20 RR015577, P20 RR020143, P30 AR053483, P50 AR48940, R01 DE015223, R01 AI31584, R01 AI070983R01 AR42460, R37 AI24717] FX We thank Dr Raul Torres (National Jewish Health and University of Colorado Denver School of Medicine) for providing the pL53In vector, Dr Yong Choi (Ochsner Clinic Foundation) for providing the HK FDC line, and Carissa Homme and Lauren Kuhlman (University of Colorado Denver School of Medicine, Aurora, CO, USA) for technical assistance. We also thank Dr Peter Gregersen (Feinstein Institute for Medical Research, Manhassat, NY, USA) for contributing DNA samples from control subjects to LLAS, and the Wake Forest University Health Sciences Center for Public Health Genomics for assistance with the principal component analysis of the genotyping data from LLAS1. The pL53In constructs were sequenced by the University of Colorado Cancer Center DNA Sequencing and Analysis Core (http://loki.uchsc.edu), which is supported by the NIH/NCI Cancer Core Support Grant (P30 CA046934). The quality of the RNA samples prepared from healthy human subjects was evaluated in the University of Colorado Cancer Center Microarray Core. Quantitative RT-PCR was carried out in the DERC Molecular Biology Core Facility, which is supported by National Institutes of Health (NIH) grant P30 DK57516. Other support for this work included grants from the American College of Rheumatology Research and Education Foundation, the Alliance for Lupus Research, the US Department of Veterans Affairs, Kirkland Scholar/Hospital for Special Surgery and Rheuminations, and NIH (NIAID-DAIT-B AA-05-11, N01 AR12253, N01 AR62277, P01 AR049084, P20 RR015577, P20 RR020143, P30 AR053483, P50 AR48940, R01 DE015223, R01 AI31584, R01 AI070983R01 AR42460, and R37 AI24717). NR 44 TC 27 Z9 27 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL PY 2009 VL 10 IS 5 BP 457 EP 469 DI 10.1038/gene.2009.27 PG 13 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 472YH UT WOS:000268168800010 PM 19387458 ER PT J AU Namjou, B Gray-McGuire, C Sestak, AL Gilkeson, GS Jacob, CO Merrill, JT James, JA Wakeland, EK Li, QZ Langefeld, CD Divers, J Ziegler, J Moser, KL Kelly, JA Kaufman, KM Harley, JB AF Namjou, B. Gray-McGuire, C. Sestak, A. L. Gilkeson, G. S. Jacob, C. O. Merrill, J. T. James, J. A. Wakeland, E. K. Li, Q-Z Langefeld, C. D. Divers, J. Ziegler, J. Moser, K. L. Kelly, J. A. Kaufman, K. M. Harley, J. B. TI Evaluation of C1q genomic region in minority racial groups of lupus SO GENES AND IMMUNITY LA English DT Article DE C1Q; SLE; genetics ID COMPLEMENT-SYSTEM; WIDE ASSOCIATION; DISEASE-ACTIVITY; ERYTHEMATOSUS; POLYMORPHISM; DEFICIENCIES; COMPONENT; MUTATIONS; NEPHRITIS; PATHWAY AB Complement cascade plasma proteins play a complex role in the etiopathogenesis of systemic lupus erythematosus (SLE). Hereditary C1q deficiency has been strongly related to SLE; however, there are very few published SLE studies that evaluate the polymorphisms of genes encoding for C1q (A, B and C). In this study, we evaluated 17 single nucleotide polymorphisms (SNPs) across 37 kb of C1QA, C1QB and C1QC in a lupus cohort of individuals of the African-American and Hispanic origin. In a case-only analysis, a significant association at multiple SNPs in the C1QA gene was detected in African Americans with kidney nephritis (best P = 4.91 x 10(-6)). In addition, C1QA was associated with SLE in African Americans with a lack of nephritis and accompanying photosensitivity when compared with that in normal controls (P = 6.80 x 10(-6)). A similar trend was observed in the Hispanic subjects (P = 0.003). Quantitative analysis showed that some SNPs in C1q genes might be correlated with C3 complement levels in an additive model among African Americans (best P = 0.0001). The C1QA gene is associated with subphenotypes of lupus in the African-American and Hispanic subjects. Further studies with higher SNP densities in this region and other complement components are necessary to elucidate the complex genetics and phenotypic interactions between complement components and SLE. Genes and Immunity (2009) 10, 517-524; doi: 10.1038/gene.2009.33; published online 14 May 2009 C1 [Namjou, B.; Gray-McGuire, C.; Sestak, A. L.; Merrill, J. T.; James, J. A.; Moser, K. L.; Kelly, J. A.; Kaufman, K. M.; Harley, J. B.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Gilkeson, G. S.] Med Univ S Carolina, Dept Med, Div Rheumatol, Charleston, SC 29425 USA. [Jacob, C. O.] Univ So Calif, Dept Med, Los Angeles, CA USA. [Wakeland, E. K.; Li, Q-Z] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX USA. [Langefeld, C. D.; Divers, J.; Ziegler, J.] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Kaufman, K. M.; Harley, J. B.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [James, J. A.; Harley, J. B.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. RP Harley, JB (reprint author), Oklahoma Med Res Fdn, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM john-harley@omrf.org FU NIH [AR42460, RR015577, AI31584, AR12253, AR48940, DE015223, AR053483, RR020143, AI062629, AI24717, AR62277, AI50026]; Mary Kirkland Scholarship; Alliance for Lupus Research; US Department of Veterans Affairs FX This work was supported by the NIH (AR42460, RR015577, AI31584, AR12253, AR48940, DE015223, AR053483, RR020143, AI062629, AI24717, AR62277 and AI50026, the Mary Kirkland Scholarship, the Alliance for Lupus Research and the US Department of Veterans Affairs. We thank the participants, who agreed to take part in this study by donating samples to the various collections, in particular the Lupus Family Registry and Repository (LFRR: http://lupus.omrf.org). NR 29 TC 16 Z9 17 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL PY 2009 VL 10 IS 5 BP 517 EP 524 DI 10.1038/gene.2009.33 PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 472YH UT WOS:000268168800018 PM 19440201 ER PT J AU Guo, L Deshmukh, H Lu, R Vidal, GS Kelly, JA Kaufman, KM Dominguez, N Klein, W Kim-Howard, X Bruner, GR Scofield, RH Moser, KL Gaffney, PM Dozmorov, IM Gilkeson, GS Wakeland, EK Li, QZ Langefeld, CD Marion, MC Williams, AH Divers, J Alarcon, GS Brown, EE Kimberly, RP Edberg, JC Ramsey-Goldman, R Reveille, JD McGwin, G Vila, LM Petri, MA Vyse, TJ Merrill, JT James, JA Nath, SK Harley, JB Guthridge, JM AF Guo, L. Deshmukh, H. Lu, R. Vidal, G. S. Kelly, J. A. Kaufman, K. M. Dominguez, N. Klein, W. Kim-Howard, X. Bruner, G. R. Scofield, R. H. Moser, K. L. Gaffney, P. M. Dozmorov, I. M. Gilkeson, G. S. Wakeland, E. K. Li, Q-Z Langefeld, C. D. Marion, M. C. Williams, A. H. Divers, J. Alarcon, G. S. Brown, E. E. Kimberly, R. P. Edberg, J. C. Ramsey-Goldman, R. Reveille, J. D. McGwin, G., Jr. Vila, L. M. Petri, M. A. Vyse, T. J. Merrill, J. T. James, J. A. Nath, S. K. Harley, J. B. Guthridge, J. M. TI Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-derived population SO GENES AND IMMUNITY LA English DT Article DE systemic lupus erythematosus; replication; association; European; BANK1 ID GENOME-WIDE ASSOCIATION; VARIANTS; LINKAGE; ITGAM AB Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value = 1.97 x 10(-5), odds ratio (OR) = 1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value = 2.59 x 10(-5), OR = 1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus. Genes and Immunity (2009) 10, 531-538; doi: 10.1038/gene.2009.18; published online 2 April 2009 C1 [Lu, R.; Vidal, G. S.; Dominguez, N.; Klein, W.; James, J. A.; Guthridge, J. M.] Oklahoma Med Res Fdn, Clin Immunol Program, Oklahoma City, OK 73104 USA. [Guo, L.; Deshmukh, H.; Kelly, J. A.; Kaufman, K. M.; Kim-Howard, X.; Bruner, G. R.; Scofield, R. H.; Moser, K. L.; Gaffney, P. M.; Dozmorov, I. M.; Nath, S. K.; Harley, J. B.] Oklahoma Med Res Fdn, Arthrit & Immunol Program, Oklahoma City, OK 73104 USA. [Guo, L.; James, J. A.; Harley, J. B.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Kaufman, K. M.; Harley, J. B.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Gilkeson, G. S.] Med Univ S Carolina, Dept Med, Div Rheumatol, Charleston, SC 29425 USA. [Wakeland, E. K.; Li, Q-Z] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA. [Langefeld, C. D.; Marion, M. C.; Williams, A. H.; Divers, J.] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Alarcon, G. S.; Brown, E. E.; Kimberly, R. P.; Edberg, J. C.; McGwin, G., Jr.] Univ Alabama, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Ramsey-Goldman, R.] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Dept Med, Chicago, IL 60611 USA. [Reveille, J. D.] Univ Texas Houston Hlth Sci Ctr, Dept Internal Med, Houston, TX USA. [Vila, L. M.] Univ Puerto Rico, Div Rheumatol, Dept Med, San Juan, PR 00936 USA. [Petri, M. A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Vyse, T. J.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Rheumatol Sect, London, England. [Merrill, J. T.] Oklahoma Med Res Fdn, Dept Clin Pharmacol, Oklahoma City, OK 73104 USA. RP Guthridge, JM (reprint author), Oklahoma Med Res Fdn, Clin Immunol Program, 825 NE 13th St,MS 53, Oklahoma City, OK 73104 USA. EM guthridgej@omrf.org RI Vyse, Tim/G-3887-2011; OI Kimberly, Robert/0000-0002-5330-3086 FU National Institutes of Health [RR020143, RR015577, HHSN266200500026C, AR053483, AI063274, AI031584, AR052125, AR043247]; Kirkland Scholar awards [AR049084, AR42460, AR12253, AR62277, AI24717, AR48940]; Alliance for Lupus Research; US Department of Veterans Affairs; OHRS; Oklahoma Center for the Advancement of Science and Technology [HR08-037] FX We thank the participants, both patients and controls, who graciously agreed to take part in these studies by donating samples to the various collections, including the Lupus Family Registry and Repository (LFRR: http://lupus.omrf.org), PROFILE, BIOLUPUS, Feinstein Institute for Medical Research and many other individual or multicenter collaborators. We also thank the recruitment and technical teams at each of the sample procurement sites for their important contributions. We acknowledge the Wake Forest University Health Sciences Center for Public Health Genomics for support of the data analysis efforts by our Wake Forest University collaborators. We thank Dr Alarcon-Riquelme for her assistance in clearly identifying potential overlapping subjects between our collections to ensure the independence of this study's observed associations and Dr Peter Gregersen for providing control samples. Finally, we acknowledge the various funding sources as mentioned below for their continued support for the collection of samples and the conduct of this research.; Support: This project was funded by National Institutes of Health RR020143 (JMG and JBH), RR015577 (JMG, JBH, JAJ), HHSN266200500026C ( JMG and JAJ), AR053483 ( JMG, SKN and JAJ), AI063274 (PMG), AI031584 ( JBH, JMG, JAJ), AR052125 ( PMG), AR043247 (KLM), Kirkland Scholar awards ( JBH and JAJ), AR049084 (SKN, JBH, RPK), AR42460 (JBH), AR12253 (JBH), AR62277 (JBH), AI24717 (JBH), AR48940 (JBH, JAJ), Alliance for Lupus Research (JBH), the US Department of Veterans Affairs ( JBH) and OHRS award for project number HR08-037 from the Oklahoma Center for the Advancement of Science and Technology ( JMG). Dr Harley has received consulting fees, speaking fees and/or director's fees from Bio-Rad Laboratories; Merck; UCB Inc.; ImmunoVision Inc.; IVAX Diagnostics and JK Autoimmunity and owns stock or stock options in IVAX Diagnostics. NR 19 TC 24 Z9 25 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL PY 2009 VL 10 IS 5 BP 531 EP 538 DI 10.1038/gene.2009.18 PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 472YH UT WOS:000268168800020 PM 19339986 ER PT J AU Fancy, SPJ Baranzini, SE Zhao, C Yuk, DI Irvine, KA Kaing, S Sanai, N Franklin, RJM Rowitch, DH AF Fancy, Stephen P. J. Baranzini, Sergio E. Zhao, Chao Yuk, Dong-In Irvine, Karen-Amanda Kaing, Sovann Sanai, Nader Franklin, Robin J. M. Rowitch, David H. TI Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS SO GENES & DEVELOPMENT LA English DT Article DE Oligodendrocyte; CNS development; Wnt; multiple sclerosis; remyelination; Olig2 ID OLIGODENDROCYTE PRECURSOR CELLS; BETA-CATENIN GENE; MULTIPLE-SCLEROSIS; SPINAL-CORD; DEMYELINATED LESIONS; DIFFERENTIATION; REEXPRESSION; EXPRESSION; MATURATION; GENERATION AB The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that similar to 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned-but not normal-adult white matter. We report that beta-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt-beta-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of beta-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC(Min) mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt-beta-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders. C1 [Fancy, Stephen P. J.; Kaing, Sovann; Rowitch, David H.] Univ Calif San Francisco, Inst Regenerat Med, San Francisco, CA 94143 USA. [Fancy, Stephen P. J.; Kaing, Sovann; Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Fancy, Stephen P. J.; Zhao, Chao; Franklin, Robin J. M.] Univ Cambridge, MRC, Ctr Stem Cell Biol & Regenerat Med, Cambridge CB3 0ES, England. [Fancy, Stephen P. J.; Zhao, Chao; Franklin, Robin J. M.] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England. [Baranzini, Sergio E.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yuk, Dong-In] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Irvine, Karen-Amanda; Sanai, Nader; Rowitch, David H.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. [Rowitch, David H.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Rowitch, DH (reprint author), Univ Calif San Francisco, Inst Regenerat Med, San Francisco, CA 94143 USA. EM rjf1000@cam.ac.uk; rowitchd@peds.ucsf.edu RI Baranzini, Sergio/A-9422-2013 OI Baranzini, Sergio/0000-0003-0067-194X FU National Multiple Sclerosis Society; United Kingdom Multiple Sclerosis Society; NIH FX We thank Dr. A. Koh for help with expression profiling samples; Dr. C. Stiles for Olig1 and Olig2 antibody; Dr. S. Pleasure for discussion and providing reagents; and Drs. S. Hauser, T. Golub, and B. Vogelstein for helpful comments on the work. We are also grateful to anonymous reviewers for suggestions that improved the work. Professor M. M. Taketo (Kyoto University, Japan) generously provided activated catenin mice. We are grateful to Professor R. Reynolds and the United Kingdom MS Society Brain Bank (Imperial College, London) for supplying MS tissue. All tissues were collected with approval by the London Multicentre Research Ethics committee (MREC 02/ 2/ 39). Animal procedures were performed under a UK Home Office Project License or approved by University of California at San Francisco oversight committee. This work was supported by grants from the National Multiple Sclerosis Society (to S. E. B, R. J. M. F., and D. H. R.), the United Kingdom Multiple Sclerosis Society (to R. J. M. F), and the NIH (to D. H. R.). D. H. R. is an HHMI Investigator. NR 48 TC 266 Z9 271 U1 4 U2 18 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2009 VL 23 IS 13 BP 1571 EP 1585 DI 10.1101/gad.1806309 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 470DN UT WOS:000267954800011 PM 19515974 ER PT J AU Zhang, LF Ogawa, Y Ahn, JY Namekawa, SH Silva, SS Lee, JT AF Zhang, Li-Feng Ogawa, Yuya Ahn, Janice Y. Namekawa, Satoshi H. Silva, Susana S. Lee, Jeannie T. TI Telomeric RNAs Mark Sex Chromosomes in Stem Cells SO GENETICS LA English DT Article ID INACTIVE X-CHROMOSOME; CHROMATIN-STRUCTURE; XIST GENE; TRANSCRIPTION; TSIX; STABILIZATION; POSITION; YEAST; DIFFERENTIATION; INTERFERENCE AB Telomeric regions are known to be transcribed in several organisms. Although originally reported to be transcribed from all chromosomes with enrichment near the inactive X of female cells, we show that telomeric RNAs in fact are enriched oil both sex chromosomes of the mouse in a developmentally specific manner. In female stem cells, 13001 active Xs are marked by the RNAs. In male stem cells, both the X and the Y accumulate telomeric RNA. Distribution of telomeric RNAs changes during cell differentiation, after which they associate only with the heterochromatic sex chromosomes of each sex. FISH mapping suggests that accumulated telomeric RNAs localize at the distal telomeric end. Interestingly, telomeric expression changes in cancer and during cellular stress. Furthermore, RNA accumulation increases in Dicer-deficient stem cells, suggesting direct or indirect links to RNAi. We propose that telomeric RNAs are tied to cell differentiation and may be used to mark pluripotency and disease. C1 [Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Dept Genet, Boston, MA 02114 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 50 Blossom St, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu OI Zhang, Li-Feng/0000-0003-0917-0017; Ahn, Janice/0000-0003-3625-9906 FU Howard Hughes Medical Institute FX We thank Jerome DeJardin, Yesu Jeon, Eda Yildirim, and Bernhard Payer for critical reading of the manuscript and all members of the lab for stimulating discussion. This work was funded by an award from the Howard Hughes Medical Institute (to J.T.L). NR 53 TC 22 Z9 23 U1 1 U2 7 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 2009 VL 182 IS 3 BP 685 EP 698 DI 10.1534/genetics.109.103093 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 522BI UT WOS:000271972300006 PM 19380904 ER PT J AU Scheuner, MT de Vries, H Kim, B Meili, RC Olmstead, SH Teleki, S AF Scheuner, Maren T. de Vries, Han Kim, Benjamin Meili, Robin C. Olmstead, Sarah H. Teleki, Stephanie TI Are electronic health records ready for genomic medicine? SO GENETICS IN MEDICINE LA English DT Article DE electronic health records; family history; genetic tests ID FAMILY-HISTORY; OPPORTUNITIES; CARE AB Purpose: The goal of this project was to assess genetic/genomic content in electronic health records. Methods: Semistructured interviews were conducted with key informants. Questions addressed documentation, organization, display, decision support and security of family history and genetic test information, and challenges and opportunities relating to integrating genetic/genomics content in electronic health records. Results: There were 56 participants: 10 electronic health record specialists, 18 primary care clinicians, 16 medical geneticists, and 12 genetic counselors. Few clinicians felt their electronic record met their current genetic/genomic medicine needs. Barriers to integration were mostly related to problems with family history data collection, documentation, and organization. Lack of demand for genetics content and privacy concerns were also mentioned as challenges. Data elements and functionality requirements that clinicians see include: pedigree drawing; clinical decision support for familial risk assessment and genetic testing indications; a patient portal for patient-entered data; and standards for data elements, terminology, structure, interoperability, and clinical decision support rules. Although most said that there is little impact of genetics/genomics on electronic records today, many stated genetics/genomics would be a driver of content in the next 5-10 years. Conclusions: Electronic health records have the potential to enable clinical integration of genetic/genomic medicine and improve delivery of personalized health care; however, structured and standardized data elements and functionality requirements are needed. Genet Med 2009:11(7):510-517. C1 [Scheuner, Maren T.; de Vries, Han; Kim, Benjamin; Meili, Robin C.; Olmstead, Sarah H.; Teleki, Stephanie] RAND Corp, Santa Monica, CA 90407 USA. VA Greater Los Angeles Healthcare Syst, Ctrr Excellence Study Healthcare Provider Behav, Sepulveda, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Kim, Benjamin] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. RP Scheuner, MT (reprint author), RAND Corp, 1776 Main St,POB 2138, Santa Monica, CA 90407 USA. EM Scheuner@rand.org FU National Institutes of Health [J32 HL 66992] FX This work was funded by the RAND Corporation through an investigator-initiated Independent Research & Develo rnent Grant, and Dr. Kim was supported by a Ruth L. Kirschstein National Research Service Award from the National Institutes of Health J32 HL 66992). Preliminary results of this work have been presented at a meeting of the Department of Health and Human Services American Health Information Community in February 2008 and a meeting of the American College of Medical Genetics in March 2008. Dr. Scheuner has a patent pending (US Application No. 20060173717) for a familial risk stratification method and apparatus. NR 11 TC 28 Z9 29 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL PY 2009 VL 11 IS 7 BP 510 EP 517 DI 10.1097/GIM.0b013e3181a53331 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 472WA UT WOS:000268162200005 PM 19478682 ER PT J AU Xin, XF Rual, JF Hirozane-Kishikawa, T Hill, DE Vidal, M Boone, C Thierry-Mieg, N AF Xin, Xiaofeng Rual, Jean-Francois Hirozane-Kishikawa, Tomoko Hill, David E. Vidal, Marc Boone, Charles Thierry-Mieg, Nicolas TI Shifted Transversal Design smart-pooling for high coverage interactome mapping SO GENOME RESEARCH LA English DT Article ID PROTEIN INTERACTION NETWORK; YEAST; STRATEGY; SYSTEM; EXPRESSION; RESOURCE; BIOLOGY; MAP AB "Smart-pooling,'' in which test reagents are multiplexed in a highly redundant manner, is a promising strategy for achieving high efficiency, sensitivity, and specificity in systems-level projects. However, previous applications relied on low redundancy designs that do not leverage the full potential of smart-pooling, and more powerful theoretical constructions, such as the Shifted Transversal Design (STD), lack experimental validation. Here we evaluate STD smart-pooling in yeast two-hybrid (Y2H) interactome mapping. We employed two STD designs and two established methods to perform ORFeome-wide Y2H screens with 12 baits. We found that STD pooling achieves similar levels of sensitivity and specificity as one-on-one array-based Y2H, while the costs and workloads are divided by three. The screening-sequencing approach is the most cost- and labor-efficient, yet STD identifies about twofold more interactions. Screening-sequencing remains an appropriate method for quickly producing low-coverage interactomes, while STD pooling appears as the method of choice for obtaining maps with higher coverage. C1 [Rual, Jean-Francois; Hirozane-Kishikawa, Tomoko; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Xin, Xiaofeng; Boone, Charles] Univ Toronto, Banting & Best Dept Med Res, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada. [Xin, Xiaofeng; Boone, Charles] Univ Toronto, Dept Mol Genet, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada. [Rual, Jean-Francois; Hirozane-Kishikawa, Tomoko; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Rual, Jean-Francois; Hirozane-Kishikawa, Tomoko; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Thierry-Mieg, Nicolas] Fac Med, CNRS, UMR5525, Lab TIMC IMAG,TIMB, F-38706 La Tronche, France. RP Vidal, M (reprint author), Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu; charlie.boone@utoronto.ca; Nicolas.Thierry-Mieg@imag.fr RI Hill, David/B-6617-2011; Thierry-Mieg, Nicolas/M-6007-2014; Xin, Xiaofeng/G-7736-2016; OI Xin, Xiaofeng/0000-0002-2439-7183; Rual, Jean-Francois/0000-0003-4465-8819 FU Canadian Cancer Society; National Institutes of Health [R01-HG001715] FX We thank Haiyuan Yu, Jingjing Li, and Olivier Francois for help with the statistical analysis. This work was supported by a Canadian Cancer Society grant awarded to C. B., and grant R01-HG001715 from the National Human Genome Research Institute of the National Institutes of Health awarded to M.V.M.V. is a "Chercheur Qualifie Honoraire'' from the "Fonds de la Recherche Scientifique'' (FRS-FNRS, French Community of Belgium). NR 24 TC 21 Z9 22 U1 0 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2009 VL 19 IS 7 BP 1262 EP 1269 DI 10.1101/gr.090019.108 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 468AY UT WOS:000267786900013 PM 19447967 ER PT J AU Colak, D Kaya, N Al-Zahrani, J Al Bakheet, A Muiya, P Andres, E Quackenbush, J Dzimiri, N AF Colak, Dilek Kaya, Namik Al-Zahrani, Jawaher Al Bakheet, Albandary Muiya, Paul Andres, Editha Quackenbush, John Dzimiri, Nduna TI Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy SO GENOMICS LA English DT Article DE Idiopathic dilated cardiomyopathy; Global gene expression; Microarray gene expression; Gene up/down-regulation; Mitochondrial function; Apoptotic signaling ID HUMAN HEART-FAILURE; GENE-EXPRESSION MEASUREMENTS; ACTIVATED PROTEIN-KINASES; APOPTOSIS-INDUCING-FACTOR; CELL-LINES; OLIGONUCLEOTIDE MICROARRAYS; MALIGNANT MELANOMAS; OXIDATIVE STRESS; HUMAN MYOCARDIUM; CANDIDATE GENES AB We employed ABI high-density oligonucleotide microarrays containing 31,700 sixty-mer probes (representing 27,868 annotated human genes) to determine differential gene expression in idiopathic dilated cardiomyopathy (DCM). We identified 626 up-regulated and 636 down-regulated genes in DCM compared to controls. Most significant changes occurred in the tricarboxylic acid cycle, angiogenesis, and apoptotic signaling pathways, among which 32 apoptosis- and 13 MAPK activity-related genes were altered. Inorganic cation transporter, catalytic activities, energy metabolism and electron transport-related processes were among the most critically influenced pathways. Among the up-regulated genes were HTRA1 (6.9-fold), PDCD8(AIFM1) (5.2) and PRDX2 (4.4) and the clown-regulated genes were NR4A2 (4.8), MX1 (43), LGALS9 (4), IFNA13 (4), UNC5D (3.6) and HDAC2 (3) (p<0.05), all of which have no clearly defined cardiac-related function yet. Gene ontology and enrichment analysis also revealed significant alterations in mitochondrial oxidative phosphorylation, metabolism and Alzheimer's disease pathways. Concordance was also confirmed for a significant number of genes and pathways in an independent validation microarray dataset. Furthermore, verification by real-time RT-PCR showed a high degree of consistency with the microarray results. Our data demonstrate an association of DCM with alterations in various cellular events and multiple yet undeciphered genes that may contribute to heart muscle disease pathways. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kaya, Namik; Al-Zahrani, Jawaher; Al Bakheet, Albandary; Muiya, Paul; Andres, Editha; Dzimiri, Nduna] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Colak, Dilek] King Faisal Specialist Hosp & Res Ctr, Dept Biostat Epidemiol & Sci Comp, Riyadh 11211, Saudi Arabia. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Dzimiri, N (reprint author), King Faisal Specialist Hosp & Res Ctr, Dept Genet, POB 3354, Riyadh 11211, Saudi Arabia. EM dzimiri@kfshrc.edu.sa OI Colak, Dilek/0000-0001-6485-8768 FU Royal Cardiovascular Research [9900004]; King Faisal Specialist Hospital and Research Centre FX This work was supported by the Royal Cardiovascular Research Grant No 9900004 under the King Faisal Specialist Hospital and Research Centre. The authors express their gratitude for this financial support. NR 93 TC 24 Z9 24 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUL PY 2009 VL 94 IS 1 BP 20 EP 31 DI 10.1016/j.ygeno.2009.03.003 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 461BH UT WOS:000267238600003 PM 19332114 ER PT J AU Lin, AP Orengo-Nania, S Braun, UK AF Lin, Albert P. Orengo-Nania, Silvia Braun, Ursula K. TI Management of chronic open-angle glaucoma in the aging US population SO GERIATRICS LA English DT Article DE glaucoma; intraocular pressure; optic nerve; prostaglandin analogue; selective alpha-2 agonist; carbonic anhydrase inhibitor; trabeculectomy; tube shunt; low vision; blindness ID PHARMACY CLAIMS DATA; QUALITY-OF-LIFE; INTRAOCULAR-PRESSURE; UNITED-STATES; ADHERENCE; MEDICATIONS; PERSISTENCE; PREVALENCE; ADULTS AB Chronic open-angle glaucoma is a leading cause of blindness and visual impairment in older adults. Optic nerve damage and the associated peripheral and subsequent central vision loss are irreversible, but early diagnosis and treatment will give patients the best chance to maintain functional vision and quality of life. Primary care physicians can assist with the diagnosis of glaucoma by making appropriate referrals for routine ophthalmic examinations, especially in patients with risk factors for glaucoma. Medication adherence and persistence may also be enhanced by discussing strategies to improve medication use and efficacy in the primary care setting. Recognition of adverse reactions from glaucoma medications and surgeries will allow proper management of these potentially serious conditions. Patients with advanced visual deficits can still benefit from treatment as well as low-vision and supportive care and should be referred for an ophthalmic evaluation. With an understanding of comprehensive glaucoma management, primary care physicians play an invaluable role in assisting their patients with effective and timely therapy that will result in improved outcomes. C1 [Lin, Albert P.; Orengo-Nania, Silvia; Braun, Ursula K.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Lin, Albert P.; Orengo-Nania, Silvia; Braun, Ursula K.] Baylor Coll Med, Houston, TX 77030 USA. RP Lin, AP (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. NR 17 TC 0 Z9 0 U1 0 U2 3 PU ADVANSTAR COMMUNICATIONS INC PI WOODLAND HILLS PA 6200 CANOGA AVE, 2ND FLR, WOODLAND HILLS, CA 91367 USA SN 0016-867X J9 GERIATRICS JI Geriatrics PD JUL PY 2009 VL 64 IS 7 BP 20 EP + PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 470XT UT WOS:000268016500005 PM 19586087 ER PT J AU Chang, HL Pahlavan, N Halpern, EF MacLaughlin, DT AF Chang, Henry L. Pahlavan, Nima Halpern, Elkan F. MacLaughlin, David T. TI Serum Mullerian Inhibiting Substance/Anti-Mullerian Hormone levels in patients with adult granulosa cell tumors directly correlate with aggregate tumor mass as determined by pathology or radiology SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Adult granulosa cell tumor; Mullerian Inhibiting Substance; Anti-Mullerian hormone; Ovarian sex-cord stromal tumor ID IMMUNOASSAY; MARKER; SERTOLI; OVARY AB Objectives. Granulosa cell tumors (GCTs) comprise 2-5% of ovarian tumors. Serum Mullerian Inhibiting Substance (MI5, also known as anti-Mullerian hormone, or AMH) levels have been validated as a marker of GCT recurrence and progression. There has been little correlation between serum MIS/AMH levels and several clinical parameters in GCTs, including tumor burden. We have performed a retrospective review correlating aggregate tumor mass as reported by pathologic examination or by radiology with serum MIS/AMH levels drawn on the date of examination. Methods. We retrospectively identified 32 GCT patients at our institution over the last 15 years who had serum MIS/AMH measurements. Patients who had serum MIS/AMH measurements within three days of surgery or on the same day as abdominal computerized tomography scan (CT) or magnetic resonance imaging (MRI) were further evaluated. Results. We found a significant direct correlation between patient serum MIS/AMH levels and gross aggregate tumor mass determined by pathology (slope = 15.4 +/- 6.06, r = 0.65, p < 0.04) or by radiographic aggregate tumor mass for all data points identified (slope = 0.07 +/- 0.03, r = 0.33, p < 0.04) and after correcting for selection bias (slope = 1.45 +/- 0.17, r = 0.93, p < 0.01). We also identified a significant difference between serum MIS/AMH levels between samples drawn the same day as negative and positive abdominal CT or MRI scans (8.16 +/- 1.54 vs. 158.7 +/- 32.2 ng/ml, p < 0.0001). Conclusions. These data indicate a significant direct correlation between serum MIS/AMH levels and both gross and radiographic aggregate tumor mass in GCT patients. Together with the current literature, the present data argue for a more prominent role for serum MIS/AMH in the management of GCTs. (C) 2009 Elsevier Inc. All rights reserved. C1 [Chang, Henry L.; Pahlavan, Nima; MacLaughlin, David T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Surg Res Labs,Dept Pediat Surg, Boston, MA 02114 USA. [Halpern, Elkan F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment,Dept Biostat, Boston, MA 02114 USA. RP MacLaughlin, DT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Surg Res Labs,Dept Pediat Surg, 185 Cambridge St,CPZN 6-220, Boston, MA 02114 USA. EM maclaugh@helix.mgh.harvard.edu FU NIH/MGH T32 in Cancer Biology [T32CA071345-11]; NIH [CA77393-30]; Ovarian Cancer Research Fund; McBride Family Fund; Commons Development Group, Inc. FX The authors would like to thank Dr. Patricia K. Donahoe for her intellectual input and critical reading of this manuscript. HLC was supported by NIH/MGH T32 in Cancer Biology T32CA071345-11. DTM was supported by NIH CA77393-30, The Ovarian Cancer Research Fund, the McBride Family Fund. and the Commons Development Group, Inc. NR 15 TC 14 Z9 19 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 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2009 VL 114 IS 1 BP 57 EP 60 DI 10.1016/j.ygyno.2009.02.023 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 457TX UT WOS:000266957700011 PM 19359032 ER PT J AU Ziakas, PD Karsaliakos, P Mylonakis, E AF Ziakas, Panayiotis D. Karsaliakos, Petros Mylonakis, Eleftherios TI Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE lymphoma; hepatitis B; reactivation; lamivudine; prophylaxis; mortality ID NON-HODGKINS-LYMPHOMA; VIRUS-INFECTION; CARRIERS; THERAPY; RITUXIMAB; MALIGNANCIES; PREVENTION; MUTATIONS; TRANSPLANTATION; RECOMMENDATIONS AB Lamivudine prophylaxis is an effective strategy in HbSAg-positive patients receiving cancer chemotherapy. Recent data indicate that a lamividune-prophylaxis strategy results in a decrease of hepatitis B virus (HBV) reactivation rates, though its effect on HBV-mortality remains equivocal. This report evaluates the benefits from this strategy among lymphoma patients and develops a management approach for patients with prolonged immunosuppression. A Medline search was conducted to retrieve published trials on HBsAg-positive lymphoma patients receiving prophylactic lamivudine during chemotherapy. Basic inclusion criterion was to report HBV-reactivation rates with and without lamivudine prophylaxis. A meta-analysis of the risk of HBV-reactivation and HBV-related mortality was conducted, and the pooled effect was calculated as risk ratio (RR). We found that lamivudine prophylaxis is associated with a significant reduction in hepatitis B virus reactivation (RR 0.21, 95%CI 0.13-0.35) and a trend in reducing HBV-related mortality (RR 0.68, 95%CI 0.192.49). In order to study the long-term effects of anti-HBV prophylaxis when prolonged immunosuppression is needed, we used our findings to model a decision tree. Overall survival was the main outcome used in the analysis. Rituximab maintenance in B-cell lymphomas was used as a paradigm of prolonged immunosuppression. We found that extended anti-HBV prophylaxis can improve survival rates by 2.4% in HBsAg-positive patients. If 1,000 HBsAg-positive lymphoma patients receive prophylaxis, one will die from hepatitis B virus reactivation versus 25/1,000 if no prophylaxis is administered. This effect is probably mediated through a reduction of hepatitis B virus reactivation and HBV-related mortality. The ideal antiviral agent needs to be determined. C1 [Ziakas, Panayiotis D.; Karsaliakos, Petros] Hygeia Diagnost & Therapeut Ctr, Athens 15123, Greece. [Ziakas, Panayiotis D.; Mylonakis, Eleftherios] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. RP Ziakas, PD (reprint author), Hygeia Diagnost & Therapeut Ctr, 4 Erythrou Stavrou St, Athens 15123, Greece. EM zpanos@otenet.gr NR 51 TC 49 Z9 51 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUL PY 2009 VL 94 IS 7 BP 998 EP 1005 DI 10.3324/haematol.2009.005819 PG 8 WC Hematology SC Hematology GA 471LW UT WOS:000268060200015 PM 19454492 ER PT J AU Hoffman, A Pearson, SD AF Hoffman, Ari Pearson, Steven D. TI 'Marginal Medicine': Targeting Comparative Effectiveness Research To Reduce Waste SO HEALTH AFFAIRS LA English DT Article ID COST-EFFECTIVENESS ANALYSIS AB Many policymakers believe that comparative effectiveness research will reduce "waste" in the U. S. health care system by providing guidance on what health care options work best for different patients. How such research will produce findings that identify waste has not been clearly elucidated. This paper presents a conceptual framework for different evidentiary categories of what we call "marginal medicine." This framework could help clinicians, researchers, and policymakers align the results of comparative effectiveness research with efforts to identify opportunities to improve the value of health care services. [ Health Affairs 28, no. 4 ( 2009): w710-w718 (published online 25 June 2009; 10.1377/hlthaff.28.4.w710)] C1 [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Technol Assessment, ICER, Boston, MA 02114 USA. EM spearson@icer-review.org FU National Institutes of Health (NIH); Pfizer Inc; U. S. Public Health Service; U. S. Department of Health and Human Services FX Ari Hoffman is a predoctoral fellow in the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health (NIH) and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). The opinions expressed are the authors' own. They do not represent any position or policy of the NIH, the U. S. Public Health Service, or the U. S. Department of Health and Human Services. NR 19 TC 22 Z9 24 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JUL-AUG PY 2009 VL 28 IS 4 BP W710 EP W718 DI 10.1377/hlthaff.28.4.w710 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 469YY UT WOS:000267939100066 PM 19556249 ER PT J AU Ahmed, H Neuzil, P d'Avila, A Cha, YM Laragy, M Mares, K Brugge, WR Forcione, DG Ruskin, JN Packer, DL Reddy, VY AF Ahmed, Humera Neuzil, Petr d'Avila, Andre Cha, Yong-Mei Laragy, Margaret Mares, Karel Brugge, William R. Forcione, David G. Ruskin, Jeremy N. Packer, Douglas L. Reddy, Vivek Y. TI The esophageal effects of cryoenergy during cryoablation for atrial fibrillation SO HEART RHYTHM LA English DT Article DE Atrial fibrillation; Catheter ablation; Arrhythmias; Complications; Esophageal injury ID RADIOFREQUENCY ABLATION; FISTULA AB BACKGROUND Cryoenergy is being increasingly used for atrial fibrillation (AF) ablation, but the thermal effect of cryoenergy on the esophagus remains undefined. OBJECTIVE This study examines the esophageal effects of cryoenergy used during AF ablation. METHODS Catheter ablation was performed using a cryoballoon catheter in 67 AF patients (Cryoballoon group), and a spot cryocatheter to complete irrigated radiofrequency lesion sets at segments in close proximity to the esophagus in 7 AF patients (Cryo-Focal group). A temperature probe monitored the luminal esophageal temperature (LET) in all patients; LET changes did not guide therapy. Post-procedural endoscopy was performed on 35 of 67 (52%) Cryoballoon and all Cryo-Focal patients. RESULTS Significant LET decreases (>1 degrees C) occurred in 62 of 67 (93%) Cryoballoon patients. LET continued to decrease after termination of cryoablation before recovering to normal. Temperature decreases were more pronounced during ablation at the inferior (3.1 degrees C) than superior pulmonary veins (1.5 degrees C); the lowest observed temperature was 0 degrees C. Post-procedural endoscopy showed esophageal ulcerations in 6 of 35 (17%) patients. There were no atrial-esophageal fistulas, and all ulcers had heated on follow-up endoscopy. Patients with and without ulceration differed with respect to mean LET nadir, cumulative LET decrease, and number of LETs <30 degrees C. In the Cryo-Focat group, 6 2 spot cryolesions per patient resulted in 1.3 +/- 1 LET decreases per patient, and an absolute nadir of 32.5 degrees C. CONCLUSION Cryoballoon ablation can cause significant LET decreases, resulting in reversible esophageal ulcerations in 17% of patients. No ulcerations occurred with adjunctive spot cryoablation at regions near the esophagus during radiofrequency ablation procedures. C1 [Reddy, Vivek Y.] Univ Miami, Miller Sch Med, Cardiac Arrhythmia Serv, Miami, FL 33136 USA. [Mares, Karel] Homolka Hosp, Dept Gastroenterol, Prague, Czech Republic. [Brugge, William R.; Forcione, David G.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Cha, Yong-Mei; Packer, Douglas L.] Mayo Clin, Rochester, MN USA. RP Reddy, VY (reprint author), Univ Miami, Miller Sch Med, Cardiac Arrhythmia Serv, 1400 NW 12th Ave,Suite 4062, Miami, FL 33136 USA. EM vreddy@med.miami.edu RI d'Avila, Andre Luiz/F-8009-2010; d'Avila, Andre/A-7693-2009 OI d'Avila, Andre Luiz/0000-0001-8769-1411; NR 8 TC 45 Z9 47 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2009 VL 6 IS 7 BP 962 EP 969 DI 10.1016/j.hrthm.2009.03.051 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 468CS UT WOS:000267791900006 PM 19560085 ER PT J AU Desai, AA Nissenson, A Chertow, GM Farid, M Singh, I Van Oijen, MGH Esrailian, E Solomon, MD Spiegel, BMR AF Desai, Amar A. Nissenson, Allen Chertow, Glenn M. Farid, Mary Singh, Inder Van Oijen, Martijn G. H. Esrailian, Eric Solomon, Matthew D. Spiegel, Brennan M. R. TI The relationship between laboratory-based outcome measures and mortality in end-stage renal disease: A systematic review SO HEMODIALYSIS INTERNATIONAL LA English DT Review DE Hemodialysis; outcomes; end-stage renal disease (ESRD); biomarkers; systematic review; clinical performance measures ID CARDIAC TROPONIN-T; C-REACTIVE PROTEIN; CHRONIC-HEMODIALYSIS PATIENTS; UREA REDUCTION RATIO; PREDICTS ALL-CAUSE; CARDIOVASCULAR MORTALITY; PRACTICE PATTERNS; DIALYSIS PATIENTS; MAINTENANCE HEMODIALYSIS; PERITONEAL-DIALYSIS AB Despite data that traditional laboratory-based outcome measures in dialysis are improving over time, population-based data indicate that mortality rates are not improving in parallel. With increased focus on performance measures based on laboratory-based outcomes (e.g., hematocrit, albumin, and parathyroid hormone), less emphasis has been placed on other markers, some of which may be stronger predictors of mortality. We performed a systematic review to interpret the predictive value of laboratory-based outcome measures in dialysis. We identified studies with data regarding the predictive value of laboratory-based outcomes for mortality in dialysis. We calculated the sample size-weighted pooled relative risk of death with dichotomized "high" vs. "low" levels of each measure. We rank-ordered predictors by scaling the pooled relative risk of each measure by its pooled standard deviation. There were 5171 titles, of which 128 (representing 44 laboratory-based outcomes) were selected. Nine were significantly associated with mortality, in order of decreasing scaled effect size: (1) tumor necrosis factor-alpha, (2) hematocrit, (3) interleukin-6, (4) troponin T, (5) Kt/V(urea), (6) prealbumin, (7) urea reduction ratio, (8) serum albumin, and (9) C-reactive protein. Other oft-cited measures such as calcium phosphate product and parathyroid hormone were not significantly associated with mortality in pooled analysis. Quality improvement efforts to improve traditional laboratory-based outcomes in end-stage renal disease are necessary, but likely insufficient, to improve overall mortality in dialysis. Renewed consideration of cardiovascular, inflammatory, and nutritional markers that are especially strong predictors of mortality may have important implications for risk stratification and targeted therapeutic interventions. C1 [Farid, Mary; Singh, Inder; Van Oijen, Martijn G. H.; Esrailian, Eric; Solomon, Matthew D.; Spiegel, Brennan M. R.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, VA Ctr Outcomes Res & Educ CORE, Los Angeles, CA 90073 USA. [Spiegel, Brennan M. R.] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Desai, Amar A.] Stanford Univ, Ctr Hlth Policy & Primary Care Outcomes Res, Stanford, CA 94305 USA. [Nissenson, Allen; Esrailian, Eric; Solomon, Matthew D.; Spiegel, Brennan M. R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90073 USA. [Desai, Amar A.; Chertow, Glenn M.] Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. [Desai, Amar A.; Chertow, Glenn M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Van Oijen, Martijn G. H.] Radboud Univ Nijmegen, Dept Gastroenterol & Hepatol, NL-6525 ED Nijmegen, Netherlands. RP Spiegel, BMR (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, VA Ctr Outcomes Res & Educ CORE, 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu FU VA HSR&D Research Career Development Award [RCD 03-179-2]; CURE Research Center (NIH) [2P30 DK 041301-17]; Agency for Healthcare Research and Quality (AHRQ); Amgen Inc. FX Dr Spiegel is supported by VA HSR&D Research Career Development Award RCD 03-179-2 and by the CURE Research Center (NIH 2P30 DK 041301-17). Dr Desai is supported by a training grant from the Agency for Healthcare Research and Quality (AHRQ). Support for this investigator-initiated study was provided by a research grant from Amgen Inc. The principal investigator, Dr Spiegel, maintained full control over all aspects of the study design, implementation, data collection, data analysis, data interpretation, and manuscript preparation. Dr Spiegel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The contributions of individual authors is as follows: Amar Desai: Data collection, data analysis, data interpretation, manuscript preparation, and manuscript approval. Allen Nissenson: Study design, data interpretation, manuscript preparation, and manuscript approval. Glenn Chertow: Data interpretation, manuscript preparation, and manuscript approval. Mary Farid: Data collection and manuscript approval. Inder Singh: Data collection and manuscript approval. Martijn van Oijen: Data collection, manuscript preparation, and manuscript approval. Eric Esrailian: Study design, data collection, and manuscript approval. Matthew Solomon: Data interpretation, manuscript preparation, and manuscript approval. Brennan Spiegel: Study design, study implementation, data collection, data analysis, data interpretation, manuscript preparation, manuscript approval, and guarantor of article. Disclaimer: The opinions and assertions contained herein are the sole views of the authors and are not to be construed as official or as reflecting the views of the Department of Veteran Affairs. NR 117 TC 16 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1492-7535 J9 HEMODIAL INT JI Hemodial. Int. PD JUL PY 2009 VL 13 IS 3 BP 347 EP 359 DI 10.1111/j.1542-4758.2009.00377.x PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 484OZ UT WOS:000269057200018 PM 19583604 ER PT J AU Ioannou, GN Morrow, OB Connole, ML Lee, SP AF Ioannou, George N. Morrow, Olivia B. Connole, Marah L. Lee, Sum P. TI Association Between Dietary Nutrient Composition and the Incidence of Cirrhosis or Liver Cancer in the United States Population SO HEPATOLOGY LA English DT Article ID FATTY-ACIDS; DISEASE; RISK; HEPATITIS; INJURY; OMEGA-3-FATTY-ACIDS; STEATOHEPATITIS; CHOLESTEROL; INHIBITION; PREVENTION AB Little is known about the impact of dietary factors on the progression of liver disease. Our aim was to determine whether dietary intake was associated with the risk of cirrhosis-related or liver cancer-related death or hospitalization in the U.S. population. Participants included 9221 persons aged 25-74 years without evidence of cirrhosis at entry into the study or during the first 5 years of follow-up, who were subsequently followed for a mean of 13.3 years as part of the first National Health and Nutrition Examination Survey. Dietary intake was ascertained at baseline using a 24-hour dietary recall questionnaire. During follow-up, 123 of 9221 participants had a diagnosis of cirrhosis (n = 118) or liver cancer (n = 5) in hospitalization records or death certificates, including 36 who were diagnosed only on the basis of death certificates. Participants who reported a diet high in protein were at a higher risk of hospitalization or death due to cirrhosis or liver cancer (P = 0.001), whereas those who reported a diet high in carbohydrates were at a lower risk (P = 0.003), after adjusting for potential confounders (daily consumption of protein, carbohydrate, fat, tea or coffee, and alcohol, gender, race, age, educational attainment, U.S. geographical region, diabetes, body mass index, and subscapular-to-triceps skinfold ratio). Although total fat consumption was not significantly associated with the risk of cirrhosis or liver cancer, cholesterol consumption was associated with higher risk (P = 0.007), whereas serum cholesterol level was not associated with risk of cirrhosis or liver cancer. Conclusion: Diet may be an important and potentially modifiable determinant of liver disease. (HEPATOLOGY 2009;50:175-184.) C1 [Ioannou, George N.; Morrow, Olivia B.; Connole, Marah L.; Lee, Sum P.] Vet Affairs Puget Sound Hlth Care Syst, Res Enhancement Award Program, Seattle, WA 98108 USA. [Ioannou, George N.; Lee, Sum P.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Gastroenterol, Seattle, WA 98108 USA. [Ioannou, George N.; Lee, Sum P.] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Res Enhancement Award Program, S-111 Gastro,1660 S Columbian Way, Seattle, WA 98108 USA. EM georgei@medicine.washington.edu FU American Liver Foundation and American Association FX Supported by: American Liver Foundation and American Association for the Study of Liver Diseases Jan Albrecht Award (to G. N. I). NR 26 TC 48 Z9 51 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2009 VL 50 IS 1 BP 175 EP 184 DI 10.1002/hep.22941 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 465RW UT WOS:000267605500020 PM 19441103 ER PT J AU Santesso, DL Evins, AE Frank, MJ Schetter, EC Bogdan, R Pizzagalli, DA AF Santesso, Diane L. Evins, A. Eden Frank, Michael J. Schetter, Erika C. Bogdan, Ryan Pizzagalli, Diego A. TI Single Dose of a Dopamine Agonist Impairs Reinforcement Learning in Humans: Evidence From Event-Related Potentials and Computational Modeling of Striatal-Cortical Function SO HUMAN BRAIN MAPPING LA English DT Article DE dopamine agonist; feedback-related negativity; source localization; reinforcement learning; anterior cingulate cortex ID ANTERIOR CINGULATE CORTEX; ERROR-RELATED NEGATIVITY; MEDIAL FRONTAL-CORTEX; DECISION-MAKING; PREFRONTAL CORTEX; HUMAN BRAIN; INDIVIDUAL-DIFFERENCES; HEALTHY-VOLUNTEERS; REWARD PREDICTION; NUCLEUS-ACCUMBENS AB Animal findings have highlighted the modulatory role of phasic dopamine (DA) signaling in incentive learning, particularly in the acquisition of reward-related behavior. In humans, these processes remain largely unknown. In a recent study, we demonstrated that a single low dose of a D2/D3 agonist (pramipexole)-assumed to activate DA autoreceptors and thus reduce phasic DA bursts-impaired reward learning in healthy subjects performing a probabilistic reward task. The purpose of this study was to extend these behavioral findings using event-related potentials and computational modeling. Compared with the placebo group, participants receiving pramipexole showed increased feedback-related negativity to probabilistic rewards and decreased activation in dorsal anterior cingulate regions previously implicated in integrating reinforcement history over time. Additionally, findings of blunted reward learning in participants receiving pramipexole were simulated by reduced presynaptic DA signaling in response to reward in a neural network model of striatal-cortical function. These preliminary findings offer important insights on the role of phasic DA signals on reinforcement learning in humans and provide initial evidence regarding the spatiotemporal dynamics of brain mechanisms underlying these processes. Hum Brain Mapp 30:1963-1976, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Santesso, Diane L.; Schetter, Erika C.; Bogdan, Ryan; Pizzagalli, Diego A.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Evins, A. Eden] Harvard Univ, Sch Med, Boston, MA USA. [Evins, A. Eden] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Frank, Michael J.] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. RP Pizzagalli, DA (reprint author), Harvard Univ, Dept Psychol, 1220 William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. EM dap@wjh.harvard.edu OI Bogdan, Ryan/0000-0002-1430-1045 FU NIMH [R01 MH68376]; National Institute on Drug Abuse [DA022630]; Harvard College Research Program FX Contract grant sponsor: NIMH; Contract grant number: R01 MH68376; Contract grant sponsor: National Institute on Drug Abuse; Contract grant number: DA022630; Contract grant sponsor: Harvard College Research Program. NR 79 TC 59 Z9 59 U1 6 U2 16 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2009 VL 30 IS 7 BP 1963 EP 1976 DI 10.1002/hbm.20642 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 466VQ UT WOS:000267691900005 PM 18726908 ER PT J AU Lin, FH Agnew, JA Belliveau, JW Zeffiro, TA AF Lin, Fa-Hsuan Agnew, John A. Belliveau, John W. Zeffiro, Thomas A. TI Functional and Effective Connectivity of Visuomotor Control Systems Demonstrated Using Generalized Partial Least Squares and Structural Equation Modeling SO HUMAN BRAIN MAPPING LA English DT Article DE motor cortex; cerebellum; sensorimotor; functional connectivity; effective connectivity; causal modeling; parametric analysis; neural network; handedness; asymmetry; hemispheric specialization; cerebellar loop; corticocerebellar; corticostriate; fMRI ID CEREBRAL-BLOOD-FLOW; PRIMARY MOTOR CORTEX; FREQUENCY-DEPENDENT CHANGES; FINGER MOVEMENTS; PARAMETRIC ANALYSIS; SENSORIMOTOR CORTEX; BLIND SEPARATION; VISUAL PATHWAYS; ACTIVATION; FMRI AB Tasks employing parametric variation in movement rate are associated with predictable modulations in neural activity and provide a convenient context for developing new techniques for system identification. Using a multistage approach, we explored the functional and effective connectivity of a visuomotor control system by combining generalized partial least squares (gPLS) with subsequent structural equation modeling (SEM) to reveal the relationships between neural activity and finger movement rate in an experiment involving visually paced left or right thumb flexion. The gPLS in the first analysis stage automatically identified spatially distributed sets of BOLD-contrast signal changes using linear combinations of sigmoidal basis functions parameterized by kinematic variables. The gPLS provided superior sensitivity in detecting task-related functional activity patterns via a step-wise comparison with both classical linear modeling and behavior correlation analysis. These activity patterns were used in the second analysis stage, which employed SEM to characterize the areal regional interactions. The hybrid gPLS/SEM procedure allowed modeling of complex regional interactions in a network including primary motor cortex, premotor areas, cerebellum, thalamus, and basal ganglia, with differential activity modulations with respect to rate observed in the corticocerebellar and corticostriate subsystems. This effective connectivity analysis of visuomotor control circuits showed that both the left and right corticocerebellar and corticostriate circuits exhibited movement rate-related modulation. The identification of the functional connectivity among regions participating particular classes of behavior using gPLS, followed by the estimation of the effective connectivity using SEM is an efficient means to characterize the neural interactions underlying variations in sensorimotor behavior. Hum Brain Mapp 30:2232-2251., 2009. (C) 2009 Wiley-Liss, Inc. C1 [Lin, Fa-Hsuan] Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. [Lin, Fa-Hsuan; Belliveau, John W.] Massachusetts Gen Hosp, Dept Radiol, HST Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Agnew, John A.] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. [Zeffiro, Thomas A.] Massachusetts Gen Hosp, Neural Syst Grp, Boston, MA 02114 USA. RP Lin, FH (reprint author), MGH MIT HMS Athinoula A Martinos Ctr, Room 2301,Bldg 149 13th St, Charlestown, MA 02129 USA. EM fhlin@nmr.mgh.harvard.edu FU National Institutes of Health [R01DA14178, R01HD040712, R01NS037462, P41 RR14075, R01EB006847, RO1EB000790, R21EB007298]; Mental Illness and Neuroscience Discovery Institute (MIND); National Science Council, Taiwan [NSC 96-2320-B-002-085]; National Health Research Institute, Taiwan [NHRI-EX97-9715EC] FX Contract grant sponsor: National Institutes of Health; Contract grant numbers: R01DA14178, R01HD040712, R01NS037462, P41 RR14075, R01EB006847, RO1EB000790, R21EB007298; Contract grant sponsor: Mental Illness and Neuroscience Discovery Institute (MIND); Contract grant sponsor: National Science Council, Taiwan; Contract grant number: NSC 96-2320-B-002-085; Contract grant sponsor: National Health Research Institute, Taiwan; Contract grant number: NHRI-EX97-9715EC. NR 55 TC 6 Z9 6 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2009 VL 30 IS 7 BP 2232 EP 2251 DI 10.1002/hbm.20664 PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 466VQ UT WOS:000267691900028 PM 19288462 ER PT J AU Franke, B Neale, BM Faraone, SV AF Franke, Barbara Neale, Benjamin M. Faraone, Stephen V. TI Genome-wide association studies in ADHD SO HUMAN GENETICS LA English DT Review ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY-DISORDER; FAMILY-BASED ASSOCIATION; SCHIZOPHRENIA SUSCEPTIBILITY LOCI; MAJOR DEPRESSIVE DISORDER; AUTISM SPECTRUM DISORDER; QUANTITATIVE TRAIT LOCUS; CORONARY-HEART-DISEASE; NITRIC-OXIDE SYNTHASE; RECEPTOR GENE CNR1 AB Attention-deficit/hyperactivity disorder, ADHD, is a common and highly heritable neuropsychiatric disorder that is seen in children and adults. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. A novel way of performing hypothesis-free analysis of the genome suitable for the identification of disease risk genes of considerably smaller effect is the genome-wide association study (GWAS). So far, five GWAS have been performed on the diagnosis of ADHD and related phenotypes. Four of these are based on a sample set of 958 parent-child trio's collected as part of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN). The other is a pooled GWAS including adult patients with ADHD and controls. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the 'classic' ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. There is extensive overlap with findings from other psychiatric disorders. Though not genome-wide significant, findings from the individual studies converge to paint an interesting picture: whereas little evidence-as yet-points to a direct involvement of neurotransmitters (at least the classic dopaminergic, noradrenergic and serotonergic pathways) or regulators of neurotransmission, some suggestions are found for involvement of 'new' neurotransmission and cell-cell communication systems. A potential involvement of potassium channel subunits and regulators warrants further investigation. More basic processes also seem involved in ADHD, like cell division, adhesion (especially via cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and extracellular matrix regulation, and cytoskeletal remodeling processes. In conclusion, the GWAS performed so far in ADHD, though far from conclusive, provide a first glimpse at genes for the disorder. Many more (much larger studies) will be needed. For this, collaboration between researchers as well as standardized protocols for phenotyping and DNA-collection will become increasingly important. C1 [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet 855, NL-6500 HB Nijmegen, Netherlands. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Inst Brain Cognit & Behav, NL-6500 HB Nijmegen, Netherlands. [Neale, Benjamin M.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. [Neale, Benjamin M.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, 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 Franke, B (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Human Genet 855, Postbox 9101, NL-6500 HB Nijmegen, Netherlands. EM b.franke@antrg.umcn.nl RI Franke, Barbara/D-4836-2009; OI Franke, Barbara/0000-0003-4375-6572; Faraone, Stephen/0000-0002-9217-3982 NR 174 TC 194 Z9 196 U1 7 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUL PY 2009 VL 126 IS 1 BP 13 EP 50 DI 10.1007/s00439-009-0663-4 PG 38 WC Genetics & Heredity SC Genetics & Heredity GA 482JW UT WOS:000268883800003 PM 19384554 ER PT J AU Choquet, H Cavalcanti-Proenca, C Lecoeur, C Dina, C Cauchi, S Vaxillaire, M Hadjadj, S Horber, F Potoczna, N Charpentier, G Ruiz, J Hercberg, S Maimaitiming, S Roussel, R Boenhnke, M Jackson, AU Patsch, W Krempler, F Voight, BF Altshuler, D Groop, L Thorleifsson, G Steinthorsdottir, V Stefansson, K Balkau, B Froguel, P Meyre, D AF Choquet, Helene Cavalcanti-Proenca, Christine Lecoeur, Cecile Dina, Christian Cauchi, Stephane Vaxillaire, Martine Hadjadj, Samy Horber, Fritz Potoczna, Natasha Charpentier, Guillaume Ruiz, Juan Hercberg, Serge Maimaitiming, Suliya Roussel, Ronan Boenhnke, Michael Jackson, Anne U. Patsch, Wolfgang Krempler, Franz Voight, Benjamin F. Altshuler, David Groop, Leif Thorleifsson, Gudmar Steinthorsdottir, Valgerdur Stefansson, Kari Balkau, Beverley Froguel, Philippe Meyre, David TI The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects SO HUMAN MOLECULAR GENETICS LA English DT Article ID BRAIN NATRIURETIC PEPTIDE; GENOME-WIDE ASSOCIATION; K121Q POLYMORPHISM; COMMON VARIANTS; HEART-FAILURE; RISK; OBESITY; LOCI; SUSCEPTIBILITY; IMPACT AB A recent study reported an association between the brain natriuretic peptide (BNP) promoter T-381C polymorphism (rs198389) and protection against type 2 diabetes (T2D). As replication in several studies is mandatory to confirm genetic results, we analyzed the T-381C polymorphism in seven independent case-control cohorts and in 291 T2D-enriched pedigrees totalling 39 557 subjects of European origin. A meta-analysis of the seven case-control studies (n = 39 040) showed a nominal protective effect [odds ratio (OR) = 0.86 (0.79-0.94), P = 0.0006] of the CC genotype on T2D risk, consistent with the previous study. By combining all available data (n = 49 279), we further confirmed a modest contribution of the BNP T-381C polymorphism for protection against T2D [OR = 0.86 (0.80-0.92), P = 1.4 x 10(-5)]. Potential confounders such as gender, age, obesity status or family history were tested in 4335 T2D and 4179 normoglycemic subjects and they had no influence on T2D risk. This study provides further evidence of a modest contribution of the BNP T-381C polymorphism in protection against T2D and illustrates the difficulty of unambiguously proving modest-sized associations even with large sample sizes. C1 [Choquet, Helene; Cavalcanti-Proenca, Christine; Lecoeur, Cecile; Dina, Christian; Cauchi, Stephane; Vaxillaire, Martine; Froguel, Philippe; Meyre, David] Inst Pasteur, Inst Biol, CNRS 8090, F-59019 Lille, France. [Hadjadj, Samy] Univ Poitiers, CHU Poitiers, INSERM, CIC 0802,U927,UFR Med Pharm, Poitiers, France. [Horber, Fritz; Potoczna, Natasha] Dept Med, Clin Lindberg, Dept Surg & Internal Med, Winterthur, Switzerland. [Horber, Fritz; Potoczna, Natasha] Univ Bern, Bern, Switzerland. [Charpentier, Guillaume] Ctr Hosp Sud Francilien, Dept Endocrinol Diabetol, Corbeil Essonnes, France. [Ruiz, Juan] CHUV BH19, Lausanne, Switzerland. [Hercberg, Serge] Univ Paris, Cnam, INRA, INSERM,U557,U1125, Bobigny, France. [Maimaitiming, Suliya; Roussel, Ronan] INSERM, U695, Paris, France. [Maimaitiming, Suliya; Roussel, Ronan] Univ Paris 07, Fac Med Xavier Bichat, Paris, France. [Roussel, Ronan] Hop Xavier Bichat, AP HP, Paris, France. [Boenhnke, Michael; Jackson, Anne U.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Boenhnke, Michael; Jackson, Anne U.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Patsch, Wolfgang] Paracelsus Med Univ, Dept Lab Med, Salzburg, Austria. [Krempler, Franz] Krankenhaus Hallein, Dept Internal Med, A-5400 Hallein, Austria. [Voight, Benjamin F.; Altshuler, David] Broad Inst Harvard, Cambridge, MA 02142 USA. [Voight, Benjamin F.; Altshuler, David] MIT, Cambridge, MA 02142 USA. [Voight, Benjamin F.; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Voight, Benjamin F.; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Groop, Leif] Lund Univ, Malmo Univ Hosp, Diabet & Endocrinol Res Unit, Dept Clin Sci, SE-20502 Malmo, Sweden. [Groop, Leif] Univ Helsinki, Helsinki Univ Hosp, Dept Med, FIN-00300 Helsinki, Finland. [Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Stefansson, Kari] deCODE Genet, IS-101 Reykjavik, Iceland. [Balkau, Beverley] Univ Paris Sud, INSERM, U780, IFR69, Villejuif, France. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Genom Med, London W12 ONN, England. RP Froguel, P (reprint author), Inst Pasteur, Inst Biol, CNRS 8090, F-59019 Lille, France. EM p.froguel@imperial.ac.uk RI Altshuler, David/A-4476-2009; Meyre, David/D-7315-2011; Voight, Benjamin/F-1775-2011; Dina, Christian/D-3535-2015 OI Altshuler, David/0000-0002-7250-4107; Dina, Christian/0000-0002-7722-7348 FU 'le Conseil Regional Nord Pas de Calais/FEDER'; 'Agence Nationale de la Recherche' FX We thank 'le Conseil Regional Nord Pas de Calais/FEDER' and the 'Agence Nationale de la Recherche' for their financial support. NR 48 TC 20 Z9 22 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2009 VL 18 IS 13 BP 2495 EP 2501 DI 10.1093/hmg/ddp169 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 457VE UT WOS:000266961400016 PM 19377085 ER PT J AU Lerner-Ellis, JP Anastasio, N Liu, JH Coelho, D Suormala, T Stucki, M Loewy, AD Gurd, S Grundberg, E Morel, CF Watkins, D Baumgartner, MR Pastinen, T Rosenblatt, DS Fowler, B AF Lerner-Ellis, Jordan P. Anastasio, Natascia Liu, Junhui Coelho, David Suormala, Terttu Stucki, Martin Loewy, Amanda D. Gurd, Scott Grundberg, Elin Morel, Chantal F. Watkins, David Baumgartner, Matthias R. Pastinen, Tomi Rosenblatt, David S. Fowler, Brian TI Spectrum of Mutations in MMACHC, Allelic Expression, and Evidence for Genotype-Phenotype Correlations SO HUMAN MUTATION LA English DT Article DE vitamin B12; cobalamin; hyperhomocysteinemia; homocystinuria; methylmalonic aciduria; MMACHC ID COMBINED METHYLMALONIC ACIDURIA; COBALAMIN-C DISEASE; HOMOCYSTINURIA CBLC; VITAMIN-B-12; IDENTIFICATION; DIAGNOSIS; ACIDEMIA; DISORDER AB Methylmalonic aciduria and homocystinuria, cblC type, is a rare disorder of intracellular vitamin B(12) (cobalamin [Cbl]) metabolism caused by mutations in the MMACHC gene. MMACHC was sequenced from the gDNA of 118 cblC individuals. Eleven novel mutations were identified, as well as 23 mutations that were observed previously. Six sequence variants capture haplotype diversity in individuals across the MMACHC interval. Genotype-phenotype correlations of common mutations were apparent; individuals with c.394C > T tend to present with late-onset disease whereas patients with c.331C > T and c.271dupA tend to present in infancy. Other missense variants were also associated with late- or early-onset disease. Allelic expression analysis was carried out on human cblC fibroblasts compound heterozygous for different combinations of mutations including c.271dupA, c.331C > T, c.394C > T, and c.482G > A. The early-onset c.271dupA mutation was consistently underexpressed when compared to control alleles and the late-onset c.394C > T and c.482G > A mutations. The early-onset c.331C > T mutation was also underexpressed when compared to control alleles and the c.394C > T mutation. Levels of MMACHC mRNA transcript in cell lines homozygous for c.271dupA, c.331C > T, and c.394C > T were assessed using quantitative real-time RT-PCR. Cell lines homozygous for the late onset c.394C > T mutation had significantly higher levels of transcript when compared to cell lines homozygous for the early-onset mutations. Differential or preferential MMACHC transcript levels may provide a clue as to why individuals carrying c.394C > T generally present later in life. Hum Mutat 30:1072-1081, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Lerner-Ellis, Jordan P.; Anastasio, Natascia; Liu, Junhui; Loewy, Amanda D.; Watkins, David; Baumgartner, Matthias R.; Pastinen, Tomi; Rosenblatt, David S.] McGill Univ, Ctr Hlth, Dept Med Genet, Montreal, PQ, Canada. [Lerner-Ellis, Jordan P.; Anastasio, Natascia; Liu, Junhui; Loewy, Amanda D.; Gurd, Scott; Grundberg, Elin; Watkins, David; Baumgartner, Matthias R.; Pastinen, Tomi; Rosenblatt, David S.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Lerner-Ellis, Jordan P.; Gurd, Scott; Grundberg, Elin; Baumgartner, Matthias R.; Pastinen, Tomi] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Lerner-Ellis, Jordan P.; Coelho, David; Suormala, Terttu; Fowler, Brian] Univ Childrens Hosp, Metab Unit, Basel, Switzerland. [Stucki, Martin] Univ Childrens Hosp, Div Metab & Mol Pediat, Zurich, Switzerland. [Stucki, Martin] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Morel, Chantal F.] Univ Toronto, Dept Med, Univ Hlth Network, Toronto, ON, Canada. RP Lerner-Ellis, JP (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,CPZN 6822, Boston, MA 02114 USA. EM lerner-ellis@moibio.mgh.harvard.edu; natascia.anastasio@mail.mcgill.ca RI Coelho, David/F-6680-2011; Lerner-Ellis, Jordan/J-5559-2016; OI Coelho, David/0000-0001-7010-5789; Baumgartner, Matthias R./0000-0002-9270-0826 FU Swiss National Foundation [3200-066878/1, 320000-109635/1, 3200AO-109219/1]; CIHR [200510CGD, 200702OWF] FX The authors would like to thank the clinicians and families of the individuals with cblC disease for making this work possible. Bale thank Kenneth Morgan, Mary Fujiwara, Janet Atkinson, and Johanna Rommens for their discussion and comments, and Maria Galvez and Jocelyne Lavallee for mutation confirmation and complementation analyses. Supported by grants from the Swiss National Foundation (3200-066878/1, 320000-109635/1, and 3200AO-109219/1). D.S.R. is a principal Investigator in the Canadian Institute of Health Research (CIHR) Group in Medical Genetics, and Director of the Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone. J.L-E was funded in part by a Canadian Graduate Scholarship from the CIHR (200510CGD) and is the recipient of a Cl H R fellowship (200702OWF). NR 22 TC 72 Z9 78 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD JUL PY 2009 VL 30 IS 7 BP 1072 EP 1081 DI 10.1002/humu.21001 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 468CQ UT WOS:000267791700007 PM 19370762 ER PT J AU Caton, AR Bell, EM Druschel, CM Werler, MM Lin, AE Browne, ML McNutt, LA Romitti, PA Mitchell, AA Olney, RS Correa, A AF Caton, Alissa R. Bell, Erin M. Druschel, Charlotte M. Werler, Martha M. Lin, Angela E. Browne, Marilyn L. McNutt, Louise-Anne Romitti, Paul A. Mitchell, Allen A. Olney, Richard S. Correa, Adolfo CA Natl Birth Defects TI Antihypertensive Medication Use During Pregnancy and the Risk of Cardiovascular Malformations SO HYPERTENSION LA English DT Article DE hypertension; pregnancy; antihypertensive agents; congenital malformations; cardiovascular malformations ID CONVERTING ENZYME-INHIBITORS; BIRTH-DEFECTS PREVENTION; CALCIUM-CHANNEL BLOCKERS; HIGH BLOOD-PRESSURE; CONGENITAL-MALFORMATIONS; RECEPTOR-ANTAGONISTS; CHRONIC HYPERTENSION; TWIN PREGNANCIES; FETAL; EXPOSURE AB We used data from the National Birth Defects Prevention Study, a population-based, case-control study, to examine whether previously reported associations between antihypertensive medications and cardiovascular malformations could be confirmed and to explore whether new associations might be identified. Cases (n = 5021) were ascertained through birth defects surveillance systems from 1997 through 2003 in 10 US states. Controls (n = 4796) were live births without birth defects selected randomly from birth certificates or hospital discharge listings in the same geographic regions. Logistic regression was used to examine the relationship between antihypertensive medication treatment and the occurrence of cardiovascular malformations while controlling for confounding variables. First-trimester treatment with antihypertensive medication was associated with pulmonary valve stenosis (odds ratio [OR]: 2.6; 95% CI: 1.3 to 5.4), Ebstein malformation (crude OR: 11.4; exact 95% CI: 2.8 to 34.1), coarctation of the aorta (OR: 3.0; 95% CI: 1.3 to 6.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Treatment initiated after the first trimester was associated with pulmonary valve stenosis (OR: 2.4; 95% CI: 1.1 to 5.4), perimembranous ventricular septal defects (OR: 2.3; 95% CI: 1.2 to 4.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Untreated hypertension was associated with Ebstein malformation (OR: 2.1; 95% CI: 1.0 to 4.3) and secundum atrial septal defects (OR: 1.3; 95% CI: 1.0 to 1.6). Antihypertensive medication use and/or the underlying hypertension might increase the risk of having an infant with specific left and right obstructive and septal defects. Additional studies with adequate power will be needed to confirm these findings. (Hypertension. 2009; 54: 63-70.) C1 [Caton, Alissa R.] New York State Dept Hlth, Bur Environm & Occupat Epidemiol, Congenital Malformat Registry, Troy, NY 12180 USA. [Caton, Alissa R.; Bell, Erin M.; Druschel, Charlotte M.; Browne, Marilyn L.; McNutt, Louise-Anne] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Rensselaer, NY USA. [Werler, Martha M.; Mitchell, Allen A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA USA. [Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Olney, Richard S.; Correa, Adolfo] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. RP Caton, AR (reprint author), New York State Dept Hlth, Bur Environm & Occupat Epidemiol, Congenital Malformat Registry, 547 River St,Room 200, Troy, NY 12180 USA. EM arc05@health.state.ny.us RI Publications, NBDPS/B-7692-2013; OI Mitchell, Allen/0000-0003-0950-6799; Werler, Martha/0000-0003-3392-6814 FU Centers for Disease Control and Prevention [U50CCU213244] FX This research was supported by a cooperative agreement from the Centers for Disease Control and Prevention ( grant U50CCU213244). NR 44 TC 45 Z9 48 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUL PY 2009 VL 54 IS 1 BP 63 EP 70 DI 10.1161/HYPERTENSIONAHA.109.129098 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 459LF UT WOS:000267103000013 PM 19433779 ER PT J AU Chen, Z Brown, EN Barbieri, R AF Chen, Zhe Brown, Emery N. Barbieri, Riccardo TI Assessment of Autonomic Control and Respiratory Sinus Arrhythmia Using Point Process Models of Human Heart Beat Dynamics SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article; Proceedings Paper CT 33rd IEEE International Conference on Acoustics, Speech and Signal Processing CY MAR 30-APR 04, 2008 CL Las Vegas, NV DE Adaptive filters; autoregressive (AR) processes; heart rate variability (HRV); point processes; respiratory sinus arrhythmia (RSA) ID RATE-VARIABILITY; TIME-SERIES AB Tracking the autonomic control and respiratory sinus arrhythmia (RSA) from electrocardiogram and respiratory measurements is an important problem in cardiovascular control. We propose a point process adaptive filter algorithm based on an inverse Gaussian model to track heart beat intervals that incorporates respiratory measurements as a covariate and provides an analytic form for computing a dynamic estimate of RSA gain. We use Kolmogorov-Smirnov tests and autocorrelation function analyses to assess model goodness-of-fit. We illustrate the properties of the new dynamic estimate of RSA in the analysis of simulated heart beat data and actual heart beat data recorded from subjects in a four-state postural study of heart beat dynamics: control, sympathetic blockade, parasympathetic blockade, and combined sympathetic and parasympathetic blockade. In addition to giving an accurate description of the heart beat data, our adaptive filter algorithm confirms established findings pointing at a vagally mediated RSA and provides a new dynamic RSA estimate that can be used to track cardiovascular control between and within a broad range of postural, pharmacological, and age conditions. Our paradigm suggests a possible framework for designing a device for ambulatory monitoring and assessment of autonomic control in both laboratory research and clinical practice. C1 [Chen, Zhe; Brown, Emery N.; Barbieri, Riccardo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab, Boston, MA 02114 USA. [Chen, Zhe; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Chen, Z (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab, Boston, MA 02114 USA. EM zhechen@neurostat.mgh.harvard.edu; brown@neurostat.mgh.harvard.edu; barbieri@neurostat.mgh.harvard.edu OI Barbieri, Riccardo/0000-0001-9381-3833; Chen, Zhe/0000-0002-6483-6056 FU NCRR NIH HHS [RR-79]; NHLBI NIH HHS [R01 HL084502, R01 HL084502-03, R01-HL084502]; NIA NIH HHS [AG-9550]; NIDA NIH HHS [R01-DA015644, R01 DA015644]; NIGMS NIH HHS [GM-26691]; NIH HHS [DP1 OD003646-03, DP1 OD003646, DP1-OD003646] NR 35 TC 22 Z9 23 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD JUL PY 2009 VL 56 IS 7 BP 1791 EP 1802 DI 10.1109/TBME.2009.2016349 PG 12 WC Engineering, Biomedical SC Engineering GA 462TI UT WOS:000267379100003 PM 19272971 ER PT J AU Liu, Y Zhang, YY Ji, CL Malik, WQ Edwards, DJ AF Liu, Yi Zhang, Yangyang Ji, Chunlin Malik, Wasim Q. Edwards, David J. TI A Low-Complexity Receive-Antenna-Selection Algorithm for MIMO-OFDM Wireless Systems SO IEEE TRANSACTIONS ON VEHICULAR TECHNOLOGY LA English DT Article DE Antenna selection; bit error rate (BER); capacity; complexity; constrained adaptive Markov chain Monte Carlo (CAMCMC); frequency selectivity; multiple-input multiple-output (MIMO)-orthogonal frequency division multiplexing (OFDM); zero forcing (ZF) ID ERGODICITY; MCMC AB In this paper, a novel low-complexity antenna-selection algorithm based on a constrained adaptive Markov chain Monte Carlo (CAMCMC) optimization method is proposed to approach the maximum capacity or minimum bit error rate (BER) of receive-antenna-selection multiple-input multiple-output (MIMO)-orthogonal frequency division multiplexing (OFDM) systems. We analyze the performance of the proposed system as the control parameters are varied and show that both the channel capacity and the system BER achieved by the proposed CAMCMC selection algorithm are close to the optimal results obtained by the exhaustive search (ES) method. We further demonstrate that this performance can be achieved with less than 1% of the computational complexity of the ES rule and is independent of the antenna-selection criteria, outage rate requirements, antenna array configuration, and channel frequency selectivity. Similar to the existing antenna-selection algorithms, both channel capacity and system BER improvements achieved by the proposed CAMCMC method are reduced as the channel frequency selectivity increases. Therefore, we conclude that, whether it is designed to maximize the channel capacity or minimize the system BER, the CAMCMC-optimization-method-based antenna-selection technique is appropriate for a MIMO-OFDM system with low frequency selectivity. C1 [Liu, Yi] Univ Oxford, Oxford OX1 3PJ, England. [Zhang, Yangyang] Univ Coll London Adastral Pk Campus, London IP5 3RE, England. [Ji, Chunlin] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. [Malik, Wasim Q.] MIT, Cambridge, MA 02139 USA. [Malik, Wasim Q.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Edwards, David J.] Univ Oxford Wadham Coll, Oxford OX1 3PN, England. RP Liu, Y (reprint author), Univ Oxford, Oxford OX1 3PJ, England. EM y.liu@eng.ox.ac.uk; y.zhang@adastral.ucl.ac.uk; chunlin.ji@duke.edu; wqm@mit.edu; david.edwards@eng.ox.ac.uk RI Malik, Wasim/C-9982-2011 NR 22 TC 6 Z9 6 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9545 J9 IEEE T VEH TECHNOL JI IEEE Trans. Veh. Technol. PD JUL PY 2009 VL 58 IS 6 BP 2793 EP 2802 DI 10.1109/TVT.2008.2010943 PG 10 WC Engineering, Electrical & Electronic; Telecommunications; Transportation Science & Technology SC Engineering; Telecommunications; Transportation GA 470BL UT WOS:000267946800015 ER PT J AU Permaul, P Narla, A Hornick, JL Pai, SY AF Permaul, Perdita Narla, Anupama Hornick, Jason L. Pai, Sung-Yun TI Allogeneic hematopoietic stem cell transplantation for X-linked ectodermal dysplasia and immunodeficiency: case report and review of outcomes SO IMMUNOLOGIC RESEARCH LA English DT Article DE Immunodeficiency; Transplantation; Dermatitis; Enteropathy ID NF-KAPPA-B; ESSENTIAL MODULATOR MUTATION; INCONTINENTIA PIGMENTI; TUFTING ENTEROPATHY; MISSENSE MUTATIONS; NEMO MUTATION; OSTEOPETROSIS; LYMPHEDEMA; GENE; EXPRESSION AB Hypomorphic mutations in nuclear factor kappa B essential modulator (NEMO) cause X-linked ectodermal dysplasia with immunodeficiency (X-ED-ID). Clinical manifestations in boys with X-ED-ID apart from ectodermal dysplasia and immunodeficiency include osteopetrosis, lymphedema, and colitis. Further description of atypical findings in this disorder is needed. Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is in its infancy, and how or whether non-immune manifestations of defective NEMO function are impacted by HSCT is poorly described. We report an interesting case of a boy with NEMO mutation who had symptoms reminiscent of Omenn's syndrome and small intestinal villous atrophy with features reminiscent of tufting enteropathy. We describe his treatment course as well as reconstitution of immune function and correction of osteopetrosis post-HSCT, and review the cases of allogeneic HSCT reported to date in the literature. C1 [Pai, Sung-Yun] Childrens Hosp, Div Hematol, Karp Family Res Labs, Boston, MA 02115 USA. [Hornick, Jason L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hornick, Jason L.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Narla, Anupama; Pai, Sung-Yun] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Permaul, Perdita] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Permaul, Perdita; Narla, Anupama; Hornick, Jason L.; Pai, Sung-Yun] Harvard Univ, Sch Med, Boston, MA USA. RP Pai, SY (reprint author), Childrens Hosp, Div Hematol, Karp Family Res Labs, Room 08214,300 Longwood Ave, Boston, MA 02115 USA. EM sung-yun.pai@childrens.harvard.edu NR 29 TC 23 Z9 23 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD JUL PY 2009 VL 44 IS 1-3 BP 89 EP 98 DI 10.1007/s12026-008-8085-2 PG 10 WC Immunology SC Immunology GA 453AR UT WOS:000266582800011 PM 19225723 ER PT J AU Schulz, C von Andrian, UH Massberg, S AF Schulz, Christian von Andrian, Ulrich H. Massberg, Steffen TI Hematopoietic stem and progenitor cells: their mobilization and homing to bone marrow and peripheral tissue SO IMMUNOLOGIC RESEARCH LA English DT Article DE Hematopoietic stem cells; Progenitor cells; Migration; Homing; Bone marrow; Peripheral tissue ID GROWTH-FACTOR-BETA; SPHINGOSINE 1-PHOSPHATE; TGF-BETA; NICHE; RECEPTOR; BLOOD; MIGRATION; ADHESION; MICE; TRAFFICKING AB Hematopoietic stem and progenitor cells (HSPCs) are a rare population of precursor cells that possess the capacity for self-renewal and multilineage differentiation. In the bone marrow (BM), HSPCs warrant blood cell homeostasis. In addition, they may also replenish tissue-resident myeloid cells and directly participate in innate immune responses once they home to peripheral tissues. In this review, we summarize recent data on the signaling molecules that modulate the mobilization of HSPCs from BM and their migration to peripheral tissues. C1 [Schulz, Christian; Massberg, Steffen] Tech Univ Munich, Deutsch Herzzentrum, D-80636 Munich, Germany. [von Andrian, Ulrich H.; Massberg, Steffen] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [von Andrian, Ulrich H.; Massberg, Steffen] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. RP Massberg, S (reprint author), Tech Univ Munich, Deutsch Herzzentrum, Lazarettstr 36, D-80636 Munich, Germany. EM massberg@dhm.mhn.de RI Schulz, Christian/J-8545-2012; von Andrian, Ulrich/A-5775-2008 OI Schulz, Christian/0000-0003-3878-7833; NR 63 TC 18 Z9 19 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD JUL PY 2009 VL 44 IS 1-3 BP 160 EP 168 DI 10.1007/s12026-009-8109-6 PG 9 WC Immunology SC Immunology GA 453AR UT WOS:000266582800017 PM 19340403 ER PT J AU Ip, WKE Takahashi, K Ezekowitz, RA Stuart, LM AF Ip, W. K. Eddie Takahashi, Kazue Ezekowitz, R. Alan Stuart, Lynda M. TI Mannose-binding lectin and innate immunity SO IMMUNOLOGICAL REVIEWS LA English DT Review DE monocytes; macrophages; autoimmunity; immunodeficiency diseases; infectious diseases; Toll-like receptors; pattern recognition ID TOLL-LIKE RECEPTORS; LEWIS-B ANTIGENS; COMPLEMENT ACTIVATION; NALP3 INFLAMMASOME; STAPHYLOCOCCUS-AUREUS; PATTERN-RECOGNITION; REPERFUSION INJURY; BACTERIAL PEPTIDOGLYCAN; ISCHEMIA-REPERFUSION; MYOCARDIAL-ISCHEMIA AB Innate immunity is the earliest response to invading microbes and acts to contain infection in the first minutes to hours of challenge. Unlike adaptive immunity that relies upon clonal expansion of cells that emerge days after antigenic challenge, the innate immune response is immediate. Soluble mediators, including complement components and the mannose binding lectin (MBL) make an important contribution to innate immune protection and work along with epithelial barriers, cellular defenses such as phagocytosis, and pattern-recognition receptors that trigger pro-inflammatory signaling cascades. These four aspects of the innate immune system act in concert to protect from pathogen invasion. Our work has focused on understanding the protection provided by this complex defense system and, as discussed in this review, the particular contribution of soluble mediators such as MBL and phagocytic cells. Over the past two decades both human epidemiological data and mouse models have indicated that MBL plays a critical role in innate immune protection against a number of pathogens. As demonstrated by our recent in vitro work, we show that MBL and the innate immune signaling triggered by the canonical pattern-recognition receptors (PRRs), the Toll-like receptors (TLRs), are linked by their spatial localization to the phagosome. These observations demonstrated a novel role for MBL as a TLR co-receptor and establishes a new paradigm for the role of opsonins, which we propose to function not only to increase microbial uptake but also to spatially coordinate, amplify, and synchronize innate immune defenses mechanism. In this review we discuss both the attributes of MBL that make it a unique soluble pattern recognition molecule and also highlight its broader role in coordinating innate immune activation. C1 [Ezekowitz, R. Alan] Merck Res Labs, BRIE Franchise, Rahway, NJ 07065 USA. [Ip, W. K. Eddie] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Takahashi, Kazue; Stuart, Lynda M.] Harvard Univ, Sch Med, Dept Pediat, Lab Dev Immunol,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Ezekowitz, RA (reprint author), Merck Res Labs, BRIE Franchise, Rahway, NJ 07065 USA. EM alan_ezekowitz@merck.com RI Ip, Eddie/C-3042-2012 FU National Institutes of Health FX We thank members of the laboratory of Developmental Immunology, Massachusetts General Hospitals, for insightful discussion and continuous inspiration. This work was supported by grants from the National Institutes of Health to K. T. and L. M. S. NR 105 TC 169 Z9 182 U1 2 U2 23 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2009 VL 230 BP 9 EP 21 PG 13 WC Immunology SC Immunology GA 464WF UT WOS:000267539400002 PM 19594626 ER PT J AU Sackstein, R AF Sackstein, Robert TI Glycosyltransferase-programmed stereosubstitution (GPS) to create HCELL: engineering a roadmap for cell migration SO IMMUNOLOGICAL REVIEWS LA English DT Review DE stem cell; mesenchymal stem cell; E-selectin; E-selectin ligand; HCELL; regenerative medicine ID MESENCHYMAL STEM-CELLS; E-SELECTIN LIGAND; SIALYL-LEWIS-X; LYMPHOCYTE-ASSOCIATED ANTIGEN; HEMATOPOIETIC PROGENITOR CELLS; TUMOR-NECROSIS-FACTOR; HOMING T-CELLS; CORE 2 BETA-1,6-N-ACETYLGLUCOSAMINYLTRANSFERASE; LEUKOCYTE ADHESION MOLECULE-1; MANGANESE-INDUCED APOPTOSIS AB During evolution of the vertebrate cardiovascular system, the vast endothelial surface area associated with branching vascular networks mandated the development of molecular processes to efficiently and specifically recruit circulating sentinel host defense cells and tissue repair cells at localized sites of inflammation/tissue injury. The forces engendered by high-velocity blood flow commensurately required the evolution of specialized cell surface molecules capable of mediating shear-resistant endothelial adhesive interactions, thus literally capturing relevant cells from the blood stream onto the target endothelial surface and permitting subsequent extravasation. The principal effectors of these shear-resistant binding interactions comprise a family of C-type lectins known as 'selectins' that bind discrete sialofucosylated glycans on their respective ligands. This review explains the 'intelligent design' of requisite reagents to convert native CD44 into the sialofucosylated glycoform known as hematopoietic cell E-/L-selectin ligand (HCELL), the most potent E-selectin counter-receptor expressed on human cells, and will describe how ex vivo glycan engineering of HCELL expression may open the 'avenues' for the efficient vascular delivery of cells for a variety of cell therapies. C1 [Sackstein, Robert] Brigham & Womens Hosp, Dept Dermatol, Harvard Inst Med, Boston, MA 02115 USA. [Sackstein, Robert] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Sackstein, Robert] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Sackstein, R (reprint author), Brigham & Womens Hosp, Dept Dermatol, Harvard Inst Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM Rsackstein@rics.bwh.harvard.edu FU Veterans Career Development and Merit Awards; National Institutes of Health [RO1 HL60528, RO1 CA84156, RO1 HL073714, RO1 CA 121335] FX This article reviews over 20 years of laboratory effort seeking to create strategies to deliver infused cells to a predetermined anatomic site. The inspiration for this work derives from my patients undergoing hematopoietic stem cell transplantation, where the problems of lack of hematopoietic engraftment, infectious diseases (e.g. cytomegalovirus disease) and recurrence of (primary) malignant disease posttransplant (e.g. lymphoma, leukemia) made evident the imperative to optimize vascular delivery of relevant cells (hematopoietic stem cells or immune effector cells) to requisite (affected) sites in order to realize long-term cure. Thus, I dedicate this review to my patients, alive and deceased, for their lessons in courage and in humanity. Moreover, over this period of time, many technicians, students, post-docs et al. have contributed significantly to this mission. Certainly, there are no words adequate to relay my gratitude for their devotion and commitment to this endeavor. In typical acknowledgements found in scientific publications, it is uncommon for one to thank the unsung heroes: teachers/mentors and family. Regrettably, several mentors have departed - Ramzi S. Cotran, Edgar Haber, Harvey R. Colten, Yee Hon Chin, J. Wayne Streilein, and Robert A. Good - without ever knowing my eternal gratitude. I would thus like to formally thank here Drs. Adel A. Yunis, Murray Epstein, Claude P. Lechene, Emil R. Unanue, Lawrence M. Fishman, Gerald J. Elfenbein, and E. Donnall Thomas, for their example, for sharing their infinite wisdom, and for their constant encouragement and support. Last, but certainly not least, I thank my parents, Harold and Rosalina Sackstein, my wife, Beth, and my children, David and Danielle, without whom none of this would be possible.; This work was supported in part by Veterans Career Development and Merit Awards, and by National Institutes of Health grants RO1 HL60528, RO1 CA84156, RO1 HL073714, and RO1 CA 121335. NR 227 TC 26 Z9 27 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2009 VL 230 BP 51 EP 74 PG 24 WC Immunology SC Immunology GA 464WF UT WOS:000267539400005 PM 19594629 ER PT J AU Daniel, C Nolting, J von Boehmer, H AF Daniel, Carolin Nolting, Jens von Boehmer, Harald TI Mechanisms of self-nonself discrimination and possible clinical relevance SO IMMUNOTHERAPY LA English DT Review DE conversion; Foxp3; recessive and dominant tolerance; regulatory T cell; self-nonself discrimination; suppression; TGF-beta ID REGULATORY T-CELLS; THYMIC EPITHELIAL-CELLS; ARYL-HYDROCARBON RECEPTOR; PROMISCUOUS GENE-EXPRESSION; TRANSCRIPTION FACTOR FOXP3; GROWTH-FACTOR-BETA; TGF-BETA; IN-VIVO; NEGATIVE SELECTION; RETINOIC-ACID AB This review discusses different mechanisms that result in immunological tolerance, such as intrathymic deletion of immature T cells, intrathymic and extrathymic generation of regulatory T cells, effector mechanisms of regulatory T cells as well as molecular pathways involved in extrathymic generation of regulatory T cells in vivo and in vitro. These molecular mechanisms should enable investigators to develop clinical protocols aiming at the specific prevention of unwanted immune responses, thereby replacing indiscriminate immunosuppression that often has fatal consequences. C1 [Daniel, Carolin; Nolting, Jens; von Boehmer, Harald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP von Boehmer, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Smith 736, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu RI Daniel, Carolin/M-4624-2014 OI Daniel, Carolin/0000-0003-4698-7069 FU NIH [NIH-A1-53102]; LOEWE [BMBF-LPD990118-184] FX These studies were supported by NIH grant NIH-A1-53102. Carolin Daniel is a Leopoldina researchftllow (BMBF-LPD990118-184) and supported by LOEWE (LiFF) program of the Federal State of Hessen, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 120 TC 10 Z9 10 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-743X J9 IMMUNOTHERAPY JI Immunotherapy PD JUL PY 2009 VL 1 IS 4 BP 631 EP 644 DI 10.2217/IMT.09.29 PG 14 WC Immunology SC Immunology GA 542US UT WOS:000273524400014 PM 20582233 ER PT J AU Schalock, PC Dinulos, JGH AF Schalock, Peter C. Dinulos, James G. H. TI Mycoplasma pneumoniae-induced cutaneous disease SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Review ID STEVENS-JOHNSON-SYNDROME; ERYTHEMA MULTIFORME; SUBCORNEAL PUSTULES; KAWASAKI-DISEASE; INFECTION; CHILDREN; MANIFESTATIONS; URTICARIA; NODOSUM; LESIONS C1 [Schalock, Peter C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. Dartmouth Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH USA. RP Schalock, PC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, BAR622,55 Fruit St, Boston, MA 02114 USA. EM schalock@gmail.com NR 46 TC 21 Z9 25 U1 1 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0011-9059 J9 INT J DERMATOL JI Int. J. Dermatol. PD JUL PY 2009 VL 48 IS 7 BP 673 EP 681 PG 9 WC Dermatology SC Dermatology GA 459RG UT WOS:000267121300001 PM 19570071 ER PT J AU Fortier, CB Maksimovskiy, AL Venne, JR LaFleche, G McGlinchey, RE AF Fortier, Catherine Brawn Maksimovskiy, Arkadiy L. Venne, Jonathan R. LaFleche, Ginette McGlinchey, Regina E. TI Silent Trace Eliminates Differential Eyeblink Learning in Abstinent Alcoholics SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE alcohol; eyeblink classical conditioning; learning; discrimination; reversal ID TEMPORAL-LOBE AMNESIA; QUANTITATIVE-ANALYSIS; WHITE-MATTER; HEART-RATE; REVERSAL; DISCRIMINATION; SYSTEM; MEMORY; DISRUPTION; LESIONS AB Chronic alcoholism has profound effects on the brain, including volume reductions in regions critical for eyeblink classical conditioning (EBCC). The current study challenged abstinent alcoholics using delay (n = 20) and trace (n = 17) discrimination/reversal EBCC. Comparisons revealed a significant difference between delay and trace conditioning performance during reversal (t (35) = 2.08, p < 0.05). The difference between the two tasks for discrimination was not significant (p = 0.44). These data support the notion that alcoholics are increasingly impaired in the complex task of reversing a previously learned discrimination when a silent trace interval is introduced. Alcoholics' impairment in flexibly altering learned associations may be central to their continued addiction. C1 [Fortier, Catherine Brawn; Maksimovskiy, Arkadiy L.; Venne, Jonathan R.; McGlinchey, Regina E.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr GRECC, Boston, MA USA. [Fortier, Catherine Brawn; McGlinchey, Regina E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [LaFleche, Ginette] Boston Univ, Sch Med, Memory Disorders Res Ctr, Boston, MA 02118 USA. RP Fortier, CB (reprint author), VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr GRECC, Boston, MA USA. EM Catherine_Fortier@hms.harvard.edu; amaksim@heartbrain.com; jvenne@heartbrain.com; glafleche@bu.edu; Regina_McGlinchey@hms.harvard.edu RI McGlinchey, Regina/R-1971-2016 FU NIH NIAAA [14205]; VA Merit Review Awards to Catherine Brawn Fortier and Regina McGlinchey FX This research was supported by NIH NIAAA 14205 and VA Merit Review Awards to Catherine Brawn Fortier and Regina McGlinchey. We also appreciate the advice of Dr. Marlene Oscar-Berman in defining the inclusionary criteria for alcoholics in this study. NR 49 TC 7 Z9 7 U1 0 U2 2 PU MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUL PY 2009 VL 6 IS 7 BP 2007 EP 2027 DI 10.3390/ijerph6072007 PG 21 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 474XD UT WOS:000268317200006 PM 19742168 ER PT J AU Edwards, ER Spira, AP Barnes, DE Yaffe, K AF Edwards, Emily R. Spira, Adam P. Barnes, Deborah E. Yaffe, Kristine TI Neuropsychiatric symptoms in mild cognitive impairment: differences by subtype and progression to dementia SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE mild cognitive impairment; neuropsychiatric symptoms; dementia ID NURSING-HOME PLACEMENT; ALZHEIMERS-DISEASE; PSYCHIATRIC-SYMPTOMS; DEPRESSION; MEMORY; PREVALENCE; COMMUNITY; DECLINE; RISK; MCI AB Background Neuropsychiatric symptoms (NPS) are common in patients with mild cognitive impairment (MCI). Little is known, however, about how NPS vary by MCI subtype (i.e. amnestic, single domain non-memory, and multiple domain). In addition, it is unclear whether NPS increase risk of progression to dementia. We investigated the distribution of NPS across MCI subtypes and determined whether NPS increase risk of progression to dementia. Method Participants were 521 patients diagnosed with MCI at the Alzheimer's Research Centers of California between 1988 and 1999. At baseline, patients were classified into MCI subtypes and were assessed for NPS. Results The mean number of NPS was 2.3 (range 0-9.6; 74% had >= 1 NPS). Patients with >= 4 NPS had more medical comorbidities and greater functional impairment (p <= 0.0001 for both). Patients with >= 4 NIPS were more likely than patients with 0-3 NPS to have amnestic MCI (81% vs 71%, respectively, p = 0.03), and patients with amnestic MCI were more likely than those with other subtypes to exhibit depressive symptoms. Patients with >= 4 NPS had nearly 2.5 times the odds of developing dementia at follow-up than patients with 0-3 NPS (adjusted O R= 2.44, 95% CI 1.07, 5.55). Conclusion NPS are common in MCI patients. Those with an elevated number of NPS may be more likely to have the amnestic subtype of MCI, and depression may be more common in amnestic MCI than in other subtypes. An elevated number of NPS may increase risk of progression to dementia for patients with MCI. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Edwards, Emily R.; Barnes, Deborah E.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Barnes, Deborah E.; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Spira, Adam P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. RP Spira, AP (reprint author), 624 N Broadway,Hampton House,Rm 794, Baltimore, MD 21205 USA. EM aspira@jhsph.edu FU California Department of Health Services [03-75271]; NIH [K24 AG031155, 5 T32 AG000212-15] FX Supported by ADRCC grant 03-75271 from the California Department of Health Services, and by NIH grants K24 AG031155, and 5 T32 AG000212-15. NR 35 TC 25 Z9 27 U1 2 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0885-6230 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD JUL PY 2009 VL 24 IS 7 BP 716 EP 722 DI 10.1002/gps.2187 PG 7 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 466BY UT WOS:000267636800009 PM 19140134 ER PT J AU Jarboe, EA Miron, A Carlson, JW Hirsch, MS Kindelberger, D Mutter, GL Crum, CP Nucci, MR AF Jarboe, Elke A. Miron, Alexander Carlson, Joseph W. Hirsch, Michelle S. Kindelberger, David Mutter, George L. Crum, Christopher P. Nucci, Marisa R. TI Coexisting Intraepithelial Serous Carcinomas of the Endometrium and Fallopian Tube: Frequency and Potential Significance SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Endometrial serous carcinoma; Tubal intraepithelial carcinoma; Endometrial intraepithelial carcinoma; Concurrent serous carcinomas ID EPITHELIAL OVARIAN-CARCINOMA; GLANDULAR DYSPLASIA; CLINICOPATHOLOGICAL FEATURES; MULTIFOCAL TUMORIGENESIS; PATHOLOGICAL FINDINGS; PRECURSOR LESION; UTERINE; ADENOCARCINOMA; CHEMOTHERAPY; RADIOTHERAPY AB Most serous adenocarcinomas involving both the endometrium and ovary are presumed to arise in the endometrium. Recently, serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. This study explored the potential relationship between STIC and uterine serous carcinoma. Twenty-two consecutive cases of serous carcinoma involving the endometrium were studied. In each case, fallopian tubes were submitted in toto according to the protocol for sectioning and extensive examination of the fimbriated end. Extent of the endometrial tumor and presence/absence of STIC were documented. Immunostaining for p53 and Wilms tLImor-1 was performed on all cases with STIC. p53 mutation analysis was performed in a subset of matched STICs and endometrial tumors. Eleven cases showed concurrent endometrial and adnexal involvement, including 6 with endosalpingeal involvement: STIC was confirmed in 5. In all 5, the concurrent endometrial tumor was either noninvasive, or exhibited only superficial (<5%) myometrial invasion. In 2 cases, identical p53 mutations were shared by both tubal and endometrial lesions. This Study shows that noninvasive, genetically related serous carcinomas may coexist in both tube and endometrium. As management of serous neoplasms is predicated on site of origin, we propose that the sectioning and extensively examining the fimbria protocol be applied to all endometrial serous carcinomas and that tumors with concurrent STIC be classified as a distinct subset of pelvic serous carcinomas pending a clearer understanding of tumor origin. C1 [Jarboe, Elke A.; Miron, Alexander; Carlson, Joseph W.; Hirsch, Michelle S.; Kindelberger, David; Mutter, George L.; Crum, Christopher P.; Nucci, Marisa R.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. [Jarboe, Elke A.; Miron, Alexander; Carlson, Joseph W.; Hirsch, Michelle S.; Mutter, George L.; Crum, Christopher P.; Nucci, Marisa R.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Nucci, MR (reprint author), Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, 75 Francis St, Boston, MA 02115 USA. EM ccrum@partners.org RI Mutter, George/C-5819-2009; OI Carlson, Joseph/0000-0002-3006-4107 FU NCI NIH HHS [P50 CA105009, 1R21CA124688-01A1, KO8 CA108748] NR 41 TC 44 Z9 47 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2009 VL 28 IS 4 BP 308 EP 315 DI 10.1097/PGP.0b013e3181934390 PG 8 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 460ZQ UT WOS:000267232500002 PM 19483636 ER PT J AU Conway, B Miller, RG Costacou, T Fried, L Kelsey, S Evans, RW Orchard, TJ AF Conway, B. Miller, R. G. Costacou, T. Fried, L. Kelsey, S. Evans, R. W. Orchard, T. J. TI Adiposity and mortality in type 1 diabetes SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE type 1 diabetes; mortality; body mass index; underweight; overweight ID BODY-MASS INDEX; ALL-CAUSE MORTALITY; PROSPECTIVELY STUDIED COHORT; INTENTIONAL WEIGHT-LOSS; CORONARY-HEART-DISEASE; FAT-FREE MASS; PITTSBURGH EPIDEMIOLOGY; WAIST CIRCUMFERENCE; FOLLOW-UP; US ADULTS AB Background: In the general population, adiposity exhibits a J- or U-shaped relationship with mortality; however, in catabolic states this relationship is often inversely linear. We have recently documented an age-independent increase in overweight/obesity in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of type 1 diabetes (T1D). As intensified insulin therapy (IIT) may promote weight gain, the impact of weight gain in T1D is of importance. We therefore assessed the association of adiposity with mortality in 655 EDC participants during 20 years of follow-up. Methods: Individuals were categorized as underweight (body mass index (BMI) <20), normal (20 <= BMI <25), overweight (25 <= BMI <30), or obese (BMI >= 30). Cox models were constructed using BMI and covariates at baseline, updated means during follow-up, time variation (reflecting most recent status), and change during adulthood as predictors of mortality. Results: The prevalence of IIT (3 + insulin shots daily and/or pump) increased from 7 to 82%. Overweight increased by 47% and obesity increased sevenfold. There were 146 deaths. In unadjusted models, BMI (modeled continuously) showed a quadratic relationship with mortality (P = 0.002, <0.0001 <0.0001 for baseline, updated mean and time-varying models, respectively). However, only in the time-varying model were the obese significantly different from the normal weight, whereas the baseline model showed no differences by BMI category. In both the updated mean and time-varying models, the underweight were at greater risk than were the normal weight (P<0.0001 both models). The nonlinear relationship of adiposity with mortality remained after adjustment for diabetes complications and for biological or socioeconomic/lifestyle risk factors, with the exception of baseline socioeconomic/lifestyle risk factors, in which a linear association emerged. Adjustment for waist circumference eliminated risk in the obese. Finally, weight gain during follow-up was protective. Conclusion: The relationship of adiposity with mortality in T1D now seems to resemble that of the general population, albeit with a marked increased risk in those who are underweight. International Journal of Obesity (2009) 33, 796-805; doi:10.1038/ijo.2009.75; published online 19 May 2009 C1 [Conway, B.; Miller, R. G.; Costacou, T.; Kelsey, S.; Evans, R. W.; Orchard, T. J.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15217 USA. [Fried, L.] Univ Dr Div, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Orchard, TJ (reprint author), Univ Pittsburgh, Dept Epidemiol, 3512 5th Ave,2nd Fl, Pittsburgh, PA 15217 USA. EM OrchardT@edc.pitt.edu OI orchard, trevor/0000-0001-9552-3215 FU NIDDK NIH HHS [DK34818, R01 DK034818, R01 DK034818-24, R37 DK034818] NR 56 TC 24 Z9 26 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 2009 VL 33 IS 7 BP 796 EP 805 DI 10.1038/ijo.2009.75 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 470BX UT WOS:000267948800011 PM 19451912 ER PT J AU Francis, RE Myatt, SS Krol, J Hartman, J Peck, B McGovern, UB Wang, J Guest, SK Filipovic, A Gojis, O Palmieri, C Peston, D Shousha, S Yu, QY Sicinski, P Coombes, RC Lam, EWF AF Francis, Richard E. Myatt, Stephen S. Krol, Janna Hartman, Johan Peck, Barrie McGovern, Ursula B. Wang, Jun Guest, Stephanie K. Filipovic, Aleksandra Gojis, Ondrej Palmieri, Carlo Peston, David Shousha, Sami Yu, Qunyan Sicinski, Piotr Coombes, R. Charles Lam, Eric W. -F. TI FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE FoxM1; HER2; breast cancer ID FORKHEAD BOX M1; GROWTH-FACTOR RECEPTOR; TRANSCRIPTION FACTOR TRIDENT; TYROSINE KINASE INHIBITOR; S-PHASE; ADJUVANT CHEMOTHERAPY; SIGNALING PATHWAY; HEPATOCYTE ENTRY; GENE-EXPRESSION; FACTOR HFH-11B AB The tyrosine kinase receptor, HER2 is a crucial prognostic marker and therapeutic target for breast cancer; however, the downstream targets and biological effectors of HER2 remain unclear. We investigated the relationship between HER2 and the transcription factor FoxM1 in breast cancer. HER2 and FoxM1 expression levels were compared in breast carcinoma cell lines, paraffin-embedded breast cancer patient samples and at the mRNA level in purified breast epithelial cells. To further examine the relationship between HER2 and FoxM1 expression, we either overexpressed or siRNA-mediated depleted endogenous HER2 in breast cancer cell lines. Additionally, a mammary epithelium-targeted HER2 (neu) transgenic mouse model was also used to assess the effect of HER2 on FoxM1 levels. Furthermore, the effect of the HER2-tyrosine kinase inhibitor lapatinib on FoxM1 in HER2 positive breast cancer cells was investigated. HER2 protein levels directly correlated with FoxM1 expression in both breast carcinoma cell lines and paraffin-embedded breast cancer patient samples. Moreover, in purified breast epithelial cells, overexpression of HER2 was associated with high levels of FoxM1 mRNA, suggesting that the upregulation of FoxM1 expression is at least partially mediated transcriptionally. Furthermore, overexpression or ablation of endogenous HER2 resulted in parallel changes in FoxM1 expression. Critically, mammary epithelium-targeted HER2 mouse tumours also resulted in increased FoxM1 expression, Suggesting that HER2 directed FoxM1 expression occurs in. vivo and may be a critical downstream effector of HER2-targeting therapies. Indeed, treatment of breast cancer cells with lapatinib reduced FoxM1 expression at protein, mRNA and gene promoter levels. Moreover, analysis of normal and breast cancer patient samples revealed that elevated FoxM1 expression at protein and mRNA levels correlated with breast cancer development, but not significantly with cancer progression and survival. Our results indicate that the HER2 receptor regulates the expression of the FoxM1 transcription factor, which has a role in breast cancer development. C1 [Francis, Richard E.; Myatt, Stephen S.; Krol, Janna; Peck, Barrie; McGovern, Ursula B.; Wang, Jun; Guest, Stephanie K.; Filipovic, Aleksandra; Gojis, Ondrej; Palmieri, Carlo; Coombes, R. Charles; Lam, Eric W. -F.] Univ London Imperial Coll Sci Technol & Med, Can Res UK Labs, Dept Oncol, London W12 0NN, England. [Hartman, Johan] Karolinska Inst, Dept Oncol & Pathol, S-17176 Stockholm, Sweden. [Gojis, Ondrej] Charles Univ Prague, Univ Hosp Kralovske Vinohrady, Dept Pathol, Prague 10, Czech Republic. [Peston, David; Shousha, Sami] Charing Cross Hosp, Dept Histopathol, London, England. [Sicinski, Piotr] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Lam, EWF (reprint author), Univ London Imperial Coll Sci Technol & Med, Can Res UK Labs, Dept Oncol, MRC Cyclotron Bldg,Hammersmith Hosp Campus,Du Can, London W12 0NN, England. EM eric.lam@imperial.ac.uk RI Hartman, Johan/N-1406-2015 OI Hartman, Johan/0000-0002-6500-8527 FU Cancer Research UK; Association for International Cancer Research; Breast Cancer Research Trust; Biotechnology and Biological Sciences Research Council FX This study was supported by the Cancer Research UK (R.E. Francis, S.S. Myatt, R.C. Coombes, E.W.-F. Lam, A. Filipovic, C. Palmieri), the Association for International Cancer Research (R.E. Francis, E.W.-F. Lam) the Breast Cancer Research Trust (J. Krol, E.W.-F. Lam) and the Biotechnology and Biological Sciences Research Council (B. Peck, E.W.-F. Lam). NR 48 TC 59 Z9 67 U1 2 U2 11 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2009 VL 35 IS 1 BP 57 EP 68 DI 10.3892/ijo_00000313 PG 12 WC Oncology SC Oncology GA 460ZH UT WOS:000267231400007 PM 19513552 ER PT J AU Heinze, E Baldwin, S Chan, G Hansen, J Song, J Clements, D Aragon, R Nishimura, R Reeves, M Weisbart, R AF Heinze, Emil Baldwin, Scott Chan, Grace Hansen, James Song, Jason Clements, Douglas Aragon, Robert Nishimura, Robert Reeves, Mark Weisbart, Richard TI Antibody-mediated FOXP3 protein therapy induces apoptosis in cancer cells in vitro and inhibits metastasis in vivo SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE antibodies; transcription factors; gene regulation; cytotoxicity; apoptosis ID REPRESSOR; ENTEROPATHY; ONCOGENE; SCURFIN; MOUSE AB In addition to its immune suppressive function ill T-regulatory cells, the nuclear transcription factor, FOXP3, has been identified as a tumor suppressor. To evaluate the clinical efficacy of monoclonal antibody (mAb) 31310 Fv antibody-mediated FOXP3 protein therapy of cancer, the Fv-FOXP3 fusion protein produced in Pichia pastoris was tested on breast, ovarian, and colon cancer cells in vitro, and with colon cancer cells in vivo in a mouse model of colon cancer metastasis to liver. Treatment with Fv-FOXP3 resulted in dose-dependent cell death of cancer cells in vitro. Apoptosis was established as a mechanism of cell death by demonstrating increased production of the p17 activated fragment of caspase-3 by cancer cells in response to Fv-FOXP3 and inhibition of cell killing by the caspase inhibitor, Z-VAD-FMK. Fv-FOXP3 treatment resulted in clinically significant reduction in tumor burden in a syngeneic model of colon cancer metastasis to liver in Balb/c mice. These results represent the first demonstration of effective full-length FOXP3 protein therapy and emphasize the clinical potential of mAb 3E10 as an intracellular and intranuclear delivery vehicle of FOXP3 for prevention and treatment of cancer metastasis. C1 [Heinze, Emil; Chan, Grace; Hansen, James; Song, Jason; Clements, Douglas; Nishimura, Robert; Weisbart, Richard] Vet Affairs Greater Los Angeles Hlth Care Syst, Sepulveda, CA USA. [Heinze, Emil] Olive View UCLA Med Ctr, Sylmar, CA 91342 USA. [Baldwin, Scott; Aragon, Robert; Reeves, Mark] Loma Linda Vet Affairs Med Ctr, Loma Linda, CA USA. RP Weisbart, R (reprint author), Vet Affairs Med Ctr, 111S,16111 Plummer St, Sepulveda, CA 91343 USA. EM rweisbar@ucla.edu FU Veterans Affairs; Department of Surgery; Loma Linda University FX This study was supported by a grant from the Veterans Affairs (R.H. Weisbart) and a seed grant from the Department of Surgery, Loma Linda University (M.E. Reeves). We thank Michael Cho for technical assistance and Dr Joseph Gera for critical reading of the manuscript. E.H. and S.C. are co-first authors; R.N., M.R., and R.W. are co-senior authors. NR 12 TC 13 Z9 14 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2009 VL 35 IS 1 BP 167 EP 173 DI 10.3892/ijo_00000325 PG 7 WC Oncology SC Oncology GA 460ZH UT WOS:000267231400019 PM 19513564 ER PT J AU Brigger, MT Sipp, JA Hartnick, CJ AF Brigger, Matthew T. Sipp, J. Andrew Hartnick, Christopher J. TI Tracheal pH monitoring: A pilot study in tracheostomy dependent children SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Tracheostomy; Reflux; pH probe ID LARYNGOTRACHEAL RECONSTRUCTION; SUBGLOTTIC STENOSIS; REFLUX AB Objectives: 1. Determine the feasibility of measuring tracheal pH with a novel non-aqueous probe designed for oropharyngeal pH monitoring. 2. Correlate clinical and subclinical laryngopharyngeal reflux aspiration events with esophageal pH measurements. Methods: Five children with chronic indwelling tracheostomies undergoing routine endoscopy and pH probe monitoring at a tertiary care pediatric aerodigestive center between October 2007 and January 2008 were identified for this prospective feasibility pilot study. The non-aqueous Restech Dx-pH probe was subsequently affixed to each child's tracheostomy with the probe tip confirmed to be within the tracheal lumen. Esophageal and tracheal probe pH measurements were subsequently recorded until the child was unable to tolerate the study or 24 h elapsed. Tracheal pH tracings were compared directly to esophageal pH tracings. Esophageal biopsy and bronchoalveolar lavage data were reviewed for each child. Results: 3/5 children tolerated the tracheal probe for greater than 18 h. Adequate tracheal pH tracings were demonstrated for all children while the probe was in position. Mean baseline tracheal pH was 7.8. One child demonstrated direct correlation between acidic esophageal reflux events and decreased tracheal pH. Esophageal biopsy confirmed the presence of active inflammation consistent with reflux in this child. Conclusion: Tracheal pH can be accurately recorded with the Restech Dx-pH probe. The technology may allow further investigations to determine the impact of gastroesophageal refluxate aspiration and empiric antireflux therapy in children with aerodigestive symptoms. Published by Elsevier Ireland Ltd. C1 [Brigger, Matthew T.; Hartnick, Christopher J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. RP Brigger, MT (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM matt.brigger@alumni.vanderbilt.edu NR 6 TC 1 Z9 2 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD JUL PY 2009 VL 73 IS 7 BP 999 EP 1001 DI 10.1016/j.ijporl.2009.04.002 PG 3 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA 463UE UT WOS:000267456800017 PM 19443050 ER PT J AU Freeman, WJ Ahlfors, SP Menon, V AF Freeman, Walter J. Ahlfors, Seppo P. Menon, Vinod TI Combining fMRI with EEG and MEG in order to relate patterns of brain activity to cognition SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE Analytic amplitude; Black noise; Criticality; ECoG; EEG; fMRI; Ground state; MEG; Mesoscopic cortical activity; Power spectral density; PSD; Resting state; Spatial AM pattern ID DEFAULT-MODE; MULTICORTICAL PATTERNS; NEUROBIOLOGICAL THEORY; DYNAMICAL-SYSTEMS; CORTICAL NETWORK; CEREBRAL-CORTEX; NEURAL ACTIVITY; SCALP EEG; GAMMA EEG; OSCILLATIONS AB The common factor that underlies several types of functional brain imaging is the electric current of masses of dendrites. The prodigious demands for the energy that is required to drive the dendritic currents are met by hemodynamic and metabolic responses that are visualized with fMRI and PET techniques. The high current densities in parallel dendritic shafts and the broad distributions of the loop currents outside the dendrites generate both the scalp EEG and the magnetic fields seen in the MEG. The measurements of image intensities and potential fields provide state variables for modeling. The relationships between the intensities of current density and the electric, magnetic, and hemodynamic state variables are complex and far from proportionate. The state variables are complementary, because the information they convey comes from differing albeit overlapping neural populations, so that efforts to cross-validate localization of neural activity relating to specified cognitive behaviors have not always been successful. We propose an alternative way to use the three methods in combination through studies of hemisphere-wide, high-resolution spatiotemporal patterns of neural activity recorded non-invasively and analyzed with multivariate statistics. Success in this proposed endeavor requires specification of what patterns to look for. At the present level of understanding, an appropriate pattern is any significant departure from random noise in the spectral, temporal and spatial domains that can be scaled into the coarse-graining of time by fMRI/BOLD and the coarse-graining of space by EEG and MEG. Here the requisite patterns are predicted to be large-scale spatial amplitude modulation (AM) of synchronized neuronal signals in the beta and gamma ranges that are coordinated but not correlated with fMRI intensities. (c) 2009 Elsevier B.V. All rights reserved. C1 [Freeman, Walter J.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Ahlfors, Seppo P.] Massachusetts Gen Hosp, Ctr Biomed Imaging, MGH MIT HMS Athinoula A Martinos, Charlestown, MA 02129 USA. [Menon, Vinod] Stanford Univ, Sch Med, Neurosci Inst Stanford, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Menon, Vinod] Stanford Univ, Sch Med, Neurosci Inst Stanford, Program Neurosci, Stanford, CA 94305 USA. RP Freeman, WJ (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, MC 3206, Berkeley, CA 94720 USA. EM dfreeman@berkeley.edu; seppo@nmr.mgh.harvard.edu; menon@stanford.edu RI Ahlfors, Seppo/P-3644-2016; Menon, Vinod/J-6402-2013 OI Menon, Vinod/0000-0003-1622-9857 FU National Institute of Mental Health [MH 06686] FX This study was supported by grant MH 06686 from the National Institute of Mental Health to WJF, grant NCC 2-1244 from the National Aeronautics and Space Administration, grant EIA-0130352 from the National Science Foundation to Robert Kozma, NIH grant NINDSNS058899 to VM, and NIH grant NS057500 to SA. Programming was by Brian C. Burke. The MRI of the human subject was provided by Jeff H. Duyn and Tom Holroyd at the National Institute of Mental Health. We thank Sylvia Tomiyama for assistance with Fig. 1, Thomas Witzel for assistance with Fig. 3, and Maria Barth for assistance with the bibliography. NR 74 TC 32 Z9 36 U1 2 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD JUL PY 2009 VL 73 IS 1 BP 43 EP 52 DI 10.1016/j.ijpsycho.2008.12.019 PG 10 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 463TY UT WOS:000267456200008 PM 19233235 ER PT J AU DeLaney, TF Liebsch, NJ Pedlow, FX Adams, J Dean, S Yeap, BY McManus, P Rosenberg, AE Nielsen, GP Harmon, DC Spiro, IJ Raskin, KA Suit, HD Yoon, SS Hornicek, FJ AF DeLaney, Thomas F. Liebsch, Norbert J. Pedlow, Francis X. Adams, Judith Dean, Susan Yeap, Beow Y. McManus, Patricia Rosenberg, Andrew E. Nielsen, G. Petur Harmon, David C. Spiro, Ira J. Raskin, Kevin A. Suit, Herman D. Yoon, Sam S. Hornicek, Francis J. TI PHASE II STUDY OF HIGH-DOSE PHOTON/PROTON RADIOTHERAPY IN THE MANAGEMENT OF SPINE SARCOMAS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY NOV 05-09, 2006 CL Philadelphia, PA SP Amer Soc Therapeut Radiol & Oncol DE Spine; Sarcoma; Chordoma; Proton radiotherapy ID SOFT-TISSUE SARCOMAS; CARBON-ION RADIOTHERAPY; PROTON RADIATION-THERAPY; PROGNOSTIC FACTORS; CHORDOMA; CHONDROSARCOMA; IRRADIATION; BONE; MARGINS; SURGERY AB Purpose: Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of >= 66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. Methods and Materials: Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. Results: A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. Conclusions: Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity. (C) 2009 Elsevier Inc. C1 [DeLaney, Thomas F.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr,Sch Med, Boston, MA 02114 USA. [Pedlow, Francis X.; Raskin, Kevin A.; Hornicek, Francis J.] Harvard Univ, Massachusetts Gen Hosp, Dept Orthoped Surg, Sch Med, Boston, MA 02114 USA. [Rosenberg, Andrew E.; Nielsen, G. Petur] Harvard Univ, Massachusetts Gen Hosp, Dept Med Pathol, Sch Med, Boston, MA 02114 USA. [Harmon, David C.] Harvard Univ, Massachusetts Gen Hosp, Div Hematol Oncol, Sch Med, Boston, MA 02114 USA. [Yeap, Beow Y.] Harvard Univ, Massachusetts Gen Hosp, Dept Biostat, Sch Med, Boston, MA 02114 USA. [Yoon, Sam S.] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Sch Med,Sect Surg Oncol, Boston, MA 02114 USA. RP DeLaney, TF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr,Sch Med, 30 Fruit St, Boston, MA 02114 USA. EM tdelaney@partners.org FU NCI NIH HHS [P01CA021239, P01 CA021239-27, P01 CA021239-28, P01 CA021239] NR 30 TC 100 Z9 103 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2009 VL 74 IS 3 BP 732 EP 739 DI 10.1016/j.ijrobp.2008.08.058 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 455JJ UT WOS:000266754800012 PM 19095372 ER PT J AU Myerson, RJ Garofalo, MC El Naqa, I Abrams, RA Apte, A Bosch, WR Das, P Gunderson, LL Hong, TS Kim, JJJ Willett, CG Kachnic, LA AF Myerson, Robert J. Garofalo, Michael C. El Naqa, Issam Abrams, Ross A. Apte, Aditya Bosch, Walter R. Das, Prajnan Gunderson, Leonard L. Hong, Theodore S. Kim, J. J. John Willett, Christopher G. Kachnic, Lisa A. TI ELECTIVE CLINICAL TARGET VOLUMES FOR CONFORMAL THERAPY IN ANORECTAL CANCER: A RADIATION THERAPY ONCOLOGY GROUP CONSENSUS PANEL CONTOURING ATLAS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Intensity-modulated radiotherapy; Conformal pelvic radiation; Anal cancer; Rectal cancer; Contouring guidelines ID INTENSITY-MODULATED RADIOTHERAPY; ADVANCED RECTAL-CANCER; SMALL-BOWEL TOXICITY; ANAL CANCER; PREOPERATIVE RADIOTHERAPY; PELVIC IRRADIATION; CARCINOMA; CHEMORADIOTHERAPY; FLUOROURACIL; CHEMOTHERAPY AB Purpose: To develop a Radiation Therapy Oncology Group (RTOG) atlas of the elective clinical target volume (CTV) definitions to be used for planning pelvic intensity-modulated radiotherapy (IMRT) for anal and rectal cancers. Methods and Materials: The Gastrointestinal Committee of the RTOG established a task group (the nine physician co-authors) to develop this atlas. They responded to a questionnaire concerning three elective CTVs (CTVA: internal iliac, presacral, and perirectal nodal regions for both anal and rectal case planning; CTVB: external iliac nodal region for anal case planning and for selected rectal cases; CTVC: inguinal nodal region for anal case planning and for select rectal cases), and to outline these areas on individual computed tomographic images. The imaging files were shared via the Advanced Technology Consortium. A program developed by one of the co-authors (I.E.N.) used binomial maximum-likelihood estimates to generate a 95% group consensus contour. The computer-estimated consensus contours were then reviewed by the group and modified to provide a final contouring consensus atlas. Results: The panel achieved consensus CTV definitions to be used as guidelines for the adjuvant therapy of rectal cancer and definitive therapy for anal cancer. The most important difference from similar atlases for gynecologic or genitourinary cancer is mesorectal coverage. Detailed target volume contouring guidelines and images are discussed. Conclusion: This report serves as a template for the definition of the elective CTVs to be used in IMRT planning for anal and rectal cancers, as part of prospective RTOG trials. (C) 2009 Elsevier Inc. C1 [Myerson, Robert J.; El Naqa, Issam; Apte, Aditya; Bosch, Walter R.] Washington Univ, Dept Radiat Oncol, St Louis, MO 63110 USA. [Garofalo, Michael C.] Univ Maryland, Med Ctr, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Abrams, Ross A.] Rush Univ, Med Ctr, Dept Radiat Oncol, Chicago, IL 60612 USA. [Das, Prajnan] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Gunderson, Leonard L.] Mayo Clin, Dept Radiat Oncol, Scottsdale, AZ USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Kim, J. J. John] Univ Toronto, Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. [Willett, Christopher G.] Duke Univ, Dept Radiat Oncol, Durham, NC USA. [Kachnic, Lisa A.] Boston Univ, Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. RP Myerson, RJ (reprint author), Washington Univ, Dept Radiat Oncol, 4921 Parkview Pl,Box 8224, St Louis, MO 63110 USA. EM myerson@radonc.wustl.edu RI Apte, Aditya/E-5583-2010 FU National Institutes of Health/National Cancer Institute [U24 Grant CA81647]; [RTOG U10 CA21661]; [CCOP U10 CA37422]; [Stat U 10 CA321 15 NCI] FX L. A. K. and R. J. M. co-wrote the manuscript. This work was supported by RTOG U10 CA21661, CCOP U10 CA37422, Stat U 10 CA321 15 NCI grants. The contents are the sole responsibility of the authors and do not necessarily represent official views of the National Cancer Institute. Advanced Technology QA Consortium supported by National Institutes of Health/National Cancer Institute U24 Grant CA81647. NR 30 TC 138 Z9 144 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2009 VL 74 IS 3 BP 824 EP 830 DI 10.1016/j.ijrobp.2008.08.070 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 455JJ UT WOS:000266754800025 PM 19117696 ER PT J AU Schwarzer, R Siebert, U AF Schwarzer, Ruth Siebert, Uwe TI Methods, procedures, and contextual characteristics of health technology assessment and health policy decision making: Comparison of health technology assessment agencies in Germany, United Kingdom, France, and Sweden SO INTERNATIONAL JOURNAL OF TECHNOLOGY ASSESSMENT IN HEALTH CARE LA English DT Article DE Health technology assessment; Decision making; Health policy; Methods ID EUR-ASSESS PROJECT; RESOURCE-ALLOCATION DECISIONS; SUBGROUP REPORT; EUROPEAN COUNTRIES; IMPROVED CONDUCT; KEY PRINCIPLES; CARE; RECOMMENDATIONS; GENERALIZABILITY; REIMBURSEMENT AB Objectives: The objectives of this study were (i) to develop a systematic framework for describing and comparing different features of health technology assessment (HTA) agencies, (ii) to identify and describe similarities and differences between the agencies, and (iii) to draw conclusions both for producers and users of HTA in research, policy, and practice. Methods: We performed a systematic literature search, added information from HTA agencies, and developed a conceptual framework comprising eight main domains: organization, scope, processes, methods, dissemination, decision, implementation, and impact. We grouped relevant items of these domains in an evidence table and chose five HTA agencies to test our framework: DAHTA@DIMDI, HAS, IQWiG, NICE, and SBU. Item and domain similarity was assessed using the percentage of identical characteristics in pairwise comparisons across agencies. Results were interpreted across agencies by demonstrating similarities and differences. Results: Based on 306 included documents, we identified 90 characteristics of eight main domains appropriate for our framework. After applying the framework to the five agencies,we were able to show 40 percent similarities in "dissemination," 38 percent in "scope," 35 percent in "organization," 29 percent in "methods," 26 percent in "processes," 23 percent in "impact," 19 percent in "decision," and 17 percent in "implementation." Conclusion: We found considerably more differences than similarities of HTA features across agencies and countries. Our framework and comparison provides insights and clarification into the need for harmonization. Our findings could serve as descriptive database facilitating communication between producers and users. C1 [Schwarzer, Ruth] UMIT Univ Hlth Sci Med Informat & Technol, Inst Publ Hlth Med Decis Making & Hlth Technol As, Eduard Wallnoefer Ctr 1, A-6060 Hall In Tirol, Austria. [Siebert, Uwe] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth Informat Syst & Hlth Technol Asses, Eduard Wallnoefer Ctr 1, A-6060 Hall In Tirol, Austria. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Cardiovasc Res Program, Inst Technol Assessment, Boston, MA 02114 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Schwarzer, R (reprint author), UMIT Univ Hlth Sci Med Informat & Technol, Inst Publ Hlth Med Decis Making & Hlth Technol As, Eduard Wallnoefer Ctr 1, A-6060 Hall In Tirol, Austria. EM ruth.schwarzer@umit.at; public-health@umit.at FU ONCOTYROL Center of Personalized Cancer Medicine; Program on Health Technology Assessment at the Department of Public Health; Medical Informatics and Health Technology Assessment; UMIT; Austrian Research Promotion Agency (FFG); Tiroler Zukunftsstiftung; Styrian Business Promotion Agency (SFG) FX The authors are grateful to all persons who provided information on the HTA agencies German Agency for HTA at The German Institute for Medical Documentation and Information (DAHTA@DIMDI), The Institute for Quality and Efficiency in Health Care (IQWiG), La Haute Autorite de Sante (HAS), The Swedish Council on Technology Assessment in Health Care (SBU), and The International Network of Agencies for Health Technology Assessment (INAHTA). However, the findings and conclusions in this publication are exclusively those of the authors. The authors also want to thank Dr. Mark J.C. Nuijten (Erasmus University Rotterdam, the Netherlands) and Don Husereau, B.Sc.Pharm., MSc. (CADTH - Canadian Agency for Drugs and Technologies in Health, Canada) for their helpful comments. This work was supported by the ONCOTYROL Center of Personalized Cancer Medicine and the Program on Health Technology Assessment at the Department of Public Health, Medical Informatics and Health Technology Assessment, UMIT. Oncotyrol is a COMET Center funded by the Austrian Research Promotion Agency (FFG), the Tiroler Zukunftsstiftung, and the Styrian Business Promotion Agency (SFG). NR 83 TC 21 Z9 22 U1 1 U2 11 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0266-4623 J9 INT J TECHNOL ASSESS JI Int. J. Technol. Assess. Health Care PD JUL PY 2009 VL 25 IS 3 BP 305 EP 314 DI 10.1017/S0266462309990092 PG 10 WC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medical Informatics SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medical Informatics GA 477KZ UT WOS:000268519300009 PM 19619349 ER PT J AU Williams, TP Vibbert, M Mitchell, L Serwanga, R AF Williams, Timothy P. Vibbert, Martha Mitchell, Laura Serwanga, Rosette TI Health and human rights of children affected by HIV/AIDS in urban Boston and rural Uganda A cross-cultural partnership SO INTERNATIONAL SOCIAL WORK LA English DT Article ID AIDS; ORPHANS; HIV; ADOLESCENTS; ADJUSTMENT; AFRICAN C1 [Williams, Timothy P.] Massachusetts Gen Hosp, Div Global Hlth & Human Rights, Boston, MA 02114 USA. [Vibbert, Martha; Mitchell, Laura] Boston Med Ctr, SPARK Ctr, Mattapan, MA 02126 USA. [Vibbert, Martha] Boston Univ, Sch Med, Mattapan, MA 02126 USA. [Serwanga, Rosette] Namugongo Fund Special Children, Boston, MA 02125 USA. RP Williams, TP (reprint author), Massachusetts Gen Hosp, Div Global Hlth & Human Rights, 5 Emerson Pl,Suite 100, Boston, MA 02114 USA. EM twilliams@post.harvard.edu NR 21 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0020-8728 J9 INT SOC WORK JI Int. Soc. Work PD JUL PY 2009 VL 52 IS 4 BP 539 EP 545 DI 10.1177/0020872809104256 PG 7 WC Social Work SC Social Work GA 464KP UT WOS:000267504100009 ER PT J AU Zhang, X Shen, LL Jin, YP Saban, DR Chauhan, SK Dana, R AF Zhang, Xian Shen, Linling Jin, Yiping Saban, Daniel R. Chauhan, Sunil K. Dana, Reza TI Depletion of Passenger Leukocytes from Corneal Grafts: An Effective Means of Promoting Transplant Survival? SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID MHC CLASS-II; DENDRITIC CELLS; ALLOGRAFT-REJECTION; PENETRATING KERATOPLASTY; ISLET ALLOGRAFTS; DONOR CORNEA; POPULATION; TOLERANCE; ANTIGEN; ALLORECOGNITION AB PURPOSE. To develop and compare effective strategies for depleting graft-derived passenger leukocytes that include antigen-presenting cells from corneal buttons and to assess the effectiveness of this strategy in promoting graft survival using a high-risk (HR) model of corneal transplantation. METHODS. Corneal buttons harvested from C57BL/6 mice were used in three ex vivo strategies of passenger leukocyte depletion. Two strategies involved storage in medium at different temperatures for prolonged periods. A third strategy used complement-dependent cytotoxicity (CDC) by treating the buttons with anti-CD45 mAb plus complement. Wholemount corneal buttons or cells from enzyme-digested corneas were analyzed using confocal microscopy or flow cytometry, respectively, for the pan-leukocyte surface marker CD45. HR host beds were created and used to evaluate the efficacy of passenger leukocyte depletion on transplant survival. RESULTS. Passenger leukocyte numbers in the buttons were significantly reduced by all three treatments. CDC was the most efficient strategy for passenger leukocyte depletion with 39% reduction (P < 0.00005) of CD45(+) cells, and negligible damage to the endothelial layer, achievable within 24 hours. However, passenger leukocyte depletion failed to improve HR graft longevity. CONCLUSIONS. Anti-CD45 antibody plus complement-mediated targeting of donor tissue is the most efficient way to deplete corneal passenger leukocytes and can considerably reduce the time required for cell depletion. However, depletion of graft passenger leukocytes does not have a significant effect on promoting graft survival even in the HR setting. (Invest Ophthalmol Vis Sci. 2009;50:3137-3144) DOI:10.1167/iovs.08-1899 C1 [Dana, Reza] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Zhang, Xian; Shen, Linling; Jin, Yiping; Chauhan, Sunil K.; Dana, Reza] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Zhang, Xian; Shen, Linling; Jin, Yiping; Saban, Daniel R.; Chauhan, Sunil K.; Dana, Reza] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Dana, R (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM reza.dana@schepens.harvard.edu FU National Institutes of Health [EY-R01-12963] FX Supported by National Institutes of Health Grant EY-R01-12963. NR 35 TC 8 Z9 8 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2009 VL 50 IS 7 BP 3137 EP 3144 DI 10.1167/iovs.08-1899 PG 8 WC Ophthalmology SC Ophthalmology GA 461SP UT WOS:000267292100014 PM 19136708 ER PT J AU Ciolino, JB Hoare, TR Iwata, NG Behlau, I Dohlman, CH Langer, R Kohane, DS AF Ciolino, Joseph B. Hoare, Todd R. Iwata, Naomi G. Behlau, Irmgard Dohlman, Claes H. Langer, Robert Kohane, Daniel S. TI A Drug-Eluting Contact Lens SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; SURFACE-IMMOBILIZED LAYERS; IN-VITRO; INTACT LIPOSOMES; HEMA HYDROGEL; RELEASE; DELIVERY; GLAUCOMA; TIMOLOL; VIVO AB PURPOSE. To formulate and characterize a drug-eluting contact lens designed to provide extended, controlled release of a drug. METHODS. Prototype contact lenses were created by coating PLGA (poly[lactic-co-glycolic acid]) films containing test compounds with pHEMA (poly[hydroxyethyl methacrylate]) by ultraviolet light polymerization. The films, containing encapsulated fluorescein or ciprofloxacin, were characterized by scanning electron microscopy. Release studies were conducted in phosphate-buffered saline at 37 degrees C with continuous shaking. Ciprofloxacin eluted from the contact lens was studied in an antimicrobial assay to verify antimicrobial effectiveness. RESULTS. After a brief and minimal initial burst, the prototype contact lenses demonstrated controlled release of the molecules studied, with zero-order release kinetics under infinite sink conditions for over 4 weeks. The rate of drug release was controlled by changing either the ratio of drug to PLGA or the molecular mass of the PLGA used. Both the PLGA and the pHEMA affected release kinetics. Ciprofloxacin released from the contact lenses inhibited ciprofloxacin-sensitive Staphylococcus aureus at all time-points tested. CONCLUSIONS. A prototype contact lens for sustained drug release consisting of a thin drug-PLGA film coated with pHEMA could be used as a platform for ocular drug delivery with widespread therapeutic applications. (Invest Ophthalmol Vis Sci. 2009;50:3346-3352) DOI:10.1167/iovs.08-2826 C1 [Ciolino, Joseph B.; Behlau, Irmgard; Dohlman, Claes H.] Harvard Univ, Sch Med, Childrens Hosp, Dept Ophthalmol,Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Behlau, Irmgard] Harvard Univ, Sch Med, Childrens Hosp, Schepens Eye Res Inst, Boston, MA 02115 USA. [Kohane, Daniel S.] Harvard Univ, Sch Med, Childrens Hosp,Dept Anesthesiol, Lab Biomat & Drug Delivery,Div Crit Care Med, Boston, MA 02115 USA. [Hoare, Todd R.; Iwata, Naomi G.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Kohane, DS (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Bader 628,300 Longwood Ave, Boston, MA 02115 USA. EM daniel.kohane@childrens.harvard.edu FU National Institute of General Medical Sciences [GM073626]; National Institutes of Health [EB-00351]; Boston KPro Fund; Massachusetts Eye and Ear Infirmary; CIMIT/J&J ( Center for Integration of Medicine and Innovative Technology/Johnson & Johnson) Young Investigator Award FX Supported by National Institute of General Medical Sciences Grant GM073626 (DSK), a Fight for Sight Grant-in-Aid (IB), National Institutes of Health Grant EB-00351 (RL), a CIMIT/J&J ( Center for Integration of Medicine and Innovative Technology/Johnson & Johnson) Young Investigator Award ( DSK), and by the Boston KPro Fund, Massachusetts Eye and Ear Infirmary ( DSK). NR 52 TC 78 Z9 83 U1 4 U2 37 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2009 VL 50 IS 7 BP 3346 EP 3352 DI 10.1167/iovs.08-2826 PG 7 WC Ophthalmology SC Ophthalmology GA 461SP UT WOS:000267292100040 PM 19136709 ER PT J AU Frutkin, AD Lindsey, JB Mehta, SK House, JA Spertus, JA Cohen, DJ Rumsfeld, JS Marso, SP AF Frutkin, Andrew D. Lindsey, Jason B. Mehta, Sameer K. House, John A. Spertus, John A. Cohen, David J. Rumsfeld, John S. Marso, Steven P. CA NCDR TI Drug-Eluting Stents and the Use of Percutaneous Coronary Intervention Among Patients With Class I Indications for Coronary Artery Bypass Surgery Undergoing Index Revascularization Analysis From the NCDR (National Cardiovascular Data Registry) SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE percutaneous coronary intervention; coronary artery bypass grafting; drug-eluting stents ID UNPROTECTED LEFT MAIN; RANDOMIZED CONTROLLED-TRIAL; OFF-LABEL USE; 2-INSTITUTIONAL COHORT; CLINICAL-PRACTICE; IMPLANTATION; DISEASE; THROMBOSIS; RESTENOSIS; STENOSIS AB Objectives Our purpose was to evaluate percutaneous coronary intervention (PCI) attempt rates in patients with class I indications for coronary artery bypass graft (CABG) surgery after the introduction of drug-eluting stents (DES). Background In patients with severe, multivessel coronary disease, CABG has historically been recommended over PCI. Practice guidelines for CABG were last updated before the emergence of data on DES efficacy. Methods We analyzed 265,028 procedures from the NCDR (National Cardiovascular Data Registry) meeting American College of Cardiology/American Heart Association class I indications for surgical revascularization. Temporal trends in PCI attempt rates were analyzed during 3 consecutive time periods: pre-DES (before April 1, 2003), DES diffusion (April 1, 2003 to December 31, 2004), and DES (January 1, 2005 to September 30, 2006). Results The attempted rate of PCI in patients with class I indications for CABG increased over the 3 time periods (pre-DES: 29.4%, DES diffusion: 33.4%, and DES era: 34.7%, p < 0.001). In a hierarchical multivariable logistic model adjusting for patient and PCI site characteristics, PCI attempts were more likely in the DES compared with pre-DES era (odds ratio: 1.44, 95% confidence interval: 1.40 to 1.48) and the DES diffusion era (odds ratio: 1.20, 95% confidence interval: 1.17 to 1.23). PCI attempt rates increased in all 3 time periods, although the average rate of increase during the DES era was 0.6% per quarter compared with 0.3% per quarter for both the DES diffusion and the pre-DES eras (p = 0.03). Conclusions DES use in clinical practice was associated with a significant overall increase in PCI to treat patients with class I indications for CABG. Long-term follow-up of this cohort of patients is warranted. (J Am Coll Cardiol Intv 2009;2:614-21) (C) 2009 by the American College of Cardiology Foundation C1 [Frutkin, Andrew D.; Lindsey, Jason B.; Mehta, Sameer K.; House, John A.; Spertus, John A.; Cohen, David J.; Marso, Steven P.] Univ Missouri, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Rumsfeld, John S.] Univ Colorado, Hlth Sci Ctr, Denver Vet Affairs Med Ctr, Denver, CO USA. RP Marso, SP (reprint author), Univ Missouri, Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA. EM smarso@saint-lukes.org NR 30 TC 17 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD JUL PY 2009 VL 2 IS 7 BP 614 EP 621 DI 10.1016/j.jcin.2009.05.001 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 613HZ UT WOS:000278971300006 PM 19628183 ER PT J AU Slovut, DP AF Slovut, David P. TI Cutaneous Radiation Injury After Complex Coronary Intervention SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material C1 [Slovut, David P.] N Shore Med Ctr, Dept Cardiol, Salem, MA 01970 USA. [Slovut, David P.] N Shore Med Ctr, Dept Vasc Med, Salem, MA 01970 USA. [Slovut, David P.] Massachusetts Gen Hosp, Dept Vasc Med, Boston, MA 02114 USA. RP Slovut, DP (reprint author), N Shore Med Ctr, Dept Cardiol, 81 Highland Ave, Salem, MA 01970 USA. EM david.slovut@mssm.edu NR 4 TC 7 Z9 9 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD JUL PY 2009 VL 2 IS 7 BP 701 EP 702 DI 10.1016/j.jcin.2009.04.015 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 613HZ UT WOS:000278971300019 PM 19628196 ER PT J AU Triant, VA Meigs, JB Grinspoon, SK AF Triant, Virginia A. Meigs, James B. Grinspoon, Steven K. TI Association of C-Reactive Protein and HIV Infection With Acute Myocardial Infarction SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE C-reactive protein; coronary disease; HIV; myocardial infarction; risk factors ID CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; ANTIRETROVIRAL THERAPY; INFLAMMATION; ATHEROSCLEROSIS; LIPODYSTROPHY; INHIBITORS; MECHANISMS; WOMEN AB Objective: To investigate whether elevated C-reactive protein (CRP) levels and HIV infection are independently associated with acute myocardial infarction (AMI) among patients receiving care in a large US health care system. Methods: Analyses included patients receiving care in the Partners HealthCare System between January 1997 and December 2006, with a most recent CRP less than 3 years and more than 1 week before AMI. Over this period, 70,357 (487 HIV and 69,870 non-HIV) patients met these criteria, from the background population of 1,648,687 patients followed in the system. We included both CRP and high-sensitivity CRP and defined elevated CRP based on the normal range of the assay used. We used multivariate logistic regression analysis to test the association of elevated CRP and HIV with AMI after adjustment for demographic and other cardiovascular covariates, including hypertension, diabetes, and dyslipidemia. Results: In univariate analyses, elevated CRP and HIV were each significantly associated with AMI [odds ratio (OR) 2.51; 95% confidence interval (CI) 2.27 to 2.78; P < 0.0001 for elevated CRP and OR 2.07; 95% CI 1.31 to 3.10; P = 0.001 for HIV]. In a combined model including CRP category and HIV status, elevated CRP (OR 2.50; 95% CI 2.26 to 2.77; P < 0.0001) and HIV (OR 1.74; 95% CI 1.10 to 2.61; P = 0.01) were both independently associated with AMI. In a fully adjusted model controlling for age, sex, race, hypertension, diabetes, and dyslipidemia, both elevated CRP (OR 2.13; 95% CI 1.92 to 2.37; P < 0.0001) and HIV (OR 1.93; 95% CI 1.21 to 2.93; P = 0.004) remained independently associated with AMI. Compared with patients with normal CRP and without HIV, the OR for AMI was increased more than 4-fold among patients with HIV and elevated CRP. Conclusions: Elevated CRP and HIV are independently associated with increased AMI risk, and patients with HIV with increased CRP have a markedly increased relative risk of AMI. Measurement of CRP may be useful in the cardiovascular risk assessment of patients with HIV. C1 [Triant, Virginia A.; Grinspoon, Steven K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Nutr Metab,MGH, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA 02114 USA. [Triant, Virginia A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Triant, Virginia A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Grinspoon, SK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Nutr Metab,MGH, 55 Fruit St,Longfellow 207, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU MGH Clinical Research Program [T32 A107387]; [KOI A1073109]; [K24 DK080140]; [K24 DK064545] FX Funded in part by the MGH Clinical Research Program, T32 A107387 (VAT); KOI A1073109 (VA.T.); K24 DK080140 (J.B.M.); and K24 DK064545 (S.K.G). NR 21 TC 155 Z9 157 U1 1 U2 3 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 JUL 1 PY 2009 VL 51 IS 3 BP 268 EP 273 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 462UV UT WOS:000267383300005 PM 19387353 ER PT J AU April, MD Walensky, RP Chang, YC Pitt, J Freedberg, KA Losina, E Paltiel, AD Wood, R AF April, Michael D. Walensky, Rochelle P. Chang, Yuchiao Pitt, Jennifer Freedberg, Kenneth A. Losina, Elena Paltiel, A. David Wood, Robin TI HIV Testing Rates and Outcomes in a South African Community, 2001-2006: Implications for Expanded Screening Policies SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 16th Conference on Retroviruses and Opportunistic Infections CY FEB 08-11, 2009 CL Montreal, CANADA ID TO-CHILD TRANSMISSION; ANTIRETROVIRAL THERAPY; CARE; TUBERCULOSIS; CHALLENGES; PREVENTION; BOTSWANA; ACCEPTABILITY; NEVIRAPINE; PROVISION AB Background: Revised World Health Organization recommendations seek to increase HIV testing. We assessed the need for expanded testing in South Africa by examining current testing and treatment trends among a high prevalence population. Methods: We determined the numbers of adults receiving HIV testing and antiretroviral treatment (ART) during 2001-2006 using testing registers linked to patient records from 2 health care facilities believed responsible for virtually all HIV services available to the population. We evaluated annual population testing rates using census population counts; proportions of clients testing seropositive (yield); CD4 counts and World Health Organization stage at diagnosis; and ART initiation rates. Results: HIV testing rates rose from 4% in 2001 to 20% in 2006 (P < 0.001) and were highest among pregnant females receiving provider-initiated testing. Yield for first-time testers decreased from 47% in 2001 to 28% in 2006; annual incidence of seroconversion among initially HIV-negative. retesters was 1.9%. Median CD4 counts and World Health Organization stage distributions for newly diagnosed clients remained stable. HIV-infected clients receiving ART within 6 months of eligibility increased from 0% in 2001 to 68% in 2006 (P < 0.001). Conclusions: Population testing and ART initiation rates rose dramatically during 2001-2006. Yet, yield remained high, and HIV-infected persons continued to receive late diagnoses. These findings highlight the continuing need for expanded testing and linkage to care. C1 [Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. [April, Michael D.] Univ Oxford, Dept Publ Hlth, Oxford, England. [April, Michael D.; Walensky, Rochelle P.; Chang, Yuchiao; Freedberg, Kenneth A.; Losina, Elena] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Pitt, Jennifer; Wood, Robin] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Freedberg, Kenneth A.; Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Freedberg, Kenneth A.; Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Paltiel, A. David] Yale Univ, Sch Med, New Haven, CT USA. RP April, MD (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM michael_april@hms.harvard.edu RI Wood, Robin/G-8509-2011 FU NIAID NIH HHS [K24 AI062476, K24 AI062476-05, P30 AI060354, P30 AI060354-07, R01 AI058736, R01 AI058736-07]; NIMH NIH HHS [R01 MH065869-08, R01 MH065869, R01 MH073445, R01 MH073445-04] NR 29 TC 33 Z9 33 U1 0 U2 3 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 JUL 1 PY 2009 VL 51 IS 3 BP 310 EP 316 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 462UV UT WOS:000267383300011 PM 19582895 ER PT J AU Mimiaga, MJ Noonan, E Donnell, D Safren, SA Koenen, KC Gortmaker, S O'Cleirigh, C Chesney, MA Coates, TJ Koblin, BA Mayer, KH AF Mimiaga, Matthew J. Noonan, Elizabeth Donnell, Deborah Safren, Steven A. Koenen, Karestan C. Gortmaker, Steven O'Cleirigh, Conall Chesney, Margaret A. Coates, Thomas J. Koblin, Beryl A. Mayer, Kenneth H. TI Childhood Sexual Abuse Is Highly Associated With HIV Risk-Taking Behavior and Infection Among MSM in the EXPLORE Study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE child sexual abuse; EXPLORE; HIV; MSM; sexual risk taking ID BASE-LINE DATA; BISEXUAL MEN; GAY; HEALTH; AIDS; VICTIMIZATION; DEPRESSION; INTERVENTION; ORIENTATION; EXPERIENCES AB Background: Previous studies have found high rates of childhood sexual abuse (CSA) among US men who have sex with men (MSM). CSA history has been associated with a variety of negative effects later in life including behaviors that place MSM at greater risk for HIV acquisition and transmission. The present analysis is the first to examine the longitudinal association between CSA and HIV infection, unprotected anal sex, and serodiscordant unprotected anal sex, as well as mediators of these relationships among a large sample of HIV-uninfected MSM. Methods: The EXPLORE Study was a behavioral intervention trial conducted in 6 US cities over 48 months with HIV infection as the primary efficacy outcome. Behavioral assessments were done every 6 months via confidential computerized assessments. Longitudinal regression models were constructed, adjusting for randomization arm, geographical location of study site, age at enrollment, education, and race/ethnicity. Results: Of the 4295 participants enrolled, 39.7% had a history of CSA. Participants with a history of CSA [adjusted hazards ratio = 1.30, 95% confidence interval (CI): 1.02 to 1.69] were at increased risk for HIV infection over study follow-up. A significant association was seen between history of CSA and unprotected anal sex (adjusted odds ratio = 1.24, 95% CI: 1.12 to 1.36) and serodiscordant unprotected anal sex (adjusted odds ratio = 1.30, 95% CI: 1.18 to 1.43). Among participants reporting CSA, the EXPLORE intervention had no effect in reducing HIV infection rates. Participants reporting CSA were significantly more likely to have symptoms of depression and use nonprescription drugs. Conclusions: A predictive relationship between a history of CSA and subsequent HIV infection was observed among this large sample of HIV-uninfected MSM. Findings indicate that HIV-uninfected MSM with CSA histories are at greater risk for HIV infection, report higher rates of HIV sexual risk behavior, and may derive less benefit from prevention programs. Future HIV prevention interventions should address the specific mental health concerns of MSM with a history of CSA. C1 [Mimiaga, Matthew J.; Safren, Steven A.; O'Cleirigh, Conall; Mayer, Kenneth H.] Fenway Inst, Epidemiol Unit, Boston, MA 02215 USA. [Mimiaga, Matthew J.; Safren, Steven A.; O'Cleirigh, Conall] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Noonan, Elizabeth; Donnell, Deborah] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Koenen, Karestan C.; Gortmaker, Steven] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Koenen, Karestan C.; Gortmaker, Steven] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chesney, Margaret A.] Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. [Coates, Thomas J.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Koblin, Beryl A.] New York Blood Ctr, New York, NY 10021 USA. [Mayer, Kenneth H.] Miriam Hosp, Brown Med Sch, Dept Infect Dis, Providence, RI 02906 USA. [Mayer, Kenneth H.] Miriam Hosp, Brown Med Sch, Dept Community Hlth, Providence, RI 02906 USA. RP Mimiaga, MJ (reprint author), Fenway Inst, Epidemiol Unit, 1340 Boylston St, Boston, MA 02215 USA. EM mmimiaga@fenwayhealth.org RI Koenen, Karestan/K-5402-2014; OI Koenen, Karestan/0000-0003-3293-4281; Donnell, Deborah/0000-0002-0587-7480 FU HIV Network for Prevention Trials; National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health-Department of Health and Human Services [N01 A135176]; Abt Associates, Inc [N01 A135176]; Fred Hutchinson Cancer Research Center; Denver Public Health, the Fenway Community Health Center; Howard Brown Health Center; New York Blood Center; Public Health Foundation, Inc; University of Washington.; HIV Prevention Trials Network; [N01 A145200] FX Supported by the HIV Network for Prevention Trials and sponsored by the US National Institute of Allergy and Infectious Diseases and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health-Department of Health and Human Services, through contract N01 A135176 with Abt Associates, Inc; contract N01 A145200 with the Fred Hutchinson Cancer Research Center; and subcontracts with the Denver Public Health, the Fenway Community Health Center, the Howard Brown Health Center, the New York Blood Center, the Public Health Foundation, Inc, and the University of Washington. In addition, this work was supported by the HIV Prevention Trials Network and sponsored by the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research of the National Institutes of Hcalth-US Department of Health and Human Services, through a cooperative agreement with Family Health International (cooperative agreement 5 U0O1 A146749) with a subsequent subcontract to Abt Associates, Inc, with subcontracts to the Howard Brown Health Center and Denver Public Health, cooperative agreement U01 A148040 to the Fenway Community Health Center; cooperative agreement U0I A148016 to Columbia University (including a subagreement with the New York Blood Center); cooperative agreement UOI A147981 to the University of Washington; and cooperative agreement U01 A147995 to the University of California, San Francisco. NR 40 TC 107 Z9 114 U1 1 U2 15 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 JUL 1 PY 2009 VL 51 IS 3 BP 340 EP 348 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 462UV UT WOS:000267383300015 PM 19367173 ER PT J AU Melander, O Newton-Cheh, C Almgren, P Hedblad, B Berglund, G Engstrom, G Persson, M Smith, JG Magnusson, M Christensson, A Struck, J Morgenthaler, NG Bergmann, A Pencina, MJ Wang, TJ AF Melander, Olle Newton-Cheh, Christopher Almgren, Peter Hedblad, Bo Berglund, Goeran Engstrom, Gunnar Persson, Margaretha Smith, J. Gustav Magnusson, Martin Christensson, Anders Struck, Joachim Morgenthaler, Nils G. Bergmann, Andreas Pencina, Michael J. Wang, Thomas J. TI Novel and Conventional Biomarkers for Prediction of Incident Cardiovascular Events in the Community SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID C-REACTIVE PROTEIN; ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; PROATRIAL NATRIURETIC PEPTIDE; REYNOLDS RISK SCORE; MULTIPLE BIOMARKERS; PHOSPHOLIPASE A(2); IMMUNOLUMINOMETRIC ASSAY; PRO-ADRENOMEDULLIN; CASE-FATALITY AB Context Prior studies have demonstrated conflicting results regarding how much information novel biomarkers add to cardiovascular risk assessment. Objective To evaluate the utility of contemporary biomarkers for predicting cardiovascular risk when added to conventional risk factors. Design, Setting, and Participants Cohort study of 5067 participants (mean age, 58 years; 60% women) without cardiovascular disease from Malmo, Sweden, who attended a baseline examination between 1991 and 1994. Participants underwent measurement of C-reactive protein (CRP), cystatin C, lipoprotein-associated phospholipase 2, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide (N-BNP) and underwent follow-up until 2006 using the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmo register for first cardiovascular events (myocardial infarction, stroke, coronary death). Main Outcome Measures Incident cardiovascular and coronary events. Results During median follow-up of 12.8 years, there were 418 cardiovascular and 230 coronary events. Models with conventional risk factors had C statistics of 0.758 (95% confidence interval [CI], 0.734 to 0.781) and 0.760 (0.730 to 0.789) for cardiovascular and coronary events, respectively. Biomarkers retained in backward-elimination models were CRP and N-BNP for cardiovascular events and MR-proADM and N-BNP for coronary events, which increased the C statistic by 0.007 (P = .04) and 0.009 (P = .08), respectively. The proportion of participants reclassified was modest (8% for cardiovascular risk, 5% for coronary risk). Net reclassification improvement was nonsignificant for cardiovascular events (0.0%; 95% CI, -4.3% to 4.3%) and coronary events (4.7%; 95% CI, -0.76% to 10.1%). Greater improvements were observed in analyses restricted to intermediate-risk individuals (cardiovascular events: 7.4%; 95% CI, 0.7% to 14.1%; P = .03; coronary events: 14.6%; 95% CI, 5.0% to 24.2%; P = .003). However, correct reclassification was almost entirely confined to down-classification of individuals without events rather than up-classification of those with events. Conclusions Selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events. JAMA. 2009;302(1):49-57 C1 [Melander, Olle; Almgren, Peter; Hedblad, Bo; Berglund, Goeran; Engstrom, Gunnar; Persson, Margaretha; Smith, J. Gustav; Magnusson, Martin; Christensson, Anders] Lund Univ, Dept Clin Sci, SE-20502 Malmo, Sweden. [Newton-Cheh, Christopher; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Newton-Cheh, Christopher] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Newton-Cheh, Christopher; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Newton-Cheh, Christopher; Smith, J. Gustav] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Struck, Joachim; Morgenthaler, Nils G.; Bergmann, Andreas] BRAHMS AG, Res Dept, Hennigsdorf, Germany. [Pencina, Michael J.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. RP Melander, O (reprint author), Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmo Univ Hosp, Entrance 72,Bldg 91,Floor 12, SE-20502 Malmo, Sweden. EM olle.melander@med.lu.se; tjwang@partners.org FU Swedish Medical Research Council; Swedish Heart and Lung Foundation; Medical Faculty of Lund University; Malmo University Hospital; Albert Pahlsson Research Foundation; Crafoord foundation; Ernhold Lundstroms Research Foundation; Region Skane; Hulda and Conrad Mossfelt Foundation; King Gustaf V and Queen Victoria Foundation; Lennart Hanssons Memorial Fund; Wallenberg Foundation; National Institutes of Health (NIH) [K23-HL-080025, R01-HL-086875, R01-HL083197, R01-DK-081572]; Doris Duke Charitable Foundation Clinical Scientist Development Award; Burroughs Wellcome Fund Career Award for Medical Scientists; American Heart Association FX Dr Melander was supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmo University Hospital, the Albert Pahlsson Research Foundation, the Crafoord foundation, the Ernhold Lundstroms Research Foundation, the Region Skane, the Hulda and Conrad Mossfelt Foundation, the King Gustaf V and Queen Victoria Foundation, the Lennart Hanssons Memorial Fund, and the Wallenberg Foundation. Dr Newton-Cheh was supported by National Institutes of Health (NIH) grant K23-HL-080025, a Doris Duke Charitable Foundation Clinical Scientist Development Award, and a Burroughs Wellcome Fund Career Award for Medical Scientists. Dr Wang was supported by NIH grants R01-HL-086875, R01-HL083197, and R01-DK-081572 and by a grant from the American Heart Association. NR 41 TC 308 Z9 315 U1 2 U2 15 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 JUL 1 PY 2009 VL 302 IS 1 BP 49 EP 57 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 464GH UT WOS:000267492800021 PM 19567439 ER PT J AU DeMarco, RF Kendricks, M Dolmo, Y Looby, SED Rinne, K AF DeMarco, Rosanna F. Kendricks, Malkia Dolmo, Yolani Looby, Sara E. Dolan Rinne, Kirsti TI The Effect of Prevention Messages and Self-Efficacy Skill Building With Inner-City Women at Risk for HIV Infection SO JANAC-JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE LA English DT Article DE film intervention; HIV prevention; inner-city; transitional housing; women ID REDUCTION INTERVENTION; METAANALYSIS AB The purpose of this study was to examine the affect of gender-sensitive and culturally relevant HIV prevention film messages combined with self efficacy and skill building exercises on self-reported safe sex behaviors, intentions, attitudes, and self-advocacy over time. A sample of 131 women of mixed ethnicity from inner-city Boston who were living in transitional housing participated in a 4-week pre/postmeasurement design. Results showed that, despite the short duration of the intervention, participants self-reported significantly more use of safe sex behaviors and being prepared for sexual intimacy after the intervention. The study validated use of an approach originally intended for African American women with other women at risk for HIV C1 [DeMarco, Rosanna F.] Boston Coll, William F Connell Sch Nursing, Chestnut Hill, MA 02167 USA. [Kendricks, Malkia; Dolmo, Yolani] Women Connecting & Affecting Change, Dorchester, MA USA. [Looby, Sara E. Dolan] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. RP DeMarco, RF (reprint author), Boston Coll, William F Connell Sch Nursing, Chestnut Hill, MA 02167 USA. NR 33 TC 6 Z9 6 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1055-3290 J9 J ASSOC NURSE AIDS C JI J. Assoc. Nurses Aids Care PD JUL-AUG PY 2009 VL 20 IS 4 BP 283 EP 292 DI 10.1016/j.jana.2009.02.007 PG 10 WC Nursing SC Nursing GA 471FX UT WOS:000268042500005 PM 19576545 ER PT J AU Duong, TQ Muir, ER AF Duong, Timothy Q. Muir, Eric R. TI Magnetic resonance imaging of the retina SO JAPANESE JOURNAL OF OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Closed Symposium on Functional Imaging of the Retina CY APR 27, 2008 CL Ft Lauderdale, FL SP Natl Inst Sensory Organs DE blood flow; blood oxygenation level-dependent (BOLD); fMRI; oxygenation; retinal diseases ID CEREBRAL-BLOOD-FLOW; OPTICAL COHERENCE TOMOGRAPHY; HIGH-RESOLUTION; FUNCTIONAL MRI; RCS RAT; MACAQUE RETINA; SOMATOSENSORY STIMULATION; QUANTITATIVE PERFUSION; INTRAOCULAR PRESSURES; LAMINAR SPECIFICITY AB This paper reviews recent developments in high-resolution magnetic resonance imaging (MRI) and its application to image anatomy, physiology, and function in the retina of animals. It describes technical issues and solutions in performing retinal MRI, anatomical MRI, blood oxygenation level-dependent functional MRI (fMRI), and blood-flow MRI both of normal retinas and of retinal degeneration. MRI offers unique advantages over existing retinal imaging techniques, including the ability to image multiple layers without depth limitation and to provide multiple clinically relevant data in a single setting. Retinal MRI has the potential to complement existing retinal imaging techniques. C1 [Duong, Timothy Q.; Muir, Eric R.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, Dept Radiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, Dept Physiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Duong, Timothy Q.] SW Natl Primate Res Ctr, San Antonio, TX USA. [Muir, Eric R.] Georgia Inst Technol, Grad Program Biomed Engn, Atlanta, GA 30332 USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, Dept Ophthalmol, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008; Muir, Eric/H-8830-2013 FU NEI NIH HHS [R01 EY014211-08, R01 EY014211-09, R01 EY014211-01A1, R01 EY018855-03, R01 EY014211-06, R01 EY014211-07, R01 EY014211-02, R01 EY014211-03, R01 EY018855-01A1, R01 EY018855-02, R01 EY014211-05, R01 EY014211-04, R01 EY018855, R01 EY014211] NR 81 TC 20 Z9 20 U1 0 U2 1 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0021-5155 J9 JPN J OPHTHALMOL JI Jpn. J. Ophthalmol. PD JUL PY 2009 VL 53 IS 4 BP 352 EP 367 DI 10.1007/s10384-009-0688-1 PG 16 WC Ophthalmology SC Ophthalmology GA 496EY UT WOS:000269953500007 PM 19763752 ER PT J AU Shrier, LA Schillinger, JA Aneja, P Rice, PA Batteiger, BE Braslins, PG Orr, DP Fortenberry, JD AF Shrier, Lydia A. Schillinger, Julia A. Aneja, Parul Rice, Peter A. Batteiger, Byron E. Braslins, Phillip G. Orr, Donald P. Fortenberry, J. Dennis TI Depressive Symptoms and Sexual Risk Behavior in Young, Chlamydia-Infected, Heterosexual Dyads SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Depressive symptoms; Unsafe sex; Sexual partners; Dyad ID ADOLESCENT FEMALES; SUBSTANCE USE; TRANSMITTED-DISEASE; SELF-ESTEEM; DRUG-USE; ASSOCIATIONS; PARTNERS; WOMEN; MOOD; DISORDERS AB Purpose: To examine associations between depressive symptoms and dyad-level sexual risk behavior in young heterosexual dyads with sexually transmitted infection (STI). Methods: Chlamydia-positive 14-24-year-old, heterosexually active outpatients and their opposite-sex partners completed an assessment that included demographics, past and recent STI risk behaviors, and the Beck Depression Inventory (BDI). Participants in the top 25% of BDI scores within gender were categorized as depressed. Variables were created to identify dyads in which the female or male partner was depressed, as well as a measure of concordance of depression between partners. Dyad-level STI risk variables were created from the STI risk characteristics reported by each dyad member, and associations between these and the depression variables were analyzed. Results: The 130 dyads were comprised of young men and women at high STI risk. One-third of dyads had at least one depressed partner. Dyads in which the female partner was depressed had greater partner age difference, greater total number of lifetime partners, and one or more partners reporting substance use within 2 hours before sex, compared with dyads in which the female partner was not depressed. Dyads in which the male partner was depressed were more likely than the nondepressed-male dyads to report substance use before sex. All dyads in which both partners were depressed reported substance use before sex. Conclusions: In young, chlamydia-infected, heterosexual dyads, depressive symptoms, especially in women, is related to increased dyad-level STI risk, including greater partner age difference, more partners, and substance use before sex. (c) 2009 Society for Adolescent Medicine. All rights reserved. C1 [Shrier, Lydia A.] Childrens Hosp, Div Adolescent Young Adult Med, Boston, MA 02115 USA. [Shrier, Lydia A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Schillinger, Julia A.] New York City Dept Hlth & Mental Hyg, Bur Sexually Transmitted Dis Control, New York, NY USA. [Schillinger, Julia A.] US Ctr Dis Control & Prevent, Div Sexually Transmitted Dis, Atlanta, GA USA. [Aneja, Parul] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Rice, Peter A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA USA. [Batteiger, Byron E.] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN USA. [Batteiger, Byron E.] Indiana Univ, Sch Med, Dept Microbiol, Indianapolis, IN USA. [Batteiger, Byron E.] Indiana Univ, Sch Med, Dept Immunol, Indianapolis, IN USA. [Braslins, Phillip G.] Univ Queensland, Sch Med, Rural Clin Div, Brisbane, Qld 4072, Australia. [Orr, Donald P.; Fortenberry, J. Dennis] Indiana Univ, Sch Med, Riley Childrens Hosp, Indianapolis, IN USA. RP Shrier, LA (reprint author), Childrens Hosp, Div Adolescent Young Adult Med, 300 Longwood Ave, Boston, MA 02115 USA. EM lydia.shrier@childrens.harvard.edu FU Centers for Disease Control and Prevention [UR3/CCU116484, UR3/CCU 516481]; National Institute of Mental Health, National Institutes of Health [K23 MH01845-0]; Aerosmith Endowment Fund for Prevention and Treatment of AIDS and HIV Infections FX This study was funded by grants UR3/CCU116484 (Rice) and UR3/CCU 516481 (Batteiger) from the Centers for Disease Control and Prevention, grant K23 MH01845-0 (Shrier) from the National Institute of Mental Health, National Institutes of Health, and a grant (Shrier) from the Aerosmith Endowment Fund for Prevention and Treatment of AIDS and HIV Infections. NR 40 TC 21 Z9 21 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2009 VL 45 IS 1 BP 63 EP 69 DI 10.1016/j.jadohealth.2008.11.016 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 468JQ UT WOS:000267814200011 PM 19541251 ER PT J AU Lu, WD Matulonis, UA Doherty-Gilman, A Lee, H Dean-Clower, E Rosulek, A Gibson, C Goodman, A Davis, RB Buring, JE Wayne, PM Rosenthal, DS Penson, RT AF Lu, Weidong Matulonis, Ursula A. Doherty-Gilman, Anne Lee, Hang Dean-Clower, Elizabeth Rosulek, Andrew Gibson, Carolyn Goodman, Annekathryn Davis, Roger B. Buring, Julie E. Wayne, Peter M. Rosenthal, David S. Penson, Richard T. TI Acupuncture for Chemotherapy-Induced Neutropenia in Patients with Gynecologic Malignancies: A Pilot Randomized, Sham-Controlled Clinical Trial SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-of-Hematology CY DEC 08-11, 2007 CL Atlanta, GA SP Amer Soc Hematol ID COLONY-STIMULATING FACTOR; ACUTE MYELOID-LEUKEMIA; ADVANCED MULLERIAN MALIGNANCIES; PHASE-II TRIAL; BREAST-CANCER; OVARIAN-CANCER; INDUCED NAUSEA; RECOMMENDATIONS; CYCLOPHOSPHAMIDE; CROSSOVER AB Objectives: The objective of this study was to investigate the effect of acupuncture administered during myelosuppressive chemotherapy on white blood cell (WBC) count and absolute neutrophil count (ANC) in patients with ovarian cancer. Design: This study is a pilot, randomized, sham-controlled clinical trial. Patients received active acupuncture versus sham acupuncture while undergoing chemotherapy. A standardized acupuncture protocol was employed with manual and electrostimulation. The frequency of treatment was 2-3 times per week for a total of 10 sessions, starting 1 week before the second cycle of chemotherapy. Setting: The setting was two outpatient academic centers for patients with cancer. Subjects: Twenty-one (21) newly diagnosed and recurrent ovarian cancer patients were the subjects. Outcome measures: WBC count, ANC, and plasma granulocyte colony-stimulating factor (G-CSF) were assessed weekly. Results: The median leukocyte value in the acupuncture arm at the first day of the third cycle of chemotherapy was significantly higher than in the control arm after adjusting for baseline value (8600 cells/mu L, range: 4800 12,000 versus 4400 cell/mu L, range: 2300-10,000) (p=0.046). The incidence of grade 2-4 leukopenia was less in the acupuncture arm than in the sham arm (30% versus 90%; p=0.02). However, the median leukocyte nadir, neutrophil nadir, and recovering ANC were all higher but not statistically significantly different (p=0.116-0.16), after adjusting for baseline differences. There were no statistically significant differences in plasma G-CSF between the two groups. Conclusions: We observed clinically relevant trends of higher WBC values during one cycle of chemotherapy in patients with ovarian cancer, which suggests a potential myeloprotective effect of acupuncture. A larger trial is warranted to more definitively determine the efficacy of acupuncture on clinically important outcomes of chemotherapy-induced neutropenia. C1 [Lu, Weidong; Doherty-Gilman, Anne; Dean-Clower, Elizabeth; Rosulek, Andrew; Rosenthal, David S.] Dana Farber Canc Inst, Leonard P Zakim Ctr Integrat Therapies, Boston, MA 02115 USA. [Lu, Weidong; Wayne, Peter M.] New England Sch Acupuncture, Newton, MA USA. [Lu, Weidong; Davis, Roger B.; Buring, Julie E.; Wayne, Peter M.] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA USA. [Matulonis, Ursula A.; Rosenthal, David S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Gibson, Carolyn; Goodman, Annekathryn; Penson, Richard T.] Massachusetts Gen Hosp, Dept Gynecol Oncol, Boston, MA 02114 USA. RP Lu, WD (reprint author), Dana Farber Canc Inst, Leonard P Zakim Ctr Integrat Therapies, 44 Binney St, Boston, MA 02115 USA. EM Weidong_lu@dfci.harvard.edu RI Lu, Weidong/C-3844-2008 OI Lu, Weidong/0000-0003-2838-6307 FU NCCIH NIH HHS [U19 AT002022, 1U19 AT 002022-01, U19 AT002022-01] NR 43 TC 17 Z9 19 U1 0 U2 7 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD JUL PY 2009 VL 15 IS 7 BP 745 EP 753 DI 10.1089/acm.2008.0589 PG 9 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 468FB UT WOS:000267801100009 PM 19552597 ER PT J AU Wood, HM Lee, UJ Vurbic, D Sabanegh, E Ross, JH Li, TS Damaser, MS AF Wood, Hadley M. Lee, Una J. Vurbic, Drina Sabanegh, Edmund Ross, Jonathan H. Li, Tiansen Damaser, Margot S. TI Sexual Development and Fertility of Loxl1(-/-) Male Mice SO JOURNAL OF ANDROLOGY LA English DT Article DE Mouse; elastin; penis; reproductive tract; semen analysis; testis; mouse model ID KARTAGENER SYNDROME; CRYPTORCHIDISM; 15Q24; GENE AB Our objective was to investigate the genitourinary defects and fertility of the male lysyl oxidase-like 1 gene (Loxl1) knockout (Loxl1(-/-)) mouse, with particular attention to fecundity and testicular, epididymal, gubernacular, and penile histopathology, which may lead us to a better understanding of the role of the elastin-homeostasis gene, LOXL1, in male sexual development. Genital morphometric evaluation of 6- to 9-month-old male Loxl1(-/-) mice (n = 26) was compared with C57BI/6 controls (n = 24). Measurements included: body weight, scrotal development, evidence of feminization (nipples or vaginal pouch), penile malformations, anogenital distance, and absence/presence and size of perineal bulge. Sperm production was estimated using a standardized technique. A breeding program was conducted to determine how much of the infertility observed in Loxl(1-/-) pairs was due to the male factor. Finally, we performed histopathologic comparison of the genitourinary organs of Loxl1(-/-) and control mice. Loxl1(-/-) mice weighed less than their age-matched C57BI/6 counterparts (P < .001). Size-adjusted perineal bulge was larger (P <.001), and resting location of the gonads was higher intra-abdominally (P = .048) in the Loxl1(-/-) mice. Estimates of daily sperm counts revealed that the Loxl1(-/-) mice had lower sperm production (P = .048). Loxl1(-/-) males bred with control females demonstrated relative fecundity values intermediate between Loxl1(-/-) pairs (lowest fecundity) and control pairs (highest fecundity), suggesting a component of male-factor infertility. No histologic differences were noted using hematoxylin-eosin or specialized elastin staining of the gonads, gubernaculum, and penis. Although further studies are warranted, these findings suggest a subtle and likely multifactorial role of the LOXL1 protein in male sexual development and fertility. C1 [Damaser, Margot S.] Cleveland Clin, Dept Biomed Engn, Lerner Res Inst, Cleveland, OH 44195 USA. [Wood, Hadley M.; Lee, Una J.; Sabanegh, Edmund; Ross, Jonathan H.; Damaser, Margot S.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44195 USA. [Vurbic, Drina; Damaser, Margot S.] Wade Pk Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Li, Tiansen] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA USA. RP Damaser, MS (reprint author), Cleveland Clin, Dept Biomed Engn, Lerner Res Inst, 9500 Carnegie Ave ND20, Cleveland, OH 44195 USA. EM damasem@ccf.org NR 17 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 J9 J ANDROL JI J. Androl. PD JUL-AUG PY 2009 VL 30 IS 4 BP 452 EP 459 DI 10.2164/jandrol.108.006122 PG 8 WC Andrology SC Endocrinology & Metabolism GA 469NG UT WOS:000267905700016 PM 19201700 ER PT J AU Thompson, GR Wiederhold, NP Sutton, DA Fothergill, A Patterson, TF AF Thompson, George R., III Wiederhold, Nathan P. Sutton, Deanna A. Fothergill, Annette Patterson, Thomas F. TI In vitro activity of isavuconazole against Trichosporon, Rhodotorula, Geotrichum, Saccharomyces and Pichia species SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article; Proceedings Paper CT 19th Annual Focus on Fungal Infections CY 2009 CL Ft Myers, FL DE triazoles; MICs; rare yeasts; Blastoschizomyces capitatum ID ANTIFUNGAL SUSCEPTIBILITIES; FUNGAL PATHOGENS; ASPERGILLUS; FLUCONAZOLE; INFECTIONS; CANDIDA AB Objectives: The emergence of less common, but clinically important, fungal pathogens including the rare yeasts has contributed to the substantial morbidity and mortality observed in immunocompromised patients. These organisms can be resistant or refractory to existing antifungal agents. We sought to evaluate the activity of the new triazole isavuconazole against these difficult pathogens. Methods: MICs of isavuconazole, voriconazole, posaconazole, fluconazole, amphotericin B and flucytosine were determined for 54 Trichosporon, 7 Geotrichum capitatum, 18 Saccharomyces cerevisiae, 11 Pichia and 14 Rhodotorula species in accordance with the M27-A2 reference method. Minimum fungicidal concentrations were also measured for each agent. Results: Isavuconazole demonstrated excellent in vitro activity against each species tested. MIC(90) values ranged between 0.125 and 0.25 mg/L against Trichosporon isolates, and between 0.03 and 0.5 mg/L against the other yeast tested. The geometric mean MICs of isavuconazole were similar to those of voriconazole and similar or less than those of posaconazole, fluconazole, amphotericin B and flucytosine for all species tested. This activity was also maintained against one Trichosporon asahii and nine Rhodotorula isolates that were resistant to fluconazole. Conclusions: Isavuconazole is a welcome addition to the growing antifungal armamentarium with potent in vitro activity against emerging yeast pathogens. Although this agent may be useful in the treatment of the rare yeasts, clinical data are needed to verify these results. C1 [Thompson, George R., III] UTHSCSA, Med ID, Div Infect Dis, Dept Med, San Antonio, TX 78229 USA. [Thompson, George R., III; Wiederhold, Nathan P.; Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Wiederhold, Nathan P.] Univ Texas Austin, Coll Pharm, Austin, TX USA. [Sutton, Deanna A.; Fothergill, Annette] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, Grad Sch Biomed Sci, San Antonio, TX USA. RP Thompson, GR (reprint author), UTHSCSA, Med ID, Div Infect Dis, Dept Med, 7703 Floyd Curl Dr,MSC 7881, San Antonio, TX 78229 USA. EM thompsong2@uthscsa.edu OI Wiederhold, Nathan/0000-0002-2225-5122 NR 10 TC 28 Z9 28 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JUL PY 2009 VL 64 IS 1 BP 79 EP 83 DI 10.1093/jac/dkp138 PG 5 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 457VJ UT WOS:000266962100014 PM 19406849 ER PT J AU Darouiche, RO Mansouri, MD Gawande, PV Madhyastha, S AF Darouiche, Rabih O. Mansouri, Mohammad D. Gawande, Purushottam V. Madhyastha, Srinivasa TI Antimicrobial and antibiofilm efficacy of triclosan and DispersinB (R) combination SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE infection; catheter; bacteria ID BIOFILM FORMATION; STAPHYLOCOCCUS-AUREUS; NOSOCOMIAL INFECTIONS; BACTERIAL BIOFILMS; URINARY CATHETERS; IN-VITRO; DETACHMENT AB Objectives: The objectives of this study were to examine: (i) synergy of the combination of triclosan and DispersinB (R) (DspB); (ii) in vitro efficacy and durability of triclosan + DspB-coated vascular catheters; and (iii) in vivo efficacy of triclosan + DspB-coated catheters compared with chlorhexidine-silver sulfadiazine (CH-SS)-coated and uncoated (control) vascular catheters in preventing colonization by Staphylococcus aureus. Methods: We investigated the potential synergistic antimicrobial and antibiofilm activity of triclosan and DspB by biofilm assays. The in vitro antimicrobial efficacy of triclosan + DspB-coated catheters was determined by microbial colonization assays. Antimicrobial durability of the coated catheters was tested by soaking segments in bovine serum for 7 days and determining antimicrobial activity, and by a serial plate transfer method. The in vivo efficacy of triclosan + DspB-coated catheters compared with CH-SS-coated and uncoated catheters was assessed by subcutaneous implantation of segments in a rabbit model of S. aureus infection. Results: The combination of triclosan and DspB showed synergistic antimicrobial and antibiofilm activity against S. aureus, Staphylococcus epidermidis and Escherichia coli, significantly reduced bacterial colonization (P<0.05) and generally demonstrated a prolonged superior antimicrobial activity against clinical pathogens compared with CH-SS-coated catheters. Triclosan + DspB-coated and CH-SS-coated catheters exhibited equal in vivo efficacy (P <= 0.05) in reducing colonization by S. aureus compared with uncoated catheters. Conclusions: Catheters coated with the triclosan + DspB combination showed synergistic, broad-spectrum and durable antimicrobial activity. Furthermore, the in vivo efficacy of catheters coated with this unique antimicrobial/antibiofilm composition prompts clinical evaluation of such an innovative approach. C1 [Darouiche, Rabih O.; Mansouri, Mohammad D.] Michael E Debakey Vet Affairs Med Ctr, Ctr Prostheses Infect, Houston, TX USA. [Darouiche, Rabih O.; Mansouri, Mohammad D.] Michael E Debakey Vet Affairs Med Ctr, Infect Dis Sect, Houston, TX USA. [Darouiche, Rabih O.; Mansouri, Mohammad D.] Baylor Coll Med, Houston, TX 77030 USA. [Gawande, Purushottam V.; Madhyastha, Srinivasa] Kane Biotech Inc, Winnipeg, MB R3T 6C6, Canada. RP Darouiche, RO (reprint author), Michael E Debakey Vet Affairs Med Ctr, Ctr Prostheses Infect, Houston, TX USA. EM rdarouiche@aol.com RI Gawande, Purushottam/C-5487-2014 OI Gawande, Purushottam/0000-0001-8675-9293 FU Kane Biotech Inc.; Winnipeg, MB, Canada FX Kane Biotech Inc., Winnipeg, MB, Canada provided funds for conducting this study. NR 24 TC 66 Z9 68 U1 5 U2 31 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JUL PY 2009 VL 64 IS 1 BP 88 EP 93 DI 10.1093/jac/dkp158 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 457VJ UT WOS:000266962100016 PM 19447791 ER PT J AU Harris, RS Winkler, T Musch, G Melo, MFV Schroeder, T Tgavalekos, N Venegas, JG AF Harris, R. Scott Winkler, Tilo Musch, Guido Melo, Marcos F. Vidal Schroeder, Tobias Tgavalekos, Nora Venegas, Jose G. TI The prone position results in smaller ventilation defects during bronchoconstriction in asthma SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE ventilation-perfusion ratio; pulmonary gas exchange; emission-computed tomography; nitrogen isotopes ID METHACHOLINE-INDUCED BRONCHOCONSTRICTION; REGIONAL VENTILATION; PULMONARY PERFUSION; AIRWAY-CLOSURE; BODY POSTURE; SUPINE MEN; LUNG; PET; HUMANS; VOLUME AB Harris RS, Winkler T, Musch G, Vidal Melo MF, Schroeder T, Tgavalekos N, Venegas JG. The prone position results in smaller ventilation defects during bronchoconstriction in asthma. J Appl Physiol 107: 266-274, 2009. First published May 14, 2009; doi:10.1152/japplphysiol.91386.2008.-The effect of body posture on regional ventilation during bronchoconstriction is unknown. In five subjects with asthma, we measured spirometry, low-frequency (0.15Hz) lung elastance, and resistance and regional ventilation by intravenous (13)NN-saline positron emission tomography before and after nebulized methacholine. The subjects were imaged prone on 1 day and supine on another, but on both days the methacholine was delivered while prone. From the residual (13)NN after washout, ventilation defective areas were defined, and their location, volume, ventilation, and fractional gas content relative to the rest of the lung were calculated. Independent of posture, all subjects developed ventilation defective areas. Although ventilation within these areas was similarly reduced in both postures, their volume was smaller in prone than supine (25 vs. 41%, P < 0.05). The geometric center of the ventilation defective areas was gravitationally dependent relative to that of the lung in both postures. Mean lung fractional gas content was greater in the prone position before methacholine and did not increase as much as in the supine position after methacholine. In the prone position at baseline, areas that became ventilation defects had lower gas content than the rest of the lung. In both positions at baseline, there was a gradient of gas content in the vertical direction. In asthma, the size and location of ventilation defects is affected by body position and likely affected by small differences in lung expansion during bronchoconstriction. C1 [Harris, R. Scott] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Tgavalekos, Nora] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP Harris, RS (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Dept Med, Bulfinch 148,55 Fruit St, Boston, MA 02114 USA. EM rharris@partners.org RI Winkler, Tilo/B-5337-2009; OI Winkler, Tilo/0000-0002-7276-5550; Schroeder, Tobias/0000-0002-4439-8060 FU National Heart, Lung, and Blood Institute [HL-068011, HL-086717] FX This study was supported in part by National Heart, Lung, and Blood Institute Grants HL-068011 and HL-086717. NR 36 TC 11 Z9 13 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUL PY 2009 VL 107 IS 1 BP 266 EP 274 DI 10.1152/japplphysiol.91386.2008 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 464VK UT WOS:000267535800037 PM 19443742 ER PT J AU Sahyoun, CP Soulieres, I Belliveau, JW Mottron, L Mody, M AF Sahyoun, Cherif P. Soulieres, Isabelle Belliveau, John W. Mottron, Laurent Mody, Maria TI Cognitive Differences in Pictorial Reasoning Between High-Functioning Autism and Asperger's Syndrome SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE High-functioning autism; Asperger's syndrome; Reasoning; Pictures; Language; Visuospatial ID PERVASIVE DEVELOPMENTAL DISORDERS; SPECTRUM DISORDERS; WORKING-MEMORY; CHILDREN; INDIVIDUALS; PERCEPTION; PROFILES; SUPERIOR; ABILITY; ANALOGY AB We investigated linguistic and visuospatial processing during pictorial reasoning in high-functioning autism (HFA), Asperger's syndrome (ASP), and age and IQ-matched typically developing participants (CTRL), using three conditions designed to differentially engage linguistic mediation or visuospatial processing (visuospatial, V; semantic, S; visuospatial + semantic, V + S). The three groups did not differ in accuracy, but showed different response time profiles. ASP and CTRL participants were fastest on V + S, amenable to both linguistic and nonlinguistic mediation, whereas HFA participants were equally fast on V and V + S, where visuospatial strategies were available, and slowest on S. HFA participants appeared to favor visuospatial over linguistic mediation. The results support the use of linguistic versus visuospatial tasks for characterizing subtypes on the autism spectrum. C1 [Sahyoun, Cherif P.; Belliveau, John W.; Mody, Maria] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sahyoun, Cherif P.; Soulieres, Isabelle; Belliveau, John W.; Mody, Maria] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, MGH MIT HMS, Charlestown, MA 02129 USA. [Soulieres, Isabelle; Mottron, Laurent] Hop Riviere des Prairies, Clin Specialisee Autisme, Montreal, PQ, Canada. RP Sahyoun, CP (reprint author), Harvard Mit Div Hlth Sci & Technol, 77 Massachusetts Ave,E25-519, Cambridge, MA 02139 USA. EM cherif@mit.edu; mottronl@istar.ca; maria@nmr.mgh.harvard.edu FU NICHD NIH HHS [HD40712, R01 HD040712]; NINDS NIH HHS [-NS037462, R01 NS037462, R56 NS037462] NR 56 TC 30 Z9 30 U1 3 U2 16 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD JUL PY 2009 VL 39 IS 7 BP 1014 EP 1023 DI 10.1007/s10803-009-0712-9 PG 10 WC Psychology, Developmental SC Psychology GA 457EM UT WOS:000266911300006 PM 19267190 ER PT J AU Park, JM Park, LT Siefert, CJ Abraham, ME Fry, CR Silvert, MS AF Park, Jennifer M. Park, Lawrence T. Siefert, Caleb J. Abraham, Melissa E. Fry, Christine R. Silvert, Mark S. TI Factors Associated with Extended Length of Stay for Patients Presenting to an Urban Psychiatric Emergency Service: A Case-Control Study SO JOURNAL OF BEHAVIORAL HEALTH SERVICES & RESEARCH LA English DT Article ID HEALTH-CARE; RISK AB This study assessed factors associated with extended length of stay (ELOS) for patients presenting to a psychiatric emergency service (PES). Two hundred six subjects with a length of stay of 24 h or longer were compared with time-matched controls (patients that presented directly after the ELOS patient). Binary logistic regression was used to identify risk factors for ELOS. ELOS was associated with suicidal ideation, disposition to an inpatient unit, homicidal ideation, lack of insurance, homelessness, male gender, past history of psychiatric hospitalization, diagnosis of substance abuse, significant psychiatric co-morbidity (represented by three or more Axis I diagnoses), and diagnosis of a psychotic disorder. Lack of insurance, suicidal ideation, disposition to inpatient unit, and homicidal ideation all made nonredundant contributions to predicting stays of 24 h or longer. C1 [Park, Jennifer M.] Massachusetts Gen Hosp, Freedom Trail Clin, Boston, MA 02114 USA. [Park, Lawrence T.; Siefert, Caleb J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Fry, Christine R.] Univ Calif Berkeley, Goldman Sch Publ Policy, Berkeley, CA 94720 USA. [Silvert, Mark S.] Royal Free Hosp, London NW3 3DS, England. RP Park, JM (reprint author), Massachusetts Gen Hosp, Freedom Trail Clin, Boston, MA 02114 USA. EM jmpark@partners.org; lpark@partners.org; csiefert@partners.org; mabraham2@partners.org; christinefry@gmail.com; markssilvert@hotmail.com NR 19 TC 12 Z9 12 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1094-3412 J9 J BEHAV HEALTH SER R JI J. Behav. Health Serv. Res. PD JUL PY 2009 VL 36 IS 3 BP 300 EP 308 DI 10.1007/s11414-008-9160-0 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 446AP UT WOS:000266092900003 PM 19089640 ER PT J AU Sato, M Ito, Y Arima, N Baba, M Sobel, M Wakao, M Suda, Y AF Sato, Masaki Ito, Yuji Arima, Naomichi Baba, Masanori Sobel, Michael Wakao, Masahiro Suda, Yasuo TI High-Sensitivity Analysis of Naturally Occurring Sugar Chains, Using a Novel Fluorescent Linker Molecule SO JOURNAL OF BIOCHEMISTRY LA English DT Article DE immobilization; sugar chain; high sensitivity; analysis; fluorescence; linker molecule; mass spectrometry ID SURFACE-PLASMON RESONANCE; PERFORMANCE LIQUID-CHROMATOGRAPHY; MASS-SPECTROMETRY; OLIGOSACCHARIDES; GLYCOMICS; IMMOBILIZATION; STRATEGY; GLYCANS AB To analyse the binding of sugar chains to proteins, viruses and cells, the surface plasmon resonance (SPR) technique is very convenient and effective because it is a real-time, non-destructive detection system. Key to this method is linker compounds for immobilization of the sugar chains to the gold-coated chip for SPR. Also, well-designed fluorescent labelling reagents are essential when analysing the structure of trace amounts of sugar chains derived from natural sources, such as glycoproteins on the surface of specific cells. In this report, we developed a novel linker molecule, named 'f-mono', which has both of these properties: simple immobilization chemistry and a fluorescent label. Since the molecule contains a 2,5-diaminopyridyl group and a thioctic acid group, conjugation with sugar chains can be achieved using the well-established reductive amination reaction. This conjugate of sugar chain and fluorescent linker (fluorescent ligand-conjugate, FLC) has fluorescent properties (ex. 335 nm, em. 380 nm), and as little as 1 mu g of FLC can be easily purified using HPLC with a fluorescent detector. MS and MS/MS analysis of the FLC is also possible. As a +2 Da larger MS peak ([M + H + 2](+) ion) was always associated with the theoretical MS peak ([M + H](+)) (due to the reduction of the thioctic acid moiety), the MS peaks of the FLC were easily found, even using unfractionated crude samples. Immobilization of the FLC onto gold-coated chips, and their subsequent SPR analyses were successively accomplished, as had been performed previously using non-fluorescent ligand conjugates. C1 [Sato, Masaki; Wakao, Masahiro; Suda, Yasuo] Kagoshima Univ, Grad Sch Sci & Engn, Dept Nanostruct & Adv Mat, Kagoshima 8900065, Japan. [Ito, Yuji] Kagoshima Univ, Grad Sch Sci & Engn, Dept Bioengn, Kagoshima 8900065, Japan. [Arima, Naomichi; Baba, Masanori] Kagoshima Univ, Grad Sch Med & Dent Sci, Ctr Chron Viral Dis, Kagoshima 8900065, Japan. [Sobel, Michael] Univ Washington, Sch Med, Seattle, WA USA. [Sobel, Michael] VA Puget Sound HCS, Dept Surg, Seattle, WA USA. [Suda, Yasuo] SUDx Biotec Corp, Kagoshima 8900013, Japan. RP Suda, Y (reprint author), Kagoshima Univ, Grad Sch Sci & Engn, Dept Nanostruct & Adv Mat, 1-21-40 Kohrimoto, Kagoshima 8900065, Japan. EM ysuda@eng.kagoshima-u.ac.jp RI Baba, Masanori/G-3867-2011 FU Frontier Science Research Center (FSRC); Japan Science and Technology Agency; Japanese Hyogo Prefecture; National Institutes of Health, NHLBI [HL079182] FX The Frontier Science Research Center (FSRC) of Kagoshima University (to Y. S.); Japan Science and Technology Agency (to Y. S.); Japanese Hyogo Prefecture (to Y. S.); and the National Institutes of Health, NHLBI (HL079182 to M. S.). NR 25 TC 7 Z9 7 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0021-924X J9 J BIOCHEM JI J. Biochem. PD JUL PY 2009 VL 146 IS 1 BP 33 EP 41 DI 10.1093/jb/mvp041 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469IF UT WOS:000267889000006 PM 19270055 ER PT J AU Wang, SH Chen, PHC Berthiaume, F Toner, M Jayaraman, A Yarmush, ML AF Wang, Sihong Chen, Pohun C. Berthiaume, Francois Toner, Mehmet Jayaraman, Arul Yarmush, Martin L. TI Dynamic Effect of Heat Shock Pretreatment on Apoptotic Responses to TNF-alpha in Liver Cells SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE heat shock; heat shock protein; apoptosis; tumor necrosis factor-alpha ID INDUCED ACTIVATION; HSP70; PROTEIN; NECROSIS; HSP90; OVEREXPRESSION; HYPERTHERMIA; THERAPY; STRESS; INJURY AB The heat shock (HS) response is a protective mechanism for cells to protect themselves against subsequent lethal stress. HS upregulated heat shock protein (HSP) expression reduced apoptosis following tumor necrosis factor-alpha (TNF-alpha) stimulation. However, vector-mediated overexpression of HSP70 failed to provide similar protection but rather sensitized cells to TNF-alpha induced apoptosis. This may be due to the fact that the kinetics of vector-mediated HSP overexpression is totally different from that of HSP upregulation by HS. We hypothesized that the response depends on the timing of TNF-alpha challenge relative to HSP expression dynamics after HS. Therefore, we investigated the correlation between the dynamic change of HSP expression and the levels of apoptosis induced by TNF-alpha after HS. Hepatoma cells were subjected to mild heat shock at 42 degrees C for 2 h followed by varied recovery times and then treated with TNF-alpha to induce apoptosis. The results from quantitative apoptosis assays using the TUNEL reaction reveal an optimal HS protection window centered around 5 h post-HS against TNF-alpha induced apoptosis. In addition, we found a window extending up to 2 h after HS where HS sensitized cells to TNF-alpha stress. Importantly, the correlation between apoptosis and HSP expression kinetics demonstrates that both high levels of HSPs and proper timing between HS and TNF-alpha stress were critical for optimal protection. Our study establishes a dynamic experimental model for further investigation of HS as a potential clinical approach to target tissue survival or death. [DOI: 10.1115/1.3118768] C1 [Chen, Pohun C.; Berthiaume, Francois; Toner, Mehmet; Yarmush, Martin L.] Shriners Burn Hosp, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Chen, Pohun C.; Berthiaume, Francois; Toner, Mehmet; Yarmush, Martin L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Wang, Sihong] CUNY City Coll, Dept Biomed Engn, New York, NY 10031 USA. [Jayaraman, Arul] Texas A&M Univ, Dept Chem Engn, College Stn, TX 77843 USA. RP Yarmush, ML (reprint author), Shriners Burn Hosp, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. EM ireis@sbi.org FU Whitaker Foundation; Shriners Burn Hospital FX This project was partially supported by the grants from the Whitaker Foundation and the Shriners Burn Hospital. NR 25 TC 0 Z9 0 U1 0 U2 5 PU ASME-AMER SOC MECHANICAL ENG PI NEW YORK PA THREE PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD JUL PY 2009 VL 131 IS 7 AR 071003 DI 10.1115/1.3118768 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 476KS UT WOS:000268439900004 PM 19640128 ER PT J AU Huppert, TJ Jones, PB Devor, A Dunn, AK Teng, IC Dale, AM Boas, DA AF Huppert, Theodore J. Jones, Phill B. Devor, Anna Dunn, Andrew K. Teng, Ivan C. Dale, Anders M. Boas, David A. TI Sensitivity of neural-hemodynamic coupling to alterations in cerebral blood flow during hypercapnia SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE neural-hemodynamic coupling; hypercapnia; cerebral blood flow ID CALIBRATED FUNCTIONAL MRI; RAT SOMATOSENSORY CORTEX; MEAN TRANSIT-TIME; OXYGEN-METABOLISM; NEURONAL-ACTIVITY; BOLD FMRI; HEMOGLOBIN CONCENTRATION; BASE-LINE; TELL US; BRAIN AB The relationship between measurements of cerebral blood oxygenation and neuronal activity is highly complex and depends on both neurovascular and neurometabolic biological coupling. While measurements of blood oxygenation changes via optical and MRI techniques have been developed to map functional brain activity, there is evidence that the specific characteristics of these signals are sensitive to the underlying vascular physiology and structure of the brain. Since baseline blood flow and oxygen saturation may vary between sessions and across subjects, functional blood oxygenation changes may be a less reliable indicator of brain activity in comparison to blood flow and metabolic changes. In this work, we use a biomechanical model to examine the relationships between neural, vascular, metabolic, and hemodynamic responses to parametric whisker stimulation under both normal and hypercapnic conditions in a rat model. We find that the relationship between neural activity and oxy- and deoxyhemoglobin changes is sensitive to hypercapnia-induced changes in baseline cerebral blood flow. In contrast, the underlying relationships between evoked neural activity, blood flow, and model-estimated oxygen metabolism changes are unchanged by the hypercapnic challenge. We conclude that evoked changes in blood flow and cerebral oxygen metabolism are more closely associated with underlying evoked neuronal responses. (C) 2009 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3210779] C1 [Huppert, Theodore J.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15213 USA. [Huppert, Theodore J.; Jones, Phill B.; Devor, Anna; Boas, David A.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Devor, Anna; Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Dunn, Andrew K.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Huppert, TJ (reprint author), Univ Pittsburgh, Dept Radiol, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM huppertt@upmc.edu RI Dale, Anders/A-5180-2010; Dunn, Andrew/I-9527-2014; OI Jones, Phillip/0000-0003-0525-6323 FU National Institutes of Health [R01-EB002482, RO1-EB000790, R01-NS051188, P41-RR14075]; NCRR; MIND institute FX This work was supported by the National Institutes of Health (R01-EB002482, RO1-EB000790, R01-NS051188, and P41-RR14075), NCRR, and the MIND institute. The authors would like to thank Heval Benav and Rickson Mesquita, and Monica Allen, Solomon Diamond, Joe Mandeville, and Bruce Rosen for their roles in the development of this model and for helpful discussion on this manuscript. NR 45 TC 11 Z9 12 U1 0 U2 4 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUL-AUG PY 2009 VL 14 IS 4 AR 044038 DI 10.1117/1.3210779 PG 16 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 503MV UT WOS:000270540100044 PM 19725749 ER PT J AU Nakajima, A Sanjay, A Chiusaroli, R Adapala, NS Neff, L Itzsteink, C Horne, WC Baron, R AF Nakajima, Arata Sanjay, Archana Chiusaroli, Riccardo Adapala, Naga Suresh Neff, Lynn Itzsteink, Cecile Horne, William C. Baron, Roland TI Loss of Cbl-b Increases Osteoclast Bone-Resorbing Activity and Induces Osteopenia SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE Cbl-b; osteoclast; osteopenia; bone resorption; differentiation ID SRC KINASE-ACTIVITY; C-CBL; DOWN-REGULATION; PHOSPHATIDYLINOSITOL 3-KINASE; NEGATIVE REGULATION; TYROSINE KINASES; FAMILY PROTEINS; BINDING-SITE; T-CELLS; ACTIVATION AB Cbl proteins are multifunctional adaptor molecules that modulate cellular activity by targeting the ubiquitylating system, endocytic complexes, and other effectors to a wide variety of regulatory proteins, especially activated receptor and nonreceptor tyrosine kinases. Cbl and Cbl-b perform unique functions in various cells, in addition to redundant functions that are required for embryonic development. We previously showed that eliminating Cbl impaired osteoclast motility, which modestly delayed embryonic bone development. We now report that Cbl-b(-/-) mice are osteopenic, because of increased bone resorption with little compensating increase in bone formation. In vitro bone-resorbing activity and differentiation of osteoclast-like cells (OCLs) were increased, as were some RANKL-induced signaling events (activation of NF-kappa B and the mitogen-activated protein kinases extracellular signal-regulated kinase [ERK] and p38), suggesting that specific RANKL-activated mechanisms contribute to the increased rate of differentiation and bone-resorbing activity. Re-expressing Cbl-b in Cbl-b(-/-) OCLs normalized the increased bone-resorbing activity and overexpressing Cbl-b in wildtype OCLs inhibited bone resorption. Cbl was without effect in either wildlype or Cbl-b(-/-) OCLs. Functional tyrosine kinase binding (TKB) and RING finger domains were required for the rescue by Cbl-b. Thus, both Cbl and Cbl-b perform regulatory functions in osteoclasts that are unique to one or the other protein (i.e., functions that cannot be compensated by the other homolog). One of Cbl-b's unique functions in osteoclasts is to downregulate bone resorption. J Bone Miner Res 2009;24:1162-1172. Published online on February 16, 2009; doi: 10.1359/JBMR.090205 C1 [Nakajima, Arata; Sanjay, Archana; Chiusaroli, Riccardo; Neff, Lynn; Itzsteink, Cecile; Horne, William C.; Baron, Roland] Yale Univ, Sch Med, Dept Orthopaed & Rehabil, New Haven, CT 06510 USA. [Sanjay, Archana; Adapala, Naga Suresh] Temple Univ, Sch Med, Dept Anat & Cell Biol, Philadelphia, PA 19122 USA. [Baron, Roland] Harvard Univ, Dept Internal Med, Sch Med, Boston, MA 02115 USA. [Baron, Roland] Massachusetts Gen Hosp, Endocrinol Sect, Boston, MA 02114 USA. [Baron, Roland] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. [Horne, William C.; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Baron, R (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave,REB 309, Boston, MA 02115 USA. EM roland_baron@hsdm.harvard.edu FU Pilot and Feasibility Project; Yale Core Centel for Musculoskeletal Diseases [2P30 AR 46032]; National Institutes of Health [AR-49879, DE-04724] FX The Cbl-b-/- mice were generously provided by Dr. Hua Gu, Columbia University. cDNAs for wildtype and mutated human Cbl-b were generously provided by Dr. Stanley Lipkowitz, National Institutes of Health. This work was supported in part by a Pilot and Feasibility Project grant (to A.S.) front the Yale Core Centel for Musculoskeletal Diseases (2P30 AR 46032) and by grants AR-49879 (to W.C.H.) and DE-04724 (to R.B.) from the National Institutes of Health. NR 47 TC 27 Z9 29 U1 0 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2009 VL 24 IS 7 BP 1162 EP 1172 DI 10.1359/JBMR.090205 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 461AE UT WOS:000267234400005 PM 19257814 ER PT J AU Casey, A Chang, BH Huddleston, J Virani, N Benson, H Dusek, JA AF Casey, Aggie Chang, Bei-Hung Huddleston, James Virani, Narmin Benson, Herbert Dusek, Jeffery A. TI A Model for Integrating a Mind/Body Approach to Cardiac Rehabilitation OUTCOMES AND CORRELATORS SO JOURNAL OF CARDIOPULMONARY REHABILITATION AND PREVENTION LA English DT Article DE cardiac rehabilitation; mind/body approach; outcomes ID CORONARY-ARTERY-DISEASE; HIGH BLOOD-PRESSURE; JOINT NATIONAL COMMITTEE; LIFE-STYLE MODIFICATION; HEART-DISEASE; MYOCARDIAL-INFARCTION; STRESS-MANAGEMENT; EXERCISE; RISK; METAANALYSIS AB PURPOSE: Although cardiac rehabilitation programs have been shown to decrease cardiovascular risk, morbidity, and mortality, few programs have integrated a balanced mind/body approach in which patients are taught the relaxation response and utilize cognitive behavior skills for stress management, along with diet and exercise. We examined the medical and psychological outcomes of patients treated in such a cardiac rehabilitation program in a general hospital setting. METHODS: From 1997 to 2005, outcomes were measured in 637 patients with coronary artery disease at baseline and after a 3-month program. Components of the intervention included smoking cessation, moderate aerobic exercise, nutrition counseling, relaxation response training, and cognitive/behavioral skills. RESULTS: Men and women improved significantly with respect to medical outcomes (blood pressure, lipids, weight, exercise conditioning, frequency of symptoms of chest pain and shortness of breath) and psychological outcomes (general severity index, depression, anxiety, and hostility) (P<.0001). Patients considered "at higher risk" for cardiac events due to high baseline measures improved their measures to a less than "at higher risk" level. Data indicate that specific components of the intervention, that is, increased relaxation response practice and exercise, significantly contributed to these improvements (P<.05). Furthermore, age and gender differences, particularly for psychological measures, were found; younger patients and female patients had greater improvements than older patients and male patients. CONCLUSIONS: This study provides preliminary data for a subsequent randomized control trial to test mind/body-based interventions to determine the most effective outcomes at an affordable cost. C1 [Casey, Aggie; Chang, Bei-Hung; Huddleston, James; Virani, Narmin; Benson, Herbert; Dusek, Jeffery A.] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Chestnut Hill, MA 02467 USA. [Dusek, Jeffery A.] Abbott NW Hosp, Inst Hlth & Healing, Minneapolis, MN 55407 USA. RP Casey, A (reprint author), Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, 824 Boylston St, Chestnut Hill, MA 02467 USA. EM acasey3@partners.org FU Center for Disease Control and Prevention [H75/CCH119124-05, 5 R01 DP000339] FX The authors thank Yue Zhao, MS, for performing the data analyses. They also thank Sarab Lynch for her secretarial assistance. The study was partially funded by the Center for Disease Control and Prevention (grant nos. H75/CCH119124-05 and 5 R01 DP000339). NR 30 TC 15 Z9 15 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-7501 J9 J CARDIOPULM REHABIL JI J. Cardiopulm. Rehabil. Prev. PD JUL-AUG PY 2009 VL 29 IS 4 BP 230 EP 238 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 479WB UT WOS:000268691300003 PM 19451830 ER PT J AU Bian, ZY Cai, J Shen, DF Chen, L Yan, L Tang, QZ Li, HL AF Bian, Zhouyan Cai, Jun Shen, Di-fei Chen, Li Yan, Ling Tang, Qizhu Li, Hongliang TI Cellular repressor of E1A-stimulated genes attenuates cardiac hypertrophy and fibrosis SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE CREG; cardiac remodelling; ERK1; 2; fibrosis ID LEFT-VENTRICULAR FUNCTION; MYOCARDIAL-INFARCTION; ANGIOTENSIN-II; TRANSDUCTION PATHWAYS; REDOX REGULATION; HEART; OVEREXPRESSION; TRANSFORMATION; EXPRESSION; DISEASE AB Cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein of 220 amino acids. It has been proposed that CREG acts as a ligand that enhances differentiation and/or reduces cell proliferation. CREG has been shown previously to attenuate cardiac hypertrophy in vitro. However, such a role has not been determined in vivo. In the present study, we tested the hypothesis that overexpression of CREG in the murine heart would protect against cardiac hypertrophy and fibrosis in vivo. The effects of constitutive human CREG expression on cardiac hypertrophy were investigated using both in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding and infusion of angiotensin II in CREG transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive over-expression of human CREG in the murine heart attenuated the hypertrophic response, markedly reduced inflammation. Cardiac function was also preserved in hearts with increased CREG levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase 1 (MEK-ERK1)/2-dependent signalling cascade. In addition, CREG expression blocked fibrosis and collagen synthesis through blocking MEK-ERK1/2-dependent Smad 2/3 activation in vitro and in vivo. Therefore, the expression of CREG improves cardiac functions and inhibits cardiac hypertrophy, inflammation and fibrosis through blocking MEK-ERK1/2-dependent signalling. C1 [Bian, Zhouyan; Shen, Di-fei; Yan, Ling; Tang, Qizhu; Li, Hongliang] Wuhan Univ, Cardiovasc Res Inst, Wuhan 430060, Peoples R China. [Bian, Zhouyan; Shen, Di-fei; Yan, Ling; Tang, Qizhu; Li, Hongliang] Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan 430060, Peoples R China. [Cai, Jun] Capital Med Univ, Beijing Chaoyang Hosp, Dept Cardiol, Beijing, Peoples R China. [Cai, Jun] Harvard Univ, Massachusettes Gen Hosp, Sch Med, Cardiovasc Res Ctr, Charlestown, MA USA. [Chen, Li] Texas A&M Univ, Baylor Coll Med, Ctr Mol Dev & Dis, Inst Biosci & Technol,Hlth Sci Ctr, Houston, TX USA. RP Tang, QZ (reprint author), Wuhan Univ, Cardiovasc Res Inst, JieFang Rd 238, Wuhan 430060, Peoples R China. EM qztang@whu.edu.cn; lihl@whu.edu.cn FU National Natural Science Foundation of China [30670216]; Higher Education of China [2007042086103] FX This work was supported by grants from National Natural Science Foundation of China (No. 30670216), and Research Fund for the Doctoral Program of Higher Education of China (no. 2007042086103) to Dr Qizhu Tang. NR 30 TC 27 Z9 30 U1 0 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD JUL PY 2009 VL 13 IS 7 BP 1302 EP 1313 DI 10.1111/j.1582-4934.2008.00633.x PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 478LG UT WOS:000268589200012 PM 19413895 ER PT J AU Lawson, EA Zhang, X Crocker, JT Wang, WL Klibanski, A AF Lawson, Elizabeth A. Zhang, Xun Crocker, Jonathan T. Wang, Wei-Lien Klibanski, Anne TI Hypoglycemia from IGF2 Overexpression Associated with Activation of Fetal Promoters and Loss of Imprinting in a Metastatic Hemangiopericytoma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-FACTOR-II; CELL TUMOR HYPOGLYCEMIA; HUMAN HEPATOCELLULAR-CARCINOMA; EPITHELIAL OVARIAN-CANCER; WILMS-TUMOR; ADRENOCORTICAL TUMORS; METHYLATION CHANGES; GENE-EXPRESSION; MESSENGER-RNA; H19 AB Context: The mechanism of IGF2 overexpression in non-islet-cell tumor hypoglycemia is not understood. Objective: We investigated the imprinting control and promoter usage for IGF2 expression to identify a mechanism for increased IGF-II production in non-islet-cell tumor hypoglycemia. Patient and Methods: A patient with metastatic hemangiopericytoma was studied. Tissue from the original hemangiopericytoma, metastatic tumor, and uninvolved liver was analyzed for IGF-II immunohistochemistry. IGF2, a paternally imprinted gene, shares a control region with maternally imprinted H19, a putative tumor suppressor. IGF-II and H19 mRNA expression was compared in metastatic tumor and uninvolved liver by quantitative RT-PCR. Imprinting of IGF2/H19 genes and IGF2 promoter usage in metastatic tumor was investigated by RT-PCR and sequence analysis, and the methylation pattern in the IGF2/H19 imprinting control region was analyzed. Results: IGF-II protein expression was increased in metastatic tumor vs. uninvolved liver and original tumor. In the metastatic tumor, IGF-II mRNA was increased 60-fold, but H19 mRNA was comparable to uninvolved liver; loss of imprinting of IGF2, but not H19, was identified; no major change in methylation of the IGF2/H19 imprinting control regions was observed; and transcripts from four different IGF2 promoters were detected, compared to two in uninvolved liver. Conclusions: IGF-2 overexpression, newly acquired in the metastatic tumor, was associated with loss of IGF2 gene imprinting and different promoter usage. The imprinting control mechanism governing the IGF2/H19 locus was intact, as evidenced by normal levels of H19, maintenance of H19 imprinting, and no major change in methylation of the imprinting control regions. (J Clin Endocrinol Metab 94: 2226-2231, 2009) C1 [Lawson, Elizabeth A.; Zhang, Xun; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Crocker, Jonathan T.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wang, Wei-Lien] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM aklibanski@partners.org NR 39 TC 10 Z9 11 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2226 EP 2231 DI 10.1210/jc.2009-0153 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500003 PM 19383775 ER PT J AU Klibanski, A AF Klibanski, Anne TI Dopamine Agonist Therapy in Prolactinomas: When Can Treatment Be Discontinued? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID LONG-TERM THERAPY; CARDIAC-VALVE REGURGITATION; CABERGOLINE THERAPY; FOLLOW-UP; DRUG-WITHDRAWAL; HYPERPROLACTINEMIA; BROMOCRIPTINE; RISK; MICROPROLACTINOMAS; REMISSION C1 [Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457,55 Fruit St, Boston, MA 02114 USA. EM aklibanski@partners.org NR 22 TC 8 Z9 9 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2247 EP 2249 DI 10.1210/jc.2009-0999 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500007 PM 19584197 ER PT J AU Wexler, T Gunnell, L Omer, Z Kuhlthau, K Beauregard, C Graham, G Utz, AL Biller, B Nachtigall, L Loeffler, J Swearingen, B Klibanski, A Miller, KK AF Wexler, Tamara Gunnell, Lindsay Omer, Zehra Kuhlthau, Karen Beauregard, Catherine Graham, Gwenda Utz, Andrea L. Biller, Beverly Nachtigall, Lisa Loeffler, Jay Swearingen, Brooke Klibanski, Anne Miller, Karen K. TI Growth Hormone Deficiency Is Associated with Decreased Quality of Life in Patients with Prior Acromegaly SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADULT GH DEFICIENCY; BODY-MASS INDEX; MAJOR DEPRESSIVE DISORDER; HYPOPITUITARY PATIENTS; FOLLOW-UP; SYMPTOM QUESTIONNAIRE; FLUOXETINE TREATMENT; REPLACEMENT THERAPY; PLUS ARGININE; QOL-AGHDA AB Context: Both GH deficiency (GHD) and GH excess are associated with a decreased quality of life. However, it is unknown whether patients with GHD after treatment for acromegaly have a poorer quality of life than those with normal GH levels after cure of acromegaly. Objective: The aim of the study was to determine whether patients with GHD and prior acromegaly have a poorer quality of life than those with GH sufficiency after cure of acromegaly. Design and Setting: We conducted a cross-sectional study in a General Clinical Research Center. Study Participants: Forty-five patients with prior acromegaly participated: 26 with GHD and 19 with GH sufficiency. Intervention: There were no interventions. Main Outcome Measures: We evaluated quality of life, as measured by 1) the Quality of Life Adult Growth Hormone Deficiency Assessment (QoL-AGHDA); 2) the Short-Form Health Survey (SF-36); and 3) the Symptom Questionnaire. Results: Mean scores on all subscales of all questionnaires, except for the anger/hostility and anxiety subscales of the Symptom Questionnaire, showed significantly impaired quality of life in the GH-deficient group compared with the GH-sufficient group. Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores (R = -0.53; P = 0.0005) and the Symptom Questionnaire Depression subscale scores (R = -0.35; P = 0.031) and positively associated with most SF-36 subscale scores. Conclusions: Our data are the first to demonstrate a reduced quality of life in patients who develop GHD after cure of acromegaly compared to those who are GH sufficient. Further studies are warranted to determine whether GH replacement would improve quality of life for patients with GHD after cure from acromegaly. (J Clin Endocrinol Metab 94: 2471-2477, 2009) C1 [Wexler, Tamara; Gunnell, Lindsay; Omer, Zehra; Beauregard, Catherine; Graham, Gwenda; Utz, Andrea L.; Biller, Beverly; Nachtigall, Lisa; Klibanski, Anne; Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Kuhlthau, Karen] Massachusetts Gen Hosp, Ctr Pediat & Adolescent Hlth Policy, Dept Pediat, Boston, MA 02114 USA. [Loeffler, Jay] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Swearingen, Brooke] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Swearingen, Brooke] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM KKMiller@Partners.org FU National Institutes of Health [MO1 RB01066, UL1 RR025758]; Pfizer Inc.; Leo and Laurie Guthart FX Disclosure Summary: A. K. received funding for this investigator-initiated study from Pfizer Inc. B. B. consults for Pfizer Inc. Noother authors have any conflicts to declare. NR 54 TC 27 Z9 28 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2471 EP 2477 DI 10.1210/jc.2008-2671 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500041 PM 19366847 ER PT J AU Finkelstein, JS Wyland, JJ Leder, BZ Burnett-Bowie, SAM Lee, H Juppner, H Neer, RM AF Finkelstein, Joel S. Wyland, Jason J. Leder, Benjamin Z. Burnett-Bowie, Sherri-Ann M. Lee, Hang Jueppner, Harald Neer, Robert M. TI Effects of Teriparatide Retreatment in Osteoporotic Men and Women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HUMAN PARATHYROID-HORMONE; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; ESTROGEN-DEFICIENCY; OVARIECTOMIZED RATS; BIOCHEMICAL MARKERS; ALENDRONATE; THERAPY; TRIAL; MASS AB Context: The stimulatory effect of teriparatide on bone mineral density (BMD) and bone turnover is initially exuberant, but then diminishes. Objective: Our objective was to determine whether retreating with teriparatide after a drug-free period can restore the initial exuberant response to teriparatide. Design and Setting: This was a planned extension of a randomized controlled trial conducted in a single university hospital. Patients and Intervention: Subjects previously participated in a 30-month randomized trial comparing the effects of alendronate (group 1), teriparatide (group 2), or both (group 3) on BMD and bone turnover in men and women with low BMD (phase 1). Subjects who completed phase 1 on their assigned therapy entered phase 2 (months 30-42), during which teriparatide was stopped in groups 2 and 3. Teriparatide was administered to all subjects during months 42 to 54 (phase 3). Main Outcome Measures: We compared changes in BMD and markers of bone turnover (serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide) between phase 1 and 3 in subjects receiving teriparatide alone. Results: Posterior-anterior and lateral spine BMD increased 12.5 +/- 1.5 and 16.9 +/- 1.7%, respectively, during the first 12 months of teriparatide administration and 5.2 +/- 0.8 and 6.2 +/- 1.8%, respectively, during teriparatide retreatment (P < 0.001 and P = 0.001). Increases in osteocalcin (P < 0.001), N-terminal propeptide of type 1 collagen (P < 0.001), and N-telopeptide (P < 0.001) were greater during the first period of teriparatide administration. Conclusion: The response to teriparatide is attenuated when readministered after a 12-month hiatus. (J Clin Endocrinol Metab 94: 2495-2501, 2009) C1 [Finkelstein, Joel S.; Wyland, Jason J.; Leder, Benjamin Z.; Burnett-Bowie, Sherri-Ann M.; Lee, Hang; Neer, Robert M.] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Dept Pediat, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Finkelstein, JS (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Thier 1051,50 Blossom St, Boston, MA 02114 USA. EM jfinkelstein@partners.org OI Burnett-Bowie, Sherri-Ann/0000-0002-0064-096X FU National Institutes of Health [5 P50 AR44855, K24 DK02759, RR-1066] FX Disclosure Summary: The authors have nothing to declare. NR 31 TC 30 Z9 31 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2495 EP 2501 DI 10.1210/jc.2009-0154 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500045 PM 19401368 ER PT J AU Cusi, K AF Cusi, Kenneth TI Thiazolidinediones in NASH An Odd Couple Meant To Be? SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Editorial Material ID PLACEBO-CONTROLLED TRIAL; NONALCOHOLIC STEATOHEPATITIS; PIOGLITAZONE; ROSIGLITAZONE; THERAPY C1 [Cusi, Kenneth] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Diabet, San Antonio, TX 78284 USA. [Cusi, Kenneth] Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78284 USA. RP Cusi, K (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Diabet, Room 3-380S,7703 Floyd Curl Dr, San Antonio, TX 78284 USA. EM cusi@uthscsa.edu NR 16 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD JUL PY 2009 VL 43 IS 6 BP 503 EP 505 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 461LN UT WOS:000267268600001 PM 19384246 ER PT J AU Cortelli, SC Costa, FO Kawai, T Aquino, DR Franco, GCN Ohara, K Roman-Torres, CVG Cortelli, JR AF Cortelli, Sheila Cavalca Costa, Fernando Oliveira Kawai, Toshihisa Aquino, Davi Romeiro Nobre Franco, Gilson Cesar Ohara, Kazuhisa Goncalves Roman-Torres, Caio Vinicius Cortelli, Jose Roberto TI Diminished Treatment Response of Periodontally Diseased Patients Infected with the JP2 Clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID LOCALIZED AGGRESSIVE PERIODONTITIS; CONTROLLED CLINICAL-TRIAL; EARLY-ONSET PERIODONTITIS; JUVENILE PERIODONTITIS; PORPHYROMONAS-GINGIVALIS; LONGITUDINAL COHORT; SUBGINGIVAL PLAQUE; DENTAL PLAQUE; YOUNG-ADULTS; FOLLOW-UP AB This longitudinal study evaluated the response to periodontal treatment by subjects infected with either JP2 (n = 25) or non-JP2 (n = 25) Aggregatibacter (Actinobacillus) actinomycetemcomitans. Participants were treated during the first 4 months by receiving (i) scaling and root planing, (ii) systemic antibiotic therapy, and (iii) periodontal surgery. Probing depth (PD), clinical attachment level (CAL), and gingival and plaque indices (GI and PI, respectively) were monitored at baseline and at 12 months, along with DNA-PCR-based subgingival detection of JP2 or non-JP2 A. actinomycetemcomitans. At baseline, PD, CAL, and GI scores were statistically higher in the JP2 strain-positive group than the non-JP2-strain-positive group. At 12 months, PD, CAL, and GI scores had decreased significantly for both groups, but the reduction rates of PD and CAL were higher in the non-JP2-strain-positive group. Among JP2-strain-positive patients in the baseline, patients who remained JP2 strain positive at 12 months showed significantly higher GIs than did the patients who had lost the detectable JP2 clone. Patients who remained JP2 strain positive at 12 months appeared to be more resistant to mechanical-chemical therapy than did those who were still non-JP2 strain positive, while the elimination of JP2 A. actinomycetemcomitans remarkably diminished gingival inflammation. Early identification and elimination of the JP2 clone of A. actinomycetemcomitans will enable practitioners to effectively predict the outcome of treatments applied to periodontal patients. C1 [Cortelli, Sheila Cavalca; Aquino, Davi Romeiro; Goncalves Roman-Torres, Caio Vinicius; Cortelli, Jose Roberto] Univ Taubate, Dent Res Div, Dept Periodontol, Taubate, SP, Brazil. [Costa, Fernando Oliveira] Univ Fed Minas Gerais, Dent Res Div, Dept Periodontol, Belo Horizonte, MG, Brazil. [Kawai, Toshihisa; Ohara, Kazuhisa] Forsyth Inst, Dept Immunol, Boston, MA USA. [Nobre Franco, Gilson Cesar] Univ Taubate, Dept Oral Biol, Dent Res Div, Taubate, SP, Brazil. RP Cortelli, SC (reprint author), Rua Prof Nelson Freire Campelo,343 Jardim Eulalia, BR-12010700 Sao Paulo, Brazil. EM cavalcacortelli@uol.com.br RI Franco, Gilson/F-9312-2012 FU NIDCR [DE18310, DE18499] FX Support for this study was provided by grants DE18310 and DE18499 from NIDCR. NR 45 TC 18 Z9 18 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUL PY 2009 VL 47 IS 7 BP 2018 EP 2025 DI 10.1128/JCM.00338-09 PG 8 WC Microbiology SC Microbiology GA 467CC UT WOS:000267713000005 PM 19458180 ER PT J AU Demetri, GD Wang, YF Wehrle, E Racine, A Nikolova, Z Blanke, CD Joensuu, H von Mehren, M AF Demetri, George D. Wang, Yanfeng Wehrle, Elisabeth Racine, Amy Nikolova, Zariana Blanke, Charles D. Joensuu, Heikki von Mehren, Margaret TI Imatinib Plasma Levels Are Correlated With Clinical Benefit in Patients With Unresectable/Metastatic Gastrointestinal Stromal Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 30-JUN 03, 2008 CL Chicago, IL SP Amer Soc Clin Oncol ID CHRONIC MYELOID-LEUKEMIA; DOSE IMATINIB; POPULATION PHARMACOKINETICS; MAIN METABOLITE; PHASE-I; MESYLATE; SAFETY; TRIAL; PHARMACODYNAMICS; GLYCOPROTEIN AB Purpose To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship between IM plasma levels and long-term clinical outcomes. Patients and Methods Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (C(min)). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels at SS. The median TTP was 11.3 months for patients in the lowest C(min) quartile (Q1, < 1,110 ng/mL) compared with more than 30 months for Q2 to Q4 (P = .0029). OOBR was also inferior in Q1 patients. In patients with GIST with KIT exon 11 mutations (n = 39), the OOBR was 67% for Q1 patients versus 100% for all others (P = .001). Conclusion In patients with advanced GIST, IM trough levels at SS were associated with clinical benefit. Patients with IM C(min) below 1,100 ng/mL showed a shorter TTP and lower rate of clinical benefit (OOBR). Further studies are justified to test whether monitoring IM plasma levels might optimize clinical outcomes for patients with GIST. C1 [Demetri, George D.] Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Novartis Pharmaceut, Oncol Business Unit, Florham Pk, NJ USA. Novartis Pharmaceut AG, Oncol Business Unit & Biostat, Basel, Switzerland. Univ British Columbia, British Columbia Canc Agcy, Vancouver, BC V5Z 1M9, Canada. Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Ludwig Ctr, D1212,44 Binney St, Boston, MA 02115 USA. EM gdemetri@partners.org OI Joensuu, Heikki/0000-0003-0281-2507 NR 27 TC 155 Z9 166 U1 1 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 JUL 1 PY 2009 VL 27 IS 19 BP 3141 EP 3147 DI 10.1200/JCO.2008.20.4818 PG 7 WC Oncology SC Oncology GA 463TD UT WOS:000267454100014 PM 19451435 ER PT J AU George, S Merriam, P Maki, RG Van den Abbeele, AD Yap, JT Akhurst, T Harmon, DC Bhuchar, G O'Mara, MM D'Adamo, DR Morgan, J Schwartz, GK Wagner, AJ Butrynski, JE Demetri, GD Keohan, ML AF George, Suzanne Merriam, Priscilla Maki, Robert G. Van den Abbeele, Annick D. Yap, Jeffrey T. Akhurst, Timothy Harmon, David C. Bhuchar, Gauri O'Mara, Margaret M. D'Adamo, David R. Morgan, Jeffrey Schwartz, Gary K. Wagner, Andrew J. Butrynski, James E. Demetri, George D. Keohan, Mary L. TI Multicenter Phase II Trial of Sunitinib in the Treatment of Nongastrointestinal Stromal Tumor Sarcomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 30-JUN 03, 2008 CL Chicago, IL SP Amer Soc Clin Oncol ID RENAL-CELL CARCINOMA; POSITRON-EMISSION-TOMOGRAPHY; TYROSINE KINASE INHIBITOR; IMATINIB MESYLATE; DERMATOFIBROSARCOMA PROTUBERANS; AGGRESSIVE FIBROMATOSIS; EFFICACY; RECOMMENDATIONS; THERAPY; TARGETS AB Purpose To evaluate the potential benefit of continuous daily dosing sunitinib in patients with advanced nongastrointestinal stromal tumor (GIST) sarcomas. Patients and Methods A total of 53 patients with advanced non-GIST soft tissue sarcomas received sunitinib 37.5 mg daily. Primary end point was Response Evaluation Criteria in Solid Tumors defined response. Secondary end points were stable disease at 16 and 24 weeks. [(18)F]-fluorodeoxyglucose positron emission tomography was performed on a subset of 24 patients at baseline and after 10 to 14 days of therapy. Results Forty-eight patients were eligible for response. One patient (desmoplastic round cell tumor [DSRCT]) achieved a confirmed partial response (PR) and remained on study for 56 weeks. Ten patients (20%) achieved stable disease for at least 16 weeks. Metabolic PR was seen in 10 (47%) of 21 of patients. Metabolic stable disease was seen in 11 (52%) of 21. There were no unexpected toxicities observed. Conclusion Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma. The relevance of disease control observed in subtypes with an indolent natural history is unknown, however, the durable disease control observed in DSRCT, solitary fibrous tumor, and giant cell tumor of bone suggests that future evaluation of sunitinib in these subtypes may be warranted. C1 [George, Suzanne] Massachusetts Gen Hosp, Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr,Ludwig Ctr, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP George, S (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr,Ludwig Ctr, 44 Binney St,D1210, Boston, MA 02115 USA. EM suzanne_george@dfci.harvard.edu FU NCI NIH HHS [P01 CA047179] NR 40 TC 140 Z9 149 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2009 VL 27 IS 19 BP 3154 EP 3160 DI 10.1200/JCO.2008.20.9890 PG 7 WC Oncology SC Oncology GA 463TD UT WOS:000267454100016 PM 19451429 ER PT J AU Visvanathan, K Chlebowski, RT Hurley, P Col, NF Ropka, M Collyar, D Morrow, M Runowicz, C Pritchard, KI Hagerty, K Arun, B Garber, J Vogel, VG Wade, JL Brown, P Cuzick, J Kramer, BS Lippman, SM AF Visvanathan, Kala Chlebowski, Rowan T. Hurley, Patricia Col, Nananda F. Ropka, Mary Collyar, Deborah Morrow, Monica Runowicz, Carolyn Pritchard, Kathleen I. Hagerty, Karen Arun, Banu Garber, Judy Vogel, Victor G. Wade, James L. Brown, Powel Cuzick, Jack Kramer, Barnett S. Lippman, Scott M. TI American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID SURGICAL ADJUVANT BREAST; BOWEL PROJECT P-1; CONTINUING OUTCOMES RELEVANT; ITALIAN RANDOMIZED-TRIAL; NEGATIVE MAMMARY-TUMORS; BONE-MINERAL DENSITY; LOW-DOSE TAMOXIFEN; QUALITY-OF-LIFE; POSTMENOPAUSAL WOMEN; PREVENTION TRIAL AB Purpose To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. Methods A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER)-positive invasive tumors. Women <= 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making. J Clin Oncol 27: 3235-3258. (C) 2009 by American Society of Clinical Oncology C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Harbor UCLA Med Ctr, Los Angeles, CA USA. Patient Advocates Res, Danville, CA USA. [Visvanathan, Kala] Amer Soc Clin Oncol, Canc Policy & Clin Affairs, Alexandria, VA 22314 USA. Maine Med Ctr, Portland, ME 04102 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Neag Comprehens Canc Ctr, Farmington, CT USA. Univ Texas MD Anderson Canc Ctr, Baylor Coll Med, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Amer Canc Soc, Atlanta, GA 30329 USA. Canc Care Specialists Cent Illinois, Decatur, GA USA. Canc Res UK, London, England. NIH, Bethesda, MD 20892 USA. RP Visvanathan, K (reprint author), Amer Soc Clin Oncol, Canc Policy & Clin Affairs, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org RI Pritchard, Kathleen/I-2184-2014 OI Pritchard, Kathleen/0000-0003-0758-9666 NR 127 TC 145 Z9 148 U1 2 U2 13 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 JUL 1 PY 2009 VL 27 IS 19 BP 3235 EP 3258 DI 10.1200/JCO.2008.20.5179 PG 24 WC Oncology SC Oncology GA 463TD UT WOS:000267454100027 PM 19470930 ER PT J AU Han, TH Greenblatt, DJ Martyn, JAJ AF Han, Tae-Hyung Greenblatt, David J. Martyn, J. A. Jeevendra TI Propofol Clearance and Volume of Distribution Are Increased in Patients With Major Burns SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Anesthesiologists CY OCT 14-18, 2006 CL Chicago, IL SP Amer Soc Anesthesiologists DE Cardiac index; hepatic blood flow; hypnotics; pharmacokinetics ID CARDIAC-OUTPUT; THERMAL-INJURY; PHARMACOKINETICS; INFUSION; CHILDREN; SHOCK; PHARMACODYNAMICS; CIMETIDINE; PLASMA; MODEL AB Propofol pharmacokinetics were examined in 17 adults with major burns during the hyperdynamic convalescent phase. Eighteen nonburned surgical patients served as controls. After a 2-mg/kg intravenous dose of propofol, blood samples were collected at multiple time points. Noncompartmental methods were used to calculate the pharmacokinetic parameters. The following indices were higher in burns than controls: propofol clearance (64 +/- 17 vs 29 +/- 4 mL/kg/min, P < .001) and volume of distribution (8 +/- 3 vs 4 +/- 1 L/kg, P < .001). The area under the curve was smaller in burns (556 +/- 152 vs 1193 +/- 183 mu g/mL h, P < .001). The higher clearance of propofol in burned patients may imply that these patients require higher doses or infusion rates of propofol to attain a target plasma concentration or pharmacodynamic effect. C1 [Han, Tae-Hyung] Univ Iowa, Hosp & Clin, Dept Anesthesia, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [Greenblatt, David J.] Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02111 USA. [Greenblatt, David J.] Tufts Med Ctr, Boston, MA USA. [Martyn, J. A. Jeevendra] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol & Crit Care, Boston, MA USA. [Martyn, J. A. Jeevendra] Shriners Hosp Children, Boston, MA USA. RP Han, TH (reprint author), Univ Iowa, Hosp & Clin, Dept Anesthesia, Roy J & Lucille A Carver Coll Med, 5937 JPP,200 Hawkins Dr, Iowa City, IA 52242 USA. EM anthony-han@uiowa.edu FU NIA NIH HHS [AG-17880]; NIGMS NIH HHS [GM 31569-22, R01 GM055082, GM 2500-30, GM 55082-9] NR 33 TC 6 Z9 6 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUL PY 2009 VL 49 IS 7 BP 768 EP 772 DI 10.1177/0091270009335767 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 462CL UT WOS:000267323500002 PM 19553403 ER PT J AU Shores, MM Kivlahan, DR Sadak, TI Li, EJ Matsumoto, AM AF Shores, Molly M. Kivlahan, Daniel R. Sadak, Tatiana I. Li, Ellen J. Matsumoto, Alvin M. TI A Randomized, Double-Blind, Placebo-Controlled Study of Testosterone Treatment in Hypogonadal Older Men With Subthreshold Depression (Dysthymia or Minor Depression) SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 6th World Congress on the Aging Male CY FEB 21-24, 2008 CL Tampa, FL ID NORMALIZES ANDROGEN LEVELS; CONTROLLED CLINICAL-TRIAL; PRIMARY-CARE PATIENTS; QUALITY-OF-LIFE; REPLACEMENT THERAPY; SEXUAL FUNCTION; MAJOR DEPRESSION; BODY-COMPOSITION; BIOAVAILABLE TESTOSTERONE; REFRACTORY DEPRESSION AB Objective: Hypogonadism and subthreshold depression are common conditions in elderly men. The objective of this study was to examine the effect of testosterone treatment in older, hypogonadal men with subthreshold depression. Method: A randomized, double-blind, placebo-controlled study was conducted at a university-affiliated Veterans Affairs Medical Center among men aged 50 years or older (N = 33) with screening total testosterone levels of <= 280 ng/dL and subthreshold depression (dysthymia or minor depression, according to DSM-IV). Recruitment for the study was conducted from November 2002 through May 2005. Participants received either 7.5 g of testosterone gel or placebo gel daily for 12 weeks, followed by a 12-week open-label extension phase during which all subjects received 7.5 g of testosterone gel. The primary outcome measure was the change in the Hamilton Rating Scale for Depression (HAM-D) score from baseline to the end of the double-blind phase. Secondary outcome measures were remission of subthreshold depression (defined a priori as a HAM-D score <= 7) and changes in the Hopkins Symptom Checklist depression scale, the Medical Outcomes Study 36-Item Short-Form Health Survey, and the short-form 16-item Quality of Life Enjoyment and Satisfaction Questionnaire. Results: At the end of the double-blind phase, testosterone-treated men had a greater reduction in HAM-D scores (p = .024) and a higher remission rate of subthreshold depression (52.9% vs. 18.8%, p = .041) than did placebo-treated men, but there were no differences in other secondary outcome measures between groups. At the end of the open-label phase, the testosterone group had sustained improvement, the control group improved, and there were no differences between groups in any outcome measures. Conclusion: These results suggest that testosterone replacement may be efficacious treatment for subthreshold depression in older men with hypogonadism. Larger studies are needed to corroborate these findings. C1 [Shores, Molly M.; Matsumoto, Alvin M.] VA Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. [Kivlahan, Daniel R.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98108 USA. [Shores, Molly M.; Kivlahan, Daniel R.; Li, Ellen J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Sadak, Tatiana I.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Matsumoto, Alvin M.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. RP Shores, MM (reprint author), VA Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, 1660 S Columbian Way,S-182GRECC, Seattle, WA 98108 USA. EM mxs@u.washington.edu NR 66 TC 54 Z9 58 U1 2 U2 6 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2009 VL 70 IS 7 BP 1009 EP 1016 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 477KV UT WOS:000268518900010 PM 19653976 ER PT J AU Alexander, MP Stuss, D Gillingham, S AF Alexander, Michael P. Stuss, Donald Gillingham, Susan TI Impaired List Learning Is Not a General Property of Frontal Lesions SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID EPISODIC MEMORY RETRIEVAL; PREFRONTAL CORTEX AREA-10; LONG-TERM-MEMORY; LOBE DAMAGE; MONITORING HYPOTHESIS; FALSE RECOGNITION; TEMPORAL-LOBE; ANTERIOR; RECALL; DISTURBANCES AB Background: List-learning tasks are frequently used to provide measures of "executive functions'' that are believed necessary for successful memory performance. Small sample sizes, confounding anomia, and incomplete representation of all frontal regions have prevented consistent demonstration of distinct regional frontal effects on this task. Objective: To confirm specific effects of lesions in different frontal regions. Subjects: Forty-one patients with chronic focal frontal lesions and 38 control subjects. There were no group differences in naming scores. Methods: Two word lists were presented, one with unblocked words from related categories and one in a preblocked format. Standard measures of learning, recall, recognition, and strategies were obtained, first for the frontal group as a whole and then for large but defined frontal regions. For all measures with significant group differences, a lesion "hotspotting'' method identified possible specific regional injury effects. Results: The frontal group was impaired on almost all measures, but impairments on most measures were particularly identified with lesions in the left superior frontal lobe (approximately area 9s) and some deficits in learning processes were surprisingly more prominent on the blocked list. Conclusion: Difficulty with list learning is not a general property of all frontal lesions. Lesions in different frontal regions impair list learning through specific mechanisms, and these effects may be modified by manipulations of the task structure. C1 [Alexander, Michael P.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Stuss, Donald; Gillingham, Susan] Baycrest Hosp, Toronto, ON, Canada. RP Alexander, MP (reprint author), Beth Israel Deaconess Med Ctr, BNU 253,BIDMC,330 Brookline Ave, Boston, MA 02215 USA. EM michaelalexander1@mac.com NR 48 TC 15 Z9 15 U1 1 U2 8 PU M I T PRESS PI CAMBRIDGE PA 238 MAIN STREET, STE 500, CAMBRIDGE, MA 02142-1046 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD JUL PY 2009 VL 21 IS 7 BP 1422 EP 1434 DI 10.1162/jocn.2009.21094 PG 13 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 458KS UT WOS:000267019400015 PM 18752408 ER PT J AU Petralia, G Preda, L Giugliano, G Jereczek-Fossa, BA Rocca, A D'Andrea, G Holalkere, NS Chiesa, F Bellomi, M AF Petralia, Giuseppe Preda, Lorenzo Giugliano, Gioacchino Jereczek-Fossa, Barbara A. Rocca, Andrea D'Andrea, Gabriele Holalkere, Nagaraj Setty Chiesa, Fausto Bellomi, Massimo TI Perfusion Computed Tomography for Monitoring Induction Chemotherapy in Patients With Squamous Cell Carcinoma of the Upper Aerodigestive Tract: Correlation Between Changes in Tumor Perfusion and Tumor Volume SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE perfusion CT; chemotherapy; monitoring; tumor volume; upper aerodigestive tract ID NECK-CANCER; QUANTITATIVE MEASUREMENTS; TREATMENT RESPONSE; RECTAL-CANCER; HEAD; CT; OROPHARYNGEAL; PERMEABILITY; RADIOTHERAPY; PROTOCOL AB Objective: The aim of this study was to assess the potential of perfusion computed tomography (CTp) for monitoring induction chemotherapy in patients with squamous cell carcinoma (SCCA) of the upper aerodigestive tract. Materials and Methods: Twenty-five patients with advanced SCCA underwent CTp and volumetric CT before and after induction chemotherapy Perfusion CT parameters were calculated in the tumor, normal tissue, and muscles and correlated with tumor volume. Results: The blood flow (BF), blood volume (BV), and permeability surface were significantly higher, and the mean transit time was significantly lower in the tumor than in the normal tissue. The tumor BF and BV significantly decreased, and the mean transit time significantly increased after the therapy; decrease in B F and BV correlated with tumor volume reduction after chemotherapy. The baseline tumor BV was significantly lower in nonresponders compared with that in responders. Conclusions: In patients with SCCA, CTp showed potential for monitoring induction chemotherapy, reduction in tumor BF and BV correlated with reduction of turner volume after chemotherapy, and baseline tumor BV may predict response to chemotherapy. C1 [Petralia, Giuseppe; Preda, Lorenzo; Bellomi, Massimo] European Inst Oncol, Dept Radiol, I-20141 Milan, Italy. [Giugliano, Gioacchino; Chiesa, Fausto] European Inst Oncol, Dept Head & Neck Surg, I-20141 Milan, Italy. [Jereczek-Fossa, Barbara A.] European Inst Oncol, Dept Radiotherapy, I-20141 Milan, Italy. [Rocca, Andrea] European Inst Oncol, Dept Med Oncol, Res Med Senol Unit, I-20141 Milan, Italy. [Jereczek-Fossa, Barbara A.; D'Andrea, Gabriele; Bellomi, Massimo] Univ Milan, Sch Med, Milan, Italy. [Holalkere, Nagaraj Setty] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Petralia, G (reprint author), European Inst Oncol, Dept Radiol, 435 Via Ripamonti, I-20141 Milan, Italy. EM giuseppe.petralia@ieo.it OI PREDA, LORENZO/0000-0002-5479-2766 NR 31 TC 30 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD JUL-AUG PY 2009 VL 33 IS 4 BP 552 EP 559 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 480AF UT WOS:000268703000012 PM 19638848 ER PT J AU Xia, Y Schneyer, AL AF Xia, Yin Schneyer, Alan L. TI The biology of activin: recent advances in structure, regulation and function SO JOURNAL OF ENDOCRINOLOGY LA English DT Review ID EMBRYONIC STEM-CELLS; HORMONE BETA-SUBUNIT; GONADOTROPIN-RELEASING-HORMONE; FOLLISTATIN-RELATED PROTEIN; FIBROBLAST-GROWTH-FACTOR; RAT PANCREATIC-ISLETS; GENE-EXPRESSION; SERTOLI-CELLS; IN-VITRO; INSULIN-SECRETION AB Activin was discovered in the 1980s as a gonadal protein that stimulated FSH release front pituitary gonadotropes and was thought of as a reproductive hormone. In the ensuing decades, many additional activities of activin were described and it was found to be produced in a wide variety of cell types at nearly all stages of development. Its signaling and actions are regulated intracellularly and by extracellular antagonists. Over the past 5 years, a number of important advances have been made that clarify our understanding of the structural basis for signaling and regulation, as well as the biological roles of activin in stern cells, embryonic development and in adults. These include the crystallization of activin in complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3, as well as identification of activin's roles in gonadal sex development, follicle development, luteolysis, beta-cell proliferation and function in the islet, stem cell pluripotency and differentiation into different cell types and in immune cells. These advances are reviewed to provide perspective for future studies. journal of Endocrinology (2009) 202, 1-12 C1 [Schneyer, Alan L.] Pioneer Valley Life Sci Inst, Springfield, MA 01107 USA. [Xia, Yin] Harvard Univ, Sch Med, Program Membrane Biol, Boston, MA 02114 USA. [Xia, Yin] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Nephrol,Ctr Syst Biol, Boston, MA 02114 USA. [Schneyer, Alan L.] Univ Massachusetts Amherst, Springfield, MA 01107 USA. RP Schneyer, AL (reprint author), Pioneer Valley Life Sci Inst, 3601 Main St, Springfield, MA 01107 USA. EM alan.schneyer@bhs.org FU NIH [R01DK075058] FX This work was supported in part by the NIH (R01DK075058) to A L S. NR 153 TC 122 Z9 127 U1 0 U2 10 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD JUL PY 2009 VL 202 IS 1 BP 1 EP 12 DI 10.1677/JOE-08-0549 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530YS UT WOS:000272629500001 PM 19273500 ER PT J AU Brooks, WW Cicogna, AC Conrad, CH Robinson, KG Sen, S Bing, OHL AF Brooks, Wesley W. Cicogna, Antonio C. Conrad, Chester H. Robinson, Kathleen G. Sen, Subha Bing, Oscar H. L. TI Thyroid State and Tolerance of Mammalian Myocardium to Hypoxia SO JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-ECOLOGICAL GENETICS AND PHYSIOLOGY LA English DT Article ID RAT-HEART; CARDIAC GLYCOGEN; ENERGY-METABOLISM; MUSCLE; THYROXINE; GLUCOSE; MYOSIN; HYPERTROPHY; EXPRESSION; HORMONE AB Thyroid hormone is known to affect myocardial glycogen stores and thereby possibly limit anaerobic performance of mammalian cardiac muscle. Thyroid hormone administration (3,5,T-triiodo-L-thyroxine, 300 mu g/kg/day, sc) for 10 days decreased left ventricle (LV) glycogen concentration relative to euthyroid animals (2.78 +/- 0.46 vs. 4.28 +/- 0.29 mg/g of LV (mean +/- SEM)) while increasing the percent of V(1) myosin isozyi-ne, contractile activity and cardiac mass. In contrast, thyroidectomy increased myocardial glycogen stores (8.50 +/- 0.56 mg/g of LV) and shifted the myosin isozyme toward V(3), prolonged contractile activity and decreased LV mass. Thyroxine administration for 3, 7 and 10 days to thyroidectomized animals progressively decreased contractile duration and increased LV mass. Thyroxine administration for 3 or 7 days to thyroidectomized rats did not reduce glycogen stores (7.75 +/- 1.02 and 9.62 +/- 1.16 mg/g of LV, respectively), whereas myocardial glycogen declined to 3.30 +/- 0.58 mg/g of LV after 10 days of treatment. During hypoxia, cardiac muscle from thyroidectomized rats maintained greater active force and developed less contracture relative to euthyroid and, to a greater extent, than hyperthyroid rats. Removal of glucose from the bath decreased anaerobic performance and impaired recovery; however, myocardium from thyroidectomized rats remained more tolerant to hypoxia than the euthyroid group. Overall, the intrinsic LV glycogen content was positively correlated to anaerobic performance. These data demonstrate that the thyroid state profoundly affects myocardial growth, contractility and anaerobic performance of rat myocardium. Although energy demand may affect function during hypoxia, anaerobic substrate reserve (cardiac glycogen concentration) appears to be the primary factor determining tolerance to hypoxic stress. J. Exp. Zool. 311A:399-407, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Brooks, Wesley W.] Boston Univ, Sch Med, VA Boston Healthcare Syst, Res Serv 151, Boston, MA 02130 USA. [Cicogna, Antonio C.] Univ Estadual Paulista, Fac Med Botucatu, Dept Cardiol, Sao Paulo, Brazil. [Sen, Subha] Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA. RP Brooks, WW (reprint author), Boston Univ, Sch Med, VA Boston Healthcare Syst, Res Serv 151, 150 S Huntington Ave, Boston, MA 02130 USA. EM brooksww@bu.edu FU Department of Veterans Affairs FX This study was supported in part by Medical Research Funds from the Department of Veterans Affairs. NR 33 TC 1 Z9 1 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1932-5223 J9 J EXP ZOOL PART A JI J. Exp. Zool. Part A PD JUL 1 PY 2009 VL 311A IS 6 BP 399 EP 407 DI 10.1002/jez.537 PG 9 WC Zoology SC Zoology GA 473VX UT WOS:000268240000002 PM 19415714 ER PT J AU Kim, TH Moon, JH Savard, CE Kuver, R Lee, SP AF Kim, Tae-Hyeon Moon, Jong Ho Savard, Christopher E. Kuver, Rahul Lee, Sum P. TI Effects of lipopolysaccharide on platelet-derived growth factor isoform and receptor expression in cultured rat common bile duct fibroblasts and cholangiocytes SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE cholangitis; extrahepatic biliary system; fibrosis ID GALLBLADDER EPITHELIAL-CELLS; PACLITAXEL-INCORPORATED MEMBRANE; CHOLESTATIC LIVER-INJURY; HEPATIC STELLATE CELLS; PDGF-BETA-RECEPTOR; LONG-TERM CULTURE; OBSTRUCTIVE-JAUNDICE; BILIARY FIBROSIS; ALPHA; HEPATOLITHIASIS AB Background and Aim: Little is known about the role of platelet-derived growth factor (PDGF) in biliary fibrosis in the setting of bacterial colonization of the biliary tree. We therefore sought to investigate whether exposure to bacterial lipopolysaccharide (LPS) alters PDGF isoform and receptor expression in cultured rat common bile duct fibroblasts (CBDF) and normal rat cholangiocytes (NRC). Methods: Collagen content in cells and media was assessed by colorimetric assay and gel electrophoresis. mRNA levels of PDGF-A and -B, and PDGF-Receptors (PDGF-R) alpha and beta were measured by relative quantitative real-time PCR. Protein levels of PDGF-AA, AB and BB were measured by ELISA, and PDGF-R alpha and PDGF-R beta by Western blot. Results: In CBDF, LPS increased total soluble collagen synthesis and secretion. PDGF-R alpha and beta mRNA and protein were also increased by LPS treatment in CBDF. Lipopolysaccharide treatment elicited an increase in PDGF-A and -B mRNA levels in CBDF. In NRC, levels of PDGF-A mRNA increased in a dose-dependent fashion following LPS treatment, whereas PDGF-B mRNA showed no response. PDGF-AA secretion was higher by CBDF than by NRC. PDGF-BB levels were also higher in CBDF than in NRC. While PDGF-BB levels did not respond to LPS treatment in CBDF, there was a dose-dependent response of this isoform to LPS in NRC. Intracellular and secreted PDGF-AB increased with LPS treatment in NRC. Conclusions: These results support a model in which chronic bacterial colonization of the biliary tree induces fibrosis through PDGF-dependent mechanisms. C1 [Kuver, Rahul] Univ Washington, Sch Med, Dept Med, Div Gastroenterol, Seattle, WA 98195 USA. [Kim, Tae-Hyeon; Moon, Jong Ho; Savard, Christopher E.; Kuver, Rahul] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA USA. [Lee, Sum P.] Univ Hong Kong, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. RP Kuver, R (reprint author), Univ Washington, Sch Med, Dept Med, Div Gastroenterol, Box 356424,1959 NE Pacific St, Seattle, WA 98195 USA. EM kuver@u.washington.edu RI Lee, Sum Ping/C-4333-2009 FU Merit Review Award from the Department of Veterans Affairs; Wonkwang Institute of Clinical Medicine, Iksan, South Korea FX We thank J. Donald Ostrow for critical reading of the manuscript. This work was supported by a Merit Review Award from the Department of Veterans Affairs. Dr. Tae-Hyeon Kim was supported by the Wonkwang Institute of Clinical Medicine, Iksan, South Korea. NR 27 TC 3 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD JUL PY 2009 VL 24 IS 7 BP 1218 EP 1225 DI 10.1111/j.1440-1746.2008.05729.x PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 476QH UT WOS:000268456900013 PM 19691150 ER PT J AU Levy, DE Garber, JE Shields, AE AF Levy, Douglas E. Garber, Judy E. Shields, Alexandra E. TI Guidelines for Genetic Risk Assessment of Hereditary Breast and Ovarian Cancer: Early Disagreements and Low Utilization SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE guidelines; genetic risk assessment; hereditary; breast cancer; ovarian cancer; BRCA1/2 testing ID PRIMARY-CARE; CLINICAL-PRACTICE; FAMILY-HISTORY; MUTATION CARRIERS; AMERICAN-SOCIETY; PHYSICIANS; SUSCEPTIBILITY; BRCA2; WOMEN; STATEMENT AB BRCA1/2 testing is one of the most well-established genetic tests to predict cancer risk. Guidelines are available to help clinicians determine who will benefit most from testing. To identify women at high risk of hereditary breast and ovarian cancer and estimate their awareness of and experience with genetic testing for cancer risk. Analyses of the 2000 and 2005 National Health Interview Surveys. Women with no personal history of breast or ovarian cancer (n = 35,116). Risk of hereditary breast or ovarian cancer based on self-reported family history of cancer and national guidelines; self-reported awareness of genetic testing for cancer risk; discussion of genetic testing for cancer risk with a health professional; having undergone genetic testing for breast/ovarian cancer risk. Using guideline criteria, 0.96% of women were identified as being at high risk of hereditary breast and ovarian cancer. Among high-risk women, 54.04% were aware of genetic testing for cancer risk, 10.39% had discussed genetic testing with a health professional, and 1.41% had undergone testing for breast/ovarian cancer risk. Adjusting for survey year, high-risk women were more likely than average-risk women to have heard of genetic testing for cancer risk (RR, 1.3, 95% CI 1.2-1.4), to have discussed genetic testing with a health professional (RR 5.2, 95% CI 3.6-7.4), and to have undergone genetic testing for breast/ovarian cancer risk (RR 6.8, 95% CI 2.6-18.0). We find low provision of guideline-recommended advice to women for whom testing may be appropriate and of significant clinical benefit. C1 [Levy, Douglas E.; Shields, Alexandra E.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Levy, Douglas E.; Shields, Alexandra E.] Harvard MGH Ctr Gen Vulnerable Populat & Hlth Dis, Boston, MA USA. [Levy, Douglas E.; Garber, Judy E.; Shields, Alexandra E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Garber, Judy E.] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. RP Levy, DE (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM dlevy3@partners.org FU Dana-Farber/Harvard Cancer Center FX This analysis was supported by a Nodal Award from the Dana-Farber/Harvard Cancer Center (A. Shields, PI). We appreciate the contributions of Emily Youatt and Richard Kwong in research assistance and manuscript preparation. NR 47 TC 19 Z9 19 U1 3 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2009 VL 24 IS 7 BP 822 EP 828 DI 10.1007/s11606-009-1009-6 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 457RB UT WOS:000266948900007 PM 19455369 ER PT J AU Kertesz, SG Hwang, SW Irwin, J Ritchey, FJ LaGory, ME AF Kertesz, Stefan G. Hwang, Stephen W. Irwin, Jay Ritchey, Ferris J. LaGory, Mark E. TI Rising Inability to Obtain Needed Health Care Among Homeless Persons in Birmingham, Alabama (1995-2005) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 31st Annual Meeting of the Society-of-General-Internal-Medicine CY APR 09-12, 2008 CL Pittsburgh, PA SP Soc Gen Internal Med DE homeless persons; access to care; safety net; survey ID SUBSTANCE-ABUSE SERVICES; SAFETY-NET PROVIDERS; MEDICAL-CARE; MENTAL-HEALTH; UNMET NEED; URBAN HOMELESS; LOS-ANGELES; NEW-YORK; DRUG-USE; ADULTS AB Homeless persons depend disproportionately on the health-care safety net for medical services. National reports identify financial strains to this safety net. Whether this has affected homeless persons is unknown. We quantified changes in the proportion of homeless persons reporting unmet need for health care in Birmingham, Alabama, comparing two periods, 1995 and 2005. We assessed whether a period effect was independent of characteristics of persons surveyed. Analysis of two surveys conducted with identical methods among representative samples of homeless persons in 1995 (n = 161) and 2005 (n = 161). Report of unmet need (inability to obtain care when needed) was the dependent variable. Two survey periods (1995 and 2005) were compared, with multivariable adjustment for sociodemographic and health characteristics. Reasons for unmet need were determined among the subset of persons reporting unmet need. Unmet need for health care was more common in 2005 (54%) than in 1995 (32%) (p < 0.0001), especially for non-Blacks (64%) and females (65%). Adjusting for individual characteristics, a survey year of 2005 independently predicted unmet need (odds ratio 2.68, 95% CI 1.49-4.83). Among persons reporting unmet need (87 of 161 in 2005; 52 of 161 in 1995), financial barriers were more commonly cited in 2005 (67% of 87) than in 1995 (42% of 52) (p = 0.01). A rise in unmet health-care needs was reported among Birmingham's homeless from 1995 to 2005. This period effect was independent of population characteristics and may implicate a local safety net inadequacy. Additional data are needed to determine if this represents a national trend. C1 [Kertesz, Stefan G.] Univ Alabama, Birmingham Vet Affairs Med Ctr, Ctr Surg Med Acute Care Res & Transit, Birmingham, AL 35294 USA. [Kertesz, Stefan G.] Univ Alabama, Div Prevent Med, Birmingham, AL USA. [Hwang, Stephen W.] St Michaels Hosp, Ctr Res Inner City Hlth, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Hwang, Stephen W.] Univ Toronto, Dept Med, Div Gen Internal Med, Toronto, ON, Canada. [Irwin, Jay; Ritchey, Ferris J.; LaGory, Mark E.] Univ Alabama, Dept Sociol, Birmingham, AL 35294 USA. RP Kertesz, SG (reprint author), Univ Alabama, Birmingham Vet Affairs Med Ctr, Ctr Surg Med Acute Care Res & Transit, Birmingham, AL 35294 USA. EM skertesz@uab.edu RI Hwang, Stephen/D-2297-2011; OI Hwang, Stephen/0000-0002-1276-1101; Kertesz, Stefan/0000-0001-6101-8421 FU NIDA NIH HHS [K23 DA015487, K23-DA-015487] NR 50 TC 10 Z9 10 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2009 VL 24 IS 7 BP 841 EP 847 DI 10.1007/s11606-009-0990-0 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 457RB UT WOS:000266948900010 PM 19415393 ER PT J AU Wharam, JF Paasche-Orlow, MK Farber, NJ Sinsky, C Rucker, L Rask, KJ Figaro, MK Braddock, C Barry, MJ Sulmasy, DP AF Wharam, J. Frank Paasche-Orlow, Michael K. Farber, Neil J. Sinsky, Christine Rucker, Lisa Rask, Kimberly J. Figaro, M. Kathleen Braddock, Clarence, III Barry, Michael J. Sulmasy, Daniel P. TI High Quality Care and Ethical Pay-for-Performance: A Society of General Internal Medicine Policy Analysis SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE ethics; health policy; pay-for-performance; quality improvement; physician reimbursement ID HEALTH-CARE; OF-CARE; INNOVATIVE SURGERY; IMPROVEMENT; PROFESSIONALISM; DEFINITION; OVERSIGHT; IMPACT; RISKS; RATES AB Pay-for-performance is proliferating, yet its impact on key stakeholders remains uncertain. The Society of General Internal Medicine systematically evaluated ethical issues raised by performance-based physician compensation. We conclude that current arrangements are based on fundamentally acceptable ethical principles, but are guided by an incomplete understanding of health-care quality. Furthermore, their implementation without evidence of safety and efficacy is ethically precarious because of potential risks to stakeholders, especially vulnerable patients. We propose four major strategies to transition from risky pay-for-performance systems to ethical performance-based physician compensation and high quality care. These include implementing safeguards within current pay-for-performance systems, reaching consensus regarding the obligations of key stakeholders in improving health-care quality, developing valid and comprehensive measures of health-care quality, and utilizing a cautious evaluative approach in creating the next generation of compensation systems that reward genuine quality. C1 [Wharam, J. Frank] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02114 USA. [Wharam, J. Frank] Harvard Pilgrim Hlth Care, Boston, MA 02114 USA. [Paasche-Orlow, Michael K.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Farber, Neil J.] Univ Calif San Diego, San Diego, CA 92103 USA. [Sinsky, Christine] Med Associates Clin & Hlth Plan, Dubuque, IA USA. [Rucker, Lisa] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Rask, Kimberly J.] Emory Univ, Dept Hlth Policy & Management, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Braddock, Clarence, III] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Barry, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Med Practices Evaluat Ctr,Gen Med Unit, Boston, MA 02114 USA. [Figaro, M. Kathleen] Vanderbilt Univ, Sch Med, Dept Gen Internal Med, Nashville, TN 37212 USA. [Sulmasy, Daniel P.] St Vincents Hosp, Manhattan, KS USA. [Sulmasy, Daniel P.] New York Med Coll, New York, NY USA. RP Wharam, JF (reprint author), Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, 133 Brookline Ave,6th Floor, Boston, MA 02114 USA. EM jwharam@partners.org RI rask, kimberly/M-8001-2016; OI Paasche-Orlow, Michael/0000-0002-9276-7190 NR 60 TC 20 Z9 20 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2009 VL 24 IS 7 BP 854 EP 859 DI 10.1007/s11606-009-0947-3 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 457RB UT WOS:000266948900012 PM 19294471 ER PT J AU Bradley, KA Kivlahan, DR Williams, EC AF Bradley, Katharine A. Kivlahan, Daniel R. Williams, Emily C. TI Brief Approaches to Alcohol Screening: Practical Alternatives for Primary Care SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID IDENTIFICATION TEST AUDIT; PROBLEM DRINKING; USE DISORDERS; RISK DRINKING; CONSUMPTION; QUESTIONNAIRE; VALIDATION; HEALTH; SCORES; MISUSE C1 [Bradley, Katharine A.; Kivlahan, Daniel R.; Williams, Emily C.] VA Puget Sound Hlth Care Syst, HSR&D, Seattle, WA 98101 USA. [Bradley, Katharine A.] VA Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle, WA 98101 USA. [Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Bradley, Katharine A.; Williams, Emily C.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Bradley, KA (reprint author), VA Puget Sound Hlth Care Syst, HSR&D, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM Katharine.bradley@va.gov NR 34 TC 30 Z9 30 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2009 VL 24 IS 7 BP 881 EP 883 DI 10.1007/s11606-009-1014-9 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 457RB UT WOS:000266948900017 PM 19495888 ER PT J AU Rubenstein, LV Rigotti, NA AF Rubenstein, Lisa V. Rigotti, Nancy A. TI The SGIM Policy Analysis: Supporting the Generalist Voice for Participation in Policymaking SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Rubenstein, Lisa V.] Vet Adm Greater Los Angeles, Dept Med, Los Angeles, CA USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Rubenstein, Lisa V.] RAND Corp, Santa Monica, CA USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. RP Rubenstein, LV (reprint author), VA Greater Angeles Sepulveda, 16111 Plummer St 152, North Hills, CA 91343 USA. EM Lisar@rand.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2009 VL 24 IS 7 BP 888 EP 889 DI 10.1007/s11606-009-1025-6 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 457RB UT WOS:000266948900019 PM 19499277 ER PT J AU Bishop, J Ring, D AF Bishop, Julius Ring, David TI Management of Radial Nerve Palsy Associated With Humeral Shaft Fracture: A Decision Analysis Model SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Decision analysis; fracture; humerus; nerve palsy; radial nerve ID VISUAL ANALOG SCALE; PARALYSIS; UTILITY; TENDON AB Purpose When managing radial nerve palsy associated with a humerus fracture, both surgeon and patient must balance the risks and benefits of performing an invasive surgical procedure to address a functional deficit that is likely, but not certain, to recover with nonsurgical management. The purpose of this study was to better understand the determinants of optimal management strategy using expected-value decision analysis. Methods Probabilities for the occurrences of the potential outcomes after initial observation or early surgery were determined from a systematic review of the literature. Scores for these outcomes were obtained from a questionnaire on patient preferences completed by 82 subjects without a history of humerus fracture and radial nerve palsy and used in the model as a measure of utility. A decision tree was constructed, fold-back analysis was performed to determine optimal treatment, and sensitivity analyses were used to determine the effect on decision making of varying outcome probabilities and utilities. Results Observation was associated with a value of 8.4 and early surgery a value of 6.7 given the outcome probabilities and utilities studied in this model, making observation the optimal management strategy. When parameters were varied in sensitivity analysis, it was noted that when the rate of recovery after initial observation falls below 40% or when the utility value for successful early surgery rises above 9.4, early surgery is the preferred management strategy. Conclusions Initial observation was the preferred strategy. In clinical settings in which the likelihood of spontaneous recovery of nerve function is low or when an informed patient has a strong preference for surgery, early surgery may optimize outcome. (J Hand Surg 2009;34A:991-996. (C) 2009 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand) C1 [Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org FU Small Bone Innovations; Smith and Nephew; Wright Medical; Tomier; Acumed FX Support was received from Small Bone Innovations, Smith and Nephew, Wright Medical, Tomier, and Acumed. NR 23 TC 16 Z9 18 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 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL-AUG PY 2009 VL 34A IS 6 BP 991 EP 996 DI 10.1016/j.jhsa.2008.12.029 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 478PH UT WOS:000268599700003 PM 19361935 ER PT J AU van Kollenburg, JAPAC Brouwer, KM Jupiter, JB Ring, D AF van Kollenburg, Johan A. P. A. C. Brouwer, Kim M. Jupiter, Jesse B. Ring, David TI Magnetic Resonance Imaging Signal Abnormalities in Enthesopathy of the Extensor Carpi Radialis Longus Origin SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Lateral epicondylosis; lateral collateral ligament; tear; magnetic resonance imaging ID LATERAL EPICONDYLITIS; ROTATOR-CUFF; SURGICAL-TREATMENT; TENNIS ELBOW; INSTABILITY; INJECTIONS AB Purpose Some surgeons use magnetic resonance imaging (MRI) findings in patients with enthesopathy of the extensor carpi radialis brevis (ECRB) origin (commonly referred to as lateral epicondylitis) to plan and justify surgical treatment. Overinterpretation of defects of the origin of the ECRB or associated abnormalities of the lateral collateral ligament (LCL) could affect decision-making. We tested the hypothesis that patients with MRI signal abnormalities consistent with enthesopathy of the ECRB are equally likely to have findings consistent with an ECRB defect or LCL abnormality whether they are being evaluated as part of preoperative planning for lateral elbow pain or for an elbow condition that does not feature lateral elbow pain. Methods For each of 24 consecutive patients with enthesopathy of the ECRB who had MRI for preoperative evaluation, we selected 2 age- and gender-matched controls from a list of patients who had an elbow MRI to evaluate other elbow problems. The origin of the ECRB and the LCL were specifically evaluated. Results Patients diagnosed with enthesopathy of the ECRB were significantly more likely than control patients to have signal changes consistent with enthesopathy of the ECRB origin (24 of 24 vs 9 of 48; p < .001). The proportion of patients with a partial thickness defect of the ECRB origin (14 of 24 vs 4 of 9) was comparable between patients diagnosed with enthesopathy of the ECRB origin and controls. Signal changes in the LCL were comparable in patients diagnosed with enthesopathy of the ECRB origin and control patients (8 of 24 vs 2 of 9; p = .27), and no patient had clinical evidence of instability. Conclusions Use of MRI in the management of patients with enthesopathy of the ECRB origin merits further study. (J Hand Surg 2009;34A:1094-1098. (C) 2009 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand) C1 [Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [van Kollenburg, Johan A. P. A. C.; Brouwer, Kim M.; Jupiter, Jesse B.; Ring, David] Harvard Univ, Sch Med, Boston, MA USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St,YAW2100, Boston, MA 02114 USA. EM dring@partners.org FU Small Bone Innovations; Wright Medical; Smith and Nephew; Acumed; Tomier FX Support was received from Small Bone Innovations, Wright Medical, Smith and Nephew, Acumed, and Tomier. NR 19 TC 9 Z9 9 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL-AUG PY 2009 VL 34A IS 6 BP 1094 EP 1098 DI 10.1016/j.jhsa.2009.02.023 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 478PH UT WOS:000268599700018 PM 19501476 ER PT J AU Watson, J Shin, R Zurakowski, D Ring, D AF Watson, Jeffrey Shin, Robert Zurakowski, David Ring, David TI A Survey Regarding Physician Recommendations Regarding Return to Work SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Motivation; pain; return to work ID CARPAL-TUNNEL RELEASE; LOW-BACK-PAIN; PERCUTANEOUS SCREW FIXATION; RANDOMIZED CONTROLLED-TRIAL; HEALTH-CARE PROVIDERS; TO-WORK; OCCUPATIONAL INJURY; SCAPHOID FRACTURES; ENDOSCOPIC RELEASE; DISABILITY AB Purpose Returning patients to work may be influenced by subjective factors and physician bias. The purpose of this study was to determine whether factors such as complaints of pain and patient motivation influence physicians' recommendations regarding return to work or activity. Methods One hundred twenty-five members of the American Society for Surgery of the Hand completed an online survey describing a 25-year-old patient with surgically treated diaphyseal fractures of the radius and ulna. Physicians were asked whether the patient could be returned to work in 4 distinct scenarios varying with occupation, time since injury, radiographic union, patient motivation, and pain. Results Logistic regression analysis demonstrated that all 5 predictor variables were highly significant predictors of return to work. Pain and diminished motivation were associated with a significantly lower probability of return to work. Conclusions Although in the scenario depicted, objective factors such as radiographic union and job demands are the major determinants of physician clearance to return to work, physicians are also influenced by patient motivation and complaints of pain. (J Hand Surg 2009;34A:1 111-1118. (C) 2009 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) C1 [Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Childrens Hosp, Dept Surg, Boston, MA 02115 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org FU AO Foundation; Wright Medical; Joint Active systems; Smithland Nephew; Small bone Innovations; Biomet; Acumed; Tomier; Doris Duke Fellowship FX Unrestricted research grants were received from AO Foundation, Wright Medical, Joint Active systems, Smithland Nephew, Small bone Innovations, Biomet, Acumed, Tomier, and the Doris Duke Fellowship. NR 48 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL-AUG PY 2009 VL 34A IS 6 BP 1111 EP 1118 DI 10.1016/j.jhsa.2009.02.030 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 478PH UT WOS:000268599700021 PM 19481359 ER PT J AU Baffy, G AF Baffy, Gyoergy TI Kupffer cells in non-alcoholic fatty liver disease: The emerging view SO JOURNAL OF HEPATOLOGY LA English DT Review DE Steatohepatitis; Macrophages; Toll-like receptors; Adiponectin; Uncoupling protein ID INDUCED INSULIN-RESISTANCE; TOLL-LIKE RECEPTORS; TNF-ALPHA PRODUCTION; NORMAL RAT-LIVER; UNCOUPLING PROTEIN-2; REACTIVE OXYGEN; NADPH OXIDASE; GADOLINIUM CHLORIDE; SCAVENGER RECEPTOR; INNATE IMMUNITY AB Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder of our times. Simple steatosis, a seemingly innocent manifestation of NAFLD, may progress into steatohepatitis and cirrhosis, but this process is not well understood. Since NAFLD is associated with obesity and insulin resistance, mechanisms that link lipid metabolism to inflammation offer insights into the pathogenesis. An important parallel between obesity-related pathology of adipose tissue and liver pertains to the emerging role of macrophages and evidence is growing that Kupffer cells critically contribute to progression of NAFLD. Toll-like receptors, in particular TLR4, represent a major conduit for danger recognition linked to Kupffer cell activation and this process may be perturbed at multiple steps in NAFLD. Steatosis may interfere with sinusoid microcirculation and hepatocellular clearance of microbial and host-derived danger signals, enhancing responsiveness of Kupffer cells. Altered lipid homeostasis in NAFLD may unfavourably affect TLR4 receptor complex assembly and sorting, interfere with signalling flux redistribution, promote amplification loops, and impair negative regulation including alternative activation of Kupffer cells. These events are further promoted by altered adipokine secretion and reactive oxygen species production. Specific targeting of these interactions may provide more effective strategies in the treatment of NAFLD. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Baffy, Gyoergy] Harvard Univ, Sch Med, Brigham & Womens Hosp, Gastroenterol Sect, Boston, MA 02130 USA. [Baffy, Gyoergy] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Gastroenterol Sect, Boston, MA 02130 USA. RP Baffy, G (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Gastroenterol Sect, 150 S Huntington Ave, Boston, MA 02130 USA. EM gbaffy@partners.org FU NIDDK NIH HHS [DK 61890, K08 DK061890, K08 DK061890-05] NR 159 TC 187 Z9 200 U1 4 U2 30 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD JUL PY 2009 VL 51 IS 1 BP 212 EP 223 DI 10.1016/j.jhep.2009.03.008 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 467CF UT WOS:000267713400023 PM 19447517 ER PT J AU Uemura, Y Liu, TY Narita, Y Suzuki, M Nakatsuka, R Araki, T Matsumoto, M Iwai, LK Hirosawa, N Matsuoka, Y Murakami, M Kimura, T Hase, M Kohno, H Sasaki, Y Ichihara, Y Ishihara, O Kikuchi, H Sakamoto, Y Jiao, SC Senju, S Sonoda, Y AF Uemura, Yasushi Liu, Tian-Yi Narita, Yayoi Suzuki, Motoharu Nakatsuka, Ryusuke Araki, Tomoyuki Matsumoto, Masahito Iwai, Leo Kei Hirosawa, Narumi Matsuoka, Yoshikazu Murakami, Mari Kimura, Takashi Hase, Makoto Kohno, Hirao Sasaki, Yutaka Ichihara, Yasuko Ishihara, Osamu Kikuchi, Hirosato Sakamoto, Yasushi Jiao, Shun-Chang Senju, Satoru Sonoda, Yoshiaki TI Cytokine-Dependent Modification of IL-12p70 and IL-23 Balance in Dendritic Cells by Ligand Activation of V alpha 24 Invariant NKT Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID KILLER T-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; NONOBESE DIABETIC MICE; GROWTH-FACTOR-BETA; ROR-GAMMA-T; ALPHA-GALACTOSYLCERAMIDE; DISTINCT SUBSETS; CUTTING EDGE; T(H)17 CELLS; IN-VIVO AB CD1d-restricted invariant NKT (iNKT) cells play crucial roles in various types of immune responses, including autoimmune diseases, infectious diseases and tumor surveillance. The mechanisms underlying their adjuvant functions are well understood. Nevertheless, although IL-4 and IL-10 production characterize iNKT cells able to prevent or ameliorate some autoimmune diseases and inflammatory conditions, the precise mechanisms by which iNKT cells exert immune regulatory function remain elusive. This study demonstrates that the activation of human iNKT cells by their specific ligand alpha-galactosylceramide enhances IL-12p70 while inhibiting the IL-23 production by monocyte-derived dendritic cells, and in turn down-regulating the IL-17 production by memory CD4(+) Th cells. The ability of the iNKT cells to regulate the differential production of IL-12p70/IL-23 is mainly mediated by a remarkable hallmark of their function to produce both Th1 and Th2 cytokines. In particular, the down-regulation of IL-23 is markedly associated with a production of IL-4 and IL-10 from iNKT cells. Moreover, Th2 cytokines, such as IL-4 and IL-13 play a crucial role in defining the biased production of IL-12p70/IL-23 by enhancement of IL-12p70 in synergy with IFN-gamma, whereas inhibition of the IFN-gamma-promoted IL-23 production. Collectively, the results suggest that iNKT cells modify the IL-12p70/IL-23 balance to enhance the IL-12p70-induced cell-mediated immunity and suppress the IL-23-dependent inflammatory pathologies. These results may account for the long-appreciated contrasting beneficial and adverse consequence of ligand activation of iNKT cells. The Journal of Immunology, 2009, 183: 201-208. C1 [Uemura, Yasushi; Nakatsuka, Ryusuke; Matsuoka, Yoshikazu; Murakami, Mari; Kimura, Takashi; Hase, Makoto; Kohno, Hirao; Sasaki, Yutaka; Sonoda, Yoshiaki] Kansai Med Univ, Grad Sch Med Sci, Dept Stem Cell Biol & Regenerat Med, Osaka 5708506, Japan. [Liu, Tian-Yi; Jiao, Shun-Chang] Chinese Peoples Liberat Army Gen Hosp, Dept Oncol, Beijing, Peoples R China. [Suzuki, Motoharu; Ishihara, Osamu] Saitama Med Univ, Fac Med, Dept Obstet & Gynecol, Saitama, Japan. [Narita, Yayoi; Ichihara, Yasuko; Kikuchi, Hirosato] Saitama Med Univ, Fac Med, Dept Anesthesiol, Saitama, Japan. [Araki, Tomoyuki; Matsumoto, Masahito] Saitama Med Univ, Fac Med, Dept Mol Biol, Saitama, Japan. [Hirosawa, Narumi; Sakamoto, Yasushi] Saitama Med Univ, Fac Med, Dept Biomed, Res Ctr,Div Analyt Sci, Saitama, Japan. [Iwai, Leo Kei] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02115 USA. [Senju, Satoru] Kumamoto Univ, Grad Sch Med Sci, Dept Immunogenet, Kumamoto, Japan. RP Uemura, Y (reprint author), Kansai Med Univ, Grad Sch Med Sci, Dept Stem Cell Biol & Regenerat Med, Osaka 5708506, Japan. EM uemuraya@takii.kmu.ac.jp RI Iwai, Leo/M-1734-2013 OI Iwai, Leo/0000-0002-1571-7763 FU Ministry of Education. Culture, Sports, Science and Technology, Japan [21710069, 21791572, 21791473, 21791958, 21602005, 21591251, 20591158, 20591190, 19890205, 19790637, 18790689]; Ministry of Education, Mitsubishi Pharma Research Foundation; Takeda Science Foundation; Ochiai Memorial Award; Ichiro Kanehara Foundation; Kanzawa Medical Research Foundation; Kowa Life Science Foundation FX This work was supported in part by Grants-in-Aid 21710069, 21791572, 21791473, 21791958, 21602005, 21591251, 20591158, 20591190, 19890205, 19790637, and 18790689 from the Ministry of Education. Culture, Sports, Science and Technology, Japan, and by research grants from the 21st Century Center of Excellence Program, Ministry of Education, Mitsubishi Pharma Research Foundation (05), Takeda Science Foundation (05), Ochiai Memorial Award (07, 08), Ichiro Kanehara Foundation (08), Kanzawa Medical Research Foundation (09), and Kowa Life Science Foundation (09). NR 62 TC 16 Z9 19 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 JUL 1 PY 2009 VL 183 IS 1 BP 201 EP 208 DI 10.4049/jimmunol.0900873 PG 8 WC Immunology SC Immunology GA 563HS UT WOS:000275119400023 PM 19542431 ER PT J AU Manocha, M Svend, R Laouar, A Liao, GX Bhan, A Borst, J Terhorst, C Manjunath, N AF Manocha, Monika Svend, Rietdijk Laouar, Amale Liao, Gongxian Bhan, Atul Borst, Jannine Terhorst, Cox Manjunath, N. TI Blocking CD27-CD70 Costimulatory Pathway Suppresses Experimental Colitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CD4(+) T-CELLS; TUMOR-NECROSIS-FACTOR; RESPONSES IN-VIVO; NK-CELLS; IFN-GAMMA; CD70; CD27; STIMULATION; ACTIVATION AB The pathogenesis of human inflammatory bowel disease (IBD) and most experimental models of IBD is dependent on the activation and expansion of CD4(+) T cells via interaction with mucosal APCs. The costimulatory receptor CD70 is transiently expressed on the surface of conventional dendritic cells, but is constitutively expressed by a unique APC population in the intestinal lamina propria. We used two experimental IBD models to evaluate whether interfering the interaction between CD70 and its T cell ligand CD27 would affect the development of colitis. Adoptive transfer of naive CD27-deficient CD45RB(high) CD4(+) T cells into Rag-1(-/-) mice resulted in significantly less disease than when wild-type CD45RB(high) CD4(+) T cells were used. Moreover, a monoclonal anti-CD70 Ab prevented the disease caused by the transfer of wild-type CD45RB(high) CD4(+) T cells into Rag-1(-/-) mice and the same Ab also ameliorated an established disease. The colitis associated proinflammatory cytokines IL-6, TNF-alpha and IFN-gamma were significantly reduced after anti-CD70 Ab treatment, suggesting an overall reduction in inflammation due to blockade of pathogenic T cell expansion. Anti-CD70 Ab treatment also suppressed trinitrobenzene sulfonic acid-induced colitis in SJL/J mice. Because anti-CD70 Ab treatment suppressed multiple proinflammatory cytokines, this may be a more potent therapeutic approach for IBD than blockade of individual cytokines. The Journal of Immunology, 2009, 183: 270-276. C1 [Manocha, Monika; Laouar, Amale; Manjunath, N.] Immune Dis Inst, Dept Pediat, Boston, MA 02131 USA. [Manocha, Monika; Laouar, Amale; Bhan, Atul; Manjunath, N.] Harvard Univ, Sch Med, Boston, MA 02131 USA. [Svend, Rietdijk; Liao, Gongxian; Terhorst, Cox] Beth Israel Deaconess Med Ctr, Dept Immunol, Boston, MA 02131 USA. [Svend, Rietdijk; Liao, Gongxian; Terhorst, Cox] Harvard Ctr Life Sci, Boston, MA 02131 USA. [Bhan, Atul] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02131 USA. [Borst, Jannine] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. RP Manjunath, N (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Paul L Foster Sch Med, 5001 El Paso Dr, El Paso, TX 79905 USA. EM manjunath.swamy@ttuhsc.edu FU Crohn's and Colitis Foundation of America (CCFA); Keef Foundation; National Institutes of Health [DK47677, DK 52510]; Center for the Study of Inflammatory Bowel Disease [DK43351] FX This work was supported by grants form the Crohn's and Colitis Foundation of America (CCFA) and the Keef Foundation (to N.M.). and National Institutes of Health Grants DK47677 (A.K.B.), DK 52510 (C.T.) and the Center for the Study of Inflammatory Bowel Disease (DK43351) (to A.K.B. and C.T.). NR 39 TC 27 Z9 27 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 JUL 1 PY 2009 VL 183 IS 1 BP 270 EP 276 DI 10.4049/jimmunol.0802424 PG 7 WC Immunology SC Immunology GA 563HS UT WOS:000275119400031 PM 19525396 ER PT J AU Sultana, H Foellmer, HG Neelakanta, G Oliphant, T Engle, M Ledizet, M Krishnan, MN Bonafe, N Anthony, KG Marasco, WA Kaplan, P Montgomery, RR Diamond, MS Koski, RA Fikrig, E AF Sultana, Hameeda Foellmer, Harald G. Neelakanta, Girish Oliphant, Theodore Engle, Michael Ledizet, Michel Krishnan, Manoj N. Bonafe, Nathalie Anthony, Karen G. Marasco, Wayne A. Kaplan, Paul Montgomery, Ruth R. Diamond, Michael S. Koski, Raymond A. Fikrig, Erol TI Fusion Loop Peptide of the West Nile Virus Envelope Protein Is Essential for Pathogenesis and Is Recognized by a Therapeutic Cross-Reactive Human Monoclonal Antibody SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BLOOD-BRAIN-BARRIER; BORNE ENCEPHALITIS-VIRUS; CULTURED MOSQUITO CELLS; DENGUE VIRUS; FLAVIVIRUS FUSION; MEMBRANE-FUSION; EXPERIMENTAL-INFECTION; CRYSTAL-STRUCTURE; TYPE-2 VIRUSES; UNITED-STATES AB West Nile virus is an emerging pathogen that can cause fatal neurological disease. A recombinant human mAb, mAb11, has been described as a candidate for the prevention and treatment of West Nile disease. Using a yeast surface display epitope mapping assay and neutralization escape mutant, we show that mAb11 recognizes the fusion loop, at the distal end of domain 11 of the West Nile virus envelope protein. Ab mAb11 cross-reacts with all four dengue viruses and provides protection against dengue (serotypes 2 and 4) viruses. In contrast to the parental West Nile virus, a neutralization escape variant failed to cause lethal encephalitis (at higher infectious doses) or induce the inflammatory responses associated with blood-brain barrier permeability in mice, suggesting an important role for the fusion loop in viral pathogenesis. Our data demonstrate that an intact West Nile virus fusion loop is critical for virulence, and that human mAb11 targeting this region is efficacious against West Nile virus infection. These experiments define the molecular determinant on the envelope protein recognized by mAb11 and demonstrate the importance of this region in causing West Nile encephalitis. The Journal of Immunology, 2009, 183: 650-660. C1 [Sultana, Hameeda; Foellmer, Harald G.; Neelakanta, Girish; Krishnan, Manoj N.; Fikrig, Erol] Yale Univ, Sch Med, Infect Dis Sect, Dept Internal Med, New Haven, CT 06520 USA. [Montgomery, Ruth R.] Yale Univ, Sch Med, Rheumatol Sect, Dept Internal Med, New Haven, CT 06520 USA. [Ledizet, Michel; Bonafe, Nathalie; Anthony, Karen G.; Kaplan, Paul; Koski, Raymond A.] L2 Diagnost, New Haven, CT 06511 USA. [Oliphant, Theodore; Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63130 USA. [Engle, Michael; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63130 USA. [Engle, Michael; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Marasco, Wayne A.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Fikrig, Erol] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Fikrig, E (reprint author), Yale Univ, Sch Med, Infect Dis Sect, Dept Internal Med, S525A,300 Cedar St, New Haven, CT 06520 USA. EM erol.fikrig@yale.edu FU National Institutes of Health [AI070343, AI50031, AI061373] FX These studies were supported in part by National Institutes of Health Grants AI070343, AI50031, and AI061373. E.F. is art investigator of the Howard Hughes Medical Institute. The funding agencies had no role in conducting the study and in preparing the manuscript. NR 60 TC 30 Z9 30 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2009 VL 183 IS 1 BP 650 EP 660 DI 10.4049/jimmunol.0900093 PG 11 WC Immunology SC Immunology GA 563HS UT WOS:000275119400071 PM 19535627 ER PT J AU El-Solh, AA Amsterdam, D Alhajhusain, A Akinnusi, ME Saliba, RG Lynch, SV Wiener-Kronisch, JP AF El-Solh, Ali A. Amsterdam, Daniel Alhajhusain, Ahmad Akinnusi, Morohonfolu E. Saliba, Ranime G. Lynch, Susan V. Wiener-Kronisch, Jeanine P. TI Matrix metalloproteases in bronchoalveolar lavage fluid of patients with type III Pseudomonas aeruginosa pneumonia SO JOURNAL OF INFECTION LA English DT Article DE Pseudomonos aeruginosa; Exotoxin; Metalloproteinases; Ventilator-associated pneumonia ID VENTILATOR-ASSOCIATED PNEUMONIA; IMPAIRS HOST-DEFENSE; BACTERIAL-MENINGITIS; CYSTIC-FIBROSIS; COLLAGENASE-2 MMP-8; PROTEIN SECRETION; LUNG-DISEASE; MICE; MODEL; INFLAMMATION AB Objectives: In patients with ventilator-associated pneumonia (VAP), Pseudomonas aeruginoso type III (TTSS) secreting isolates have been linked to poor clinical outcomes. Differential expression of matrix metalloproteinases (MMPs) induced by type III effector proteins may herald an irreversible lung injury. Methods: Serial bronchoalveolar lavage fluids collected from 41 patients with P. aeruginoso at onset of VAP, day 4, and day 8 after antibiotic therapy were assayed for MMP-8, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and alpha-2 macroglobulin levels. Results: At the onset of VAP, isolates secreting ExoU had the highest MMP-9 levels. The response to antimicrobial therapy showed a differential drop in MMPs with significant decrease in MMP-8 and MMP-9 levels on days 4 and 8 in patients with TTSS- compared to TTSS+ phenotype. The ratio of MMP-9/TIMP-1 was significantly associated with alpha-2 macroglobulin at end of therapy (r = 0.4, p = 0.02). Patients who survived had a tower MMP-9/TIMP-1 ratio than those who died (p = 0.003). Conclusions: VAP linked to A aeruginosa Type III phenotype portrays a divergent antibiotic treatment response in regards to the concentrations of metalloproteinases in the alveolar space. The imbalance between MMP-9 and TIMP-1 may determine the intensity of alveolocapillary damage and ultimate outcome of P. aeruginosa VAP. Published by Elsevier Ltd on behalf of The British Infection Society. C1 [El-Solh, Ali A.; Alhajhusain, Ahmad; Akinnusi, Morohonfolu E.; Saliba, Ranime G.] Vet Affairs Western New York Healthcare Syst, Buffalo, NY 14215 USA. [El-Solh, Ali A.; Alhajhusain, Ahmad] Sch Med & Biomed Sci, Dept Med, Western New York Resp Res Ctr, Buffalo, NY USA. [Amsterdam, Daniel] Erie Cty Med Ctr & Labs, Dept Lab Med, Buffalo, NY 14215 USA. [Lynch, Susan V.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Wiener-Kronisch, Jeanine P.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP El-Solh, AA (reprint author), Vet Affairs Western New York Healthcare Syst, Med Res Bldg 20,3495 Bailey Ave, Buffalo, NY 14215 USA. EM solh@buffalo.edu RI Lynch, Susan/B-6272-2009 FU American Lung Association [NIH A1075410]; SCCOR [HL 74005, HL69809] FX Grant support: Research for Health in Erie County (AES], American Lung Association [SVL], NIH A1075410 [SVL and JPWK], SCCOR HL 74005 [JPWK], HL69809 [JPWK]. NR 38 TC 13 Z9 13 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 EI 1532-2742 J9 J INFECTION JI J. Infect. PD JUL PY 2009 VL 59 IS 1 BP 49 EP 55 DI 10.1016/j.jinf.2009.05.004 PG 7 WC Infectious Diseases SC Infectious Diseases GA 479HS UT WOS:000268650900006 PM 19535150 ER PT J AU Heffernan, TP Kawasumi, M Blasina, A Anderes, K Conney, AH Nghiem, P AF Heffernan, Timothy P. Kawasumi, Masaoki Blasina, Alessandra Anderes, Kenna Conney, Allan H. Nghiem, Paul TI ATR-Chk1 Pathway Inhibition Promotes Apoptosis after UV Treatment in Primary Human Keratinocytes: Potential Basis for the UV Protective Effects of Caffeine SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID DNA-DAMAGE CHECKPOINT; SKH-1 MICE; 7-HYDROXYSTAUROSPORINE UCN-01; RADIOSENSITIZING AGENT; TOPICAL APPLICATION; DECAFFEINATED TEA; SKIN-CANCER; CELL; P53; ATM AB New approaches to prevent and reverse UV damage are needed to combat rising sunlight-induced skin cancer rates. Mouse studies have shown that oral or topical caffeine promotes elimination of UV-damaged keratinocytes through apoptosis and markedly inhibits subsequent skin cancer development. This potentially important therapeutic effect has not been studied in human skin cells. Here, we use primary human keratinocytes to examine which of several caffeine effects mediates this process. In these cells, caffeine more than doubled apoptosis after 75 mJ cm(-2) of ultraviolet light B (UVB). Selectively targeting two of caffeine's known effects did not alter UVB-induced apoptosis: inhibition of ataxia-telangiectasia mutated and augmentation of cyclic AMP levels. In contrast, siRNA against ataxia-telangiectasia and Rad3-related (ATR) doubled apoptosis after UV through a p53-independent mechanism. Caffeine did not further augment apoptosis after UVB in cells in which ATR had been specifically depleted, suggesting that a key target of caffeine in this effect is ATR. Inhibition of a central ATR target, checkpoint kinase 1 (Chk1), through siRNA or a new and highly specific inhibitor (PF610666) also augmented UVB-induced apoptosis. These data suggest that a relevant target of caffeine is the ATR-Chk1 pathway and that inhibiting ATR or Chk1 might have promise in preventing or reversing UV damage. C1 [Heffernan, Timothy P.; Kawasumi, Masaoki; Nghiem, Paul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Blasina, Alessandra; Anderes, Kenna] Pfizer La Jolla Global Res & Dev, San Diego, CA USA. [Conney, Allan H.] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Biol Chem, Piscataway, NJ USA. [Nghiem, Paul] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. RP Nghiem, P (reprint author), Univ Washington, Dept Med, Div Dermatol, 815 Mercer St, Seattle, WA 98109 USA. EM pnghiem@u.washington.edu RI Nghiem, Paul/A-9210-2011 OI Nghiem, Paul/0000-0003-2784-963X FU NIH [R01-AR049832, K02-AR50993, R01-CA114442] FX We thank Drs Anna Mandinova and Sarah Boswell for advice and technical assistance with primary keratinocyte isolation and culture. This work was supported by NIH grants R01-AR049832 and K02-AR50993 (P. N.), Harvard Skin Cancer SPORE Career Development Award (P. N.), NIH grant R01-CA114442 (A. H. C.), and Shiseido Corporation support to the Cutaneous Biology Research Center at Massachusetts General Hospital. NR 42 TC 40 Z9 40 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2009 VL 129 IS 7 BP 1805 EP 1815 DI 10.1038/jid.2008.435 PG 11 WC Dermatology SC Dermatology GA 461ME UT WOS:000267270300028 PM 19242509 ER PT J AU Seidler, E Kimball, A AF Seidler, E. Kimball, A. TI Insurance eligibility in Psoriasis compared to other major chronic illnesses SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Medical-Dermatology-Society CY MAR 05, 2009 CL San Francisco, CA SP Med Dermatol Soc C1 [Seidler, E.; Kimball, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2009 VL 129 IS 7 MA 7 BP 1841 EP 1841 PG 1 WC Dermatology SC Dermatology GA 461ME UT WOS:000267270300043 ER PT J AU Patel, NR Swan, K Li, X Tachado, SD Koziel, H AF Patel, Naimish R. Swan, Katharine Li, Xin Tachado, Souvenir D. Koziel, Henry TI Impaired M-tuberculosis-mediated apoptosis in alveolar macrophages from HIV plus persons: potential role of IL-10 and BCL-3 SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Toll-like receptors; molecules; transcription factors; NF-kappa B ID NF-KAPPA-B; HUMAN-IMMUNODEFICIENCY-VIRUS; REGULATORY T-CELLS; MYCOBACTERIUM-TUBERCULOSIS; TNF-ALPHA; CYTOKINE SIGNALING-1; MANNOSE RECEPTORS; HOST MACROPHAGES; BLOOD MONOCYTES; INTERLEUKIN-10 AB The mechanism of increased MTb disease susceptibility in HIV+ persons remains poorly understood. Apoptosis of macrophages in response to MTb represents a critical host defense response, and decreased apoptosis may represent a mechanism of increased susceptibility to MTb in HIV. In the current study, MTb-mediated apoptosis of human AM was reduced in HIV+ subjects compared with healthy subjects in a TNF-alpha-dependent manner. IL-10 levels in BALF from HIV+ persons were significantly elevated compared with HIV-persons, and exogenous IL-10 reduced MTb-mediated apoptosis in healthy AM, suggesting that IL-10 could mediate decreased apoptosis observed in HIV. Further study showed that IL-10 reduced TNF release in response to MTb in AM through a reduction in TNF mRNA levels, and exogenous TNF could partially reverse IL-10-associated effects on AM apoptosis. IL-10 did not influence p-IRAK, I kappa B degradation, or NF-kappa B p65 nuclear translocation in response to MTb, but IL-10 did increase levels of AM BCL-3, an inhibitor of NF-kappa B nuclear activity. BCL-3 knockdown in human macrophages increased MTb-mediated TNF release. Importantly, BCL-3 levels in AM from HIV+ subjects were higher compared with healthy subjects. Taken together, these data suggest that elevated lung levels of IL-10 may impair MTb-mediated AM apoptosis in HIV through a BCL-3-dependent mechanism. BCL-3 may represent a potential therapeutic target to treat or prevent MTb disease in HIV+ persons. J. Leukoc. Biol. 86: 53-60; 2009. C1 [Patel, Naimish R.; Swan, Katharine; Li, Xin; Tachado, Souvenir D.; Koziel, Henry] Harvard Univ, Sch Med, Div Pulm Crit Care & Sleep Med, Dept Med,BIDMC, Boston, MA 02215 USA. RP Patel, NR (reprint author), Harvard Univ, Sch Med, Div Pulm Crit Care & Sleep Med, Dept Med,BIDMC, Kirstein Hall,Room KSB-23,330 Brookline Ave, Boston, MA 02215 USA. EM npatel@bidmc.harvard.edu FU NIH [R01-HL063655, K08-AI064014]; American Lung Association FX This work was supported by NIH R01-HL063655 (H.K.) and K08-AI064014 (N.R.P.) and American Lung Association Biomedical Research Grant (N.R.P.). The authors thank all study participants who consented to research bronchoscopy and to Robert Garland, Lorraine Gryniuk, Renee Andwood, and Darren Tavernelli for their excellent technical assistance. These data were presented in part at the 2007 American Thoracic Society International Meeting, San Francisco, CA, USA, and the 2008 American Thoracic Society International Meeting, Toronto, Canada. NR 57 TC 36 Z9 37 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2009 VL 86 IS 1 BP 53 EP 60 DI 10.1189/JLB.0908574 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 464ES UT WOS:000267488700008 PM 19383626 ER PT J AU Sautter, FJ Glynn, SM Thompson, KE Franklin, L Han, XT AF Sautter, Frederic J. Glynn, Shirley M. Thompson, Karin E. Franklin, Laurel Han, Xiaotong TI A Couple-Based Approach to the Reduction of PTSD Avoidance Symptoms: Preliminary Findings SO JOURNAL OF MARITAL AND FAMILY THERAPY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MALE VIETNAM VETERANS; LONGITUDINAL COURSE; YOUNG-ADULTS; RISK-FACTORS; THERAPY; EXPOSURE; BURDEN AB This study reports preliminary findings regarding the feasibility and efficacy of a novel couple-based treatment, named Strategic Approach Therapy (SAT), for reducing avoidance symptoms of posttraumatic stress disorder (PTSD). Six male Vietnam combat veterans diagnosed with PTSD and their cohabitating marital partners participated in 10 weeks of SAT treatment. Self-report, clinician ratings, and partner ratings of PTSD symptoms were obtained before the first session and after the tenth session of treatment. Veterans reported statistically significant reductions in self-reported, clinician-rated, and partner-rated effortful avoidance, emotional numbing, and overall PTSD severity. These data indicate that SAT offers promise as an effective treatment for PTSD avoidance symptoms. C1 [Sautter, Frederic J.] Mental Hlth Serv Line, SE Louisiana Vet Hlth Care Syst, New Orleans, LA 70161 USA. [Glynn, Shirley M.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Thompson, Karin E.] Vet Affairs Med Ctr, PTSD Program, Memphis, TN USA. [Franklin, Laurel] SE Louisiana Vet Hlth Care Syst, OEF OIF Trauma Recovery Program, PTSD Program, New Orleans, LA USA. [Glynn, Shirley M.] W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA USA. [Sautter, Frederic J.; Han, Xiaotong] S Cent Mental Illness Res Educ & Clin Ctr, Little Rock, AR USA. RP Sautter, FJ (reprint author), Mental Hlth Serv Line, SE Louisiana Vet Hlth Care Syst, POB 61011, New Orleans, LA 70161 USA. EM fredericsautter@msn.com NR 27 TC 32 Z9 32 U1 0 U2 2 PU AMER ASSOC MARRIAGE FAMILY THERAPY PI ALEXANDRIA PA 112 SOUTH ALFRED ST, ALEXANDRIA, VA 22314 USA SN 0194-472X J9 J MARITAL FAM THER JI J. Marital Fam. Ther. PD JUL PY 2009 VL 35 IS 3 BP 343 EP 349 DI 10.1111/j.1752-0606.2009.00125.x PG 7 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 456TZ UT WOS:000266875600006 PM 19522786 ER PT J AU Miller, FG Joffe, S AF Miller, F. G. Joffe, S. TI Limits to research risks SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID CLINICAL-RESEARCH; ETHICS; EQUIPOISE; CRITIQUE AB Risk-benefit assessment is a routine requirement for research ethics committees that review and oversee biomedical research with human subjects. Nevertheless, it remains unclear how to weigh and balance risks to research participants against the social benefits that flow from generating biomedical knowledge. In this article, we address the question of whether there are any reasonable criteria for defining the limit of permissible risks to individuals who provide informed consent for research participation. We argue against any a priori limit to permissible research risks. However, attention to the uncertainty of potential social benefit that can be derived from any particular study warrants caution in exposing prospective research participants to a substantial likelihood of serious harm. C1 [Miller, F. G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Joffe, S.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Dept Med, Boston, MA 02115 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov OI Joffe, Steven/0000-0002-0667-7384 NR 19 TC 24 Z9 26 U1 1 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD JUL PY 2009 VL 35 IS 7 BP 445 EP 449 DI 10.1136/jme.2008.026062 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 465MO UT WOS:000267590300013 PM 19567696 ER PT J AU Muzykewicz, DA Sharma, A Muse, V Numis, AL Rajagopal, J Thiele, EA AF Muzykewicz, D. A. Sharma, A. Muse, V. Numis, A. L. Rajagopal, J. Thiele, E. A. TI TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PULMONARY-FUNCTION TESTS; CT; GENE; LYMPHANGIOMYOMATOSIS; IDENTIFICATION; DISEASE; WOMEN AB Background: Lymphangioleiomyomatosis (LAM) is a prominent finding in the setting of tuberous sclerosis complex (TSC). Objective: The present study was designed to compare cystic lung changes consistent with LAM in patients with a TSC1 disease-causing mutation, TSC2 disease-causing mutation, or no mutation identified (NMI). Methods and results: We conducted a retrospective review of the chest computed tomography (CT) of 45 female and 20 male patients with TSC and found cysts consistent with LAM in 22 (49%) women and two (10%) men. In the female population, changes consistent with LAM were observed in six of 15 (40%) patients with TSC1, 11 of 23 (48%) with TSC2, and five of seven (71%) with NMI. While the predominant size of cysts did not differ across these three groups, TSC2 women with LAM had a significantly greater number of cysts than did TSC1 patients (p = 0.010). Conclusions: These findings suggest a higher rate of LAM in TSC1 than previously recognised, as well as a fundamental difference in CT presentation between TSC1 and TSC2. C1 [Muzykewicz, D. A.; Numis, A. L.; Thiele, E. A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sharma, A.; Muse, V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rajagopal, J.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Carol & James Herscot Ctr Tuberous, Sclerosis Complex,1-B Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org FU Carol and James Herscot Center for Tuberous Sclerosis Complex FX This study was supported by the Carol and James Herscot Center for Tuberous Sclerosis Complex NR 25 TC 28 Z9 29 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD JUL PY 2009 VL 46 IS 7 BP 465 EP 468 DI 10.1136/jmg.2008.065342 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 465RD UT WOS:000267603600008 PM 19419980 ER PT J AU Quarantini, LC Miranda-Scippa, A Batista-Neves, S Powell, VB Abreu, N Abreu, KC Moura, I Crane, J Sampaio, AS Netto, LR Deoliveira, IR Parana, R Bressan, RA Lacerda, ALT AF Quarantini, Lucas C. Miranda-Scippa, Angela Batista-Neves, Susana Powell, Vania B. Abreu, Neander Abreu, Katiusha C. Moura, Ilka Crane, Jacquelyn Sampaio, Aline S. Netto, Liana. R. deOliveira, Irismar R. Parana, Raymundo Bressan, Rodrigo A. Lacerda, Acioly L. T. . TI A Neuropsychological Study Comparing Patients Infected With HCV and HBV Without Psychiatric Comorbidities SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE hepatitis C virus; cognitive dysfunction; chronic liver disease; mental disorders; major depression ID HEPATITIS-C VIRUS; UNIPOLAR MAJOR DEPRESSION; TUMOR-NECROSIS-FACTOR; LIVER-DISEASE; COGNITIVE IMPAIRMENT; AFFECTIVE-DISORDERS; INTERFERON-ALPHA; BRAIN; DEFICITS; DYSFUNCTION AB Hepatitis C is one of the most common chronic infectious diseases worldwide, with well-documented extra-hepatic manifestations, such as a broad number of cognitive deficits. These impairments may be explained by psychiatric comorbidities, which have not been investigated properly in the literature. In order to elucidate a specific hepatitis C virus (HCV) induced cognitive impairment not related to mental disorders, neuropsychological performance of patients infected with HCV was compared with that of patients infected with hepatitis B virus cognitive impairment, especially psychiatric comorbidities. A total of 33 patients infected with HCV and 22 patients infected with HBV were included in the study. There were no significant differences between the two groups with regard to age or years of education. The group of patients infected with HCV performed significantly worse on visuo-spatial memory tasks after adjusting for years of education and age. There were no significant differences between patients infected with HCV and patients infected with HBV with regards to other neuropsychological functions. The data indicate that patients infected with HCV patients have poorer visuo-spacial memory performance than patients infected with HBV, suggesting that the cognitive deficit may be specific to HCV infection and not to secondary comorbid psychiatric disorders. J. Med. Virol. 81: 1184-1188, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Quarantini, Lucas C.; Miranda-Scippa, Angela; Batista-Neves, Susana; Powell, Vania B.; Abreu, Neander; Abreu, Katiusha C.; Moura, Ilka; Netto, Liana. R.; deOliveira, Irismar R.; Parana, Raymundo] Univ Fed Bahia, Univ Hosp, Salvador, BA, Brazil. [Quarantini, Lucas C.; Bressan, Rodrigo A.; Lacerda, Acioly L. T. .] Univ Fed Sao Paulo, Lab Interdisciplinar Neurociencias Clin LiNC, Sao Paulo, Brazil. [Crane, Jacquelyn] Harvard Univ, Massachusetts Gen Hosp, PNGU, Boston, MA 02115 USA. [Sampaio, Aline S.] Univ Sao Paulo, Sch Med, Dept & Inst Psychiat, Sao Paulo, Brazil. [Lacerda, Acioly L. T. .] Inst Sinapse Neurociencias Clin, Campinas, SP, Brazil. [Lacerda, Acioly L. T. .] Ctr Pesquisa & Ensaios Clin Sinapse Bairral, Itapira, Brazil. RP Quarantini, LC (reprint author), Rua Altino Serbeto de Barros 241-404, BR-41810908 Salvador, BA, Brazil. EM lcq@ufba.br RI de Oliveira, Irismar/B-4172-2009; Lacerda, Acioly/A-7052-2010; Bressan, Rodrigo/E-9178-2010; SAMPAIO, ALINE/M-1229-2013; OI Lacerda, Acioly/0000-0002-9370-0449; Bressan, Rodrigo/0000-0002-0868-4449; SAMPAIO, ALINE/0000-0001-5568-6167; Abreu, Neander/0000-0001-7636-3666 FU FAPESB [195712163383] FX Foundation for the Support of Research in the State of Bahia (FAPESB, Brazil) (partial support); Grant number: 195712163383. NR 55 TC 12 Z9 12 U1 1 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD JUL PY 2009 VL 81 IS 7 BP 1184 EP 1188 DI 10.1002/jmv.21508 PG 5 WC Virology SC Virology GA 453ME UT WOS:000266613900008 PM 19475611 ER PT J AU Choi, YK Snigdha, S Shahid, M Neill, JC Tarazi, FI AF Choi, Yong Kee Snigdha, Shikha Shahid, Mohammed Neill, Jo C. Tarazi, Frank I. TI Subchronic Effects of Phencyclidine on Dopamine and Serotonin Receptors: Implications for Schizophrenia SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Autoradiography; Caudate-putamen; Cognitive functions; Dopamine receptors; Frontal cortex; Phencyclidine; Serotonin receptors ID IONOTROPIC GLUTAMATE RECEPTORS; ANTIPSYCHOTIC-DRUG-TREATMENT; INDUCED COGNITIVE DEFICITS; MEDIAL PREFRONTAL CORTEX; RAT-BRAIN; ATYPICAL ANTIPSYCHOTICS; 5-HT1A RECEPTOR; NMDA RECEPTORS; EMERGING ROLE; D1 RECEPTORS AB Changes in representative dopamine (D(1), D(2), and D(4)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors that have been implicated in the pathophysiology and treatment of schizophrenia were autoradiographically quantified after subchronic phencyclidine (PCP) treatment (2 mg/kg for 7 days, bi-daily followed by 7 days drug free). This treatment has consistently induced robust and long-lasting cognitive deficits in adult rats, although the molecular mechanisms contributing to PCP-induced cognitive deficits remain undefined. Repeated PCP treatment significantly decreased labeling of D(1) receptors in the medial and lateral caudate-putamen (22% and 23%, respectively) and increased 5HT(1A) receptor binding in the medial-prefrontal (26%) and dorsolateral-frontal cortex (30%). No changes in D(1) or 5HT(1A) receptors were detected in other brain regions. These findings suggest that downregulation of striatal D(1) receptors and upregulation of cortical 5HT(1A) receptors may contribute to PCP-induced impairment of cognitive functions in rats. Subchronic PCP treatment did not alter levels of D(2), D(4), and 5HT(2A) receptors in all brain regions examined, which suggests a minimal role for these receptors in mediating subchronic actions of PCP in adult rats. C1 [Tarazi, Frank I.] Harvard Univ, Sch Med, Lab Psychiat Neurosci, McLean Hosp, Belmont, MA 02478 USA. [Choi, Yong Kee; Tarazi, Frank I.] Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA USA. [Choi, Yong Kee; Tarazi, Frank I.] Harvard Univ, Sch Med, Dept Psychiat & Neurosci Program, Boston, MA USA. [Snigdha, Shikha; Neill, Jo C.] Univ Bradford, Sch Pharm, Bradford BD7 1DP, W Yorkshire, England. [Shahid, Mohammed] Schering Plough Corp, Newhouse, Lanark, Scotland. RP Tarazi, FI (reprint author), Harvard Univ, Sch Med, Lab Psychiat Neurosci, McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. EM ftarazi@hms.harvard.edu RI Sia, Michelle/A-1756-2010; OI neill, Joanna/0000-0002-2717-9739 FU US NIH [HD052752] FX Supported by US NIH federal grant HD052752 (FIT). We thank Ben Grayson and Nagi Idris for excellent technical assistance. NR 56 TC 24 Z9 24 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JUL PY 2009 VL 38 IS 3 BP 227 EP 235 DI 10.1007/s12031-009-9204-9 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 458NX UT WOS:000267031900001 PM 19455435 ER PT J AU Orlando, LR Ayala, R Kett, LR Curley, AA Duffner, J Bragg, DC Tsai, LH Dunah, AW Young, AB AF Orlando, Lianna R. Ayala, Ramses Kett, Lauren R. Curley, Allison A. Duffner, Jay Bragg, D. Cristopher Tsai, Li-Huei Dunah, Anthone W. Young, Anne B. TI Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cyclin-dependent kinase 5; homer; mGluR; mGluR1; mGluR5; phosphorylation ID PROTEIN-KINASE; SYNAPTIC PLASTICITY; C PHOSPHORYLATION; NMDA RECEPTORS; EVH1 DOMAIN; CDK5; FAMILY; MGLUR5; COCAINE; COMPLEX AB Phosphorylation of neurotransmitter receptors can modify their activity and regulate neuronal excitability. Cyclin-dependent kinase 5 (cdk5) is a proline-directed serine/threonine kinase involved not only in neuronal development, but also in synaptic function and plasticity. Here we demonstrate that group I metabotropic glutamate receptors (mGluRs), which modulate post-synaptic signaling by coupling to intracellular signal transduction pathways, are phosphorylated by cdk5. In vitro kinase assays reveal that cdk5 phosphorylates mGluR5 within the domain of the receptor that interacts with the scaffolding protein homer. Using a novel phosphospecific mGluR antibody, we show that the homer-binding domain of both mGluR1 and mGluR5 are phosphorylated in vivo, and that inhibition of cdk5 with siRNA decreases the amount of phosphorylated receptor. Furthermore, kinetic binding analysis, by surface plasmon resonance, indicates that phosphorylation of mGluR5 enhances its association with homer. Homer protein complexes in the post-synaptic density, and their disruption by an activity-dependent short homer 1a isoform, have been shown to regulate the trafficking and signaling of the mGluRs and impact many neuroadaptive processes. Phosphorylation of the mGluR homer-binding domain, in contrast to homer 1a induction, provides a novel mechanism for potentially regulating a subset of homer interactions. C1 [Orlando, Lianna R.; Ayala, Ramses; Kett, Lauren R.; Curley, Allison A.; Bragg, D. Cristopher; Dunah, Anthone W.; Young, Anne B.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA. [Duffner, Jay; Bragg, D. Cristopher; Tsai, Li-Huei] Broad Inst Harvard & MIT, Cambridge, MA USA. [Tsai, Li-Huei] Howard Hughes Med Inst, Dept Brain & Cognit Sci, Cambridge, MA USA. [Tsai, Li-Huei] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. RP Young, AB (reprint author), Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, 114 16th St B114-2000, Boston, MA 02129 USA. EM young@helix.mgh.harvard.edu FU National Institute of Health [AG13617, NS049006]; Harvard NeuroDiscovery Center FX We thank P. Worley for recombinant homer constructs, R. Shigemoto for mGluR1a antibody, Y. Xu and M. Schwarzschild for mGluR5 knock-out mice, L. Moy, R. Dhvan and B. Samuels for advice with kinase assays, T. Collins for technical assistance, Z. Hollingsworth for helpful support and troubleshooting, and G. Sadri-Vakili for comments on this manuscript. This work was supported by National Institute of Health Grants AG13617 and NS049006, and the Harvard NeuroDiscovery Center (formerly the Harvard Center for Neurodegeneration and Repair). NR 47 TC 17 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2009 VL 110 IS 2 BP 557 EP 569 DI 10.1111/j.1471-4159.2009.06139.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 463IX UT WOS:000267426700011 PM 19457112 ER PT J AU Hirsch, JA Meyers, PM Barr, J Jensen, ME Derdeyn, C Manchikanti, L AF Hirsch, Joshua A. Meyers, Philip M. Barr, John Jensen, Mary E. Derdeyn, Collin Manchikanti, Laxmaiah TI Technical standards and practice guidelines: should we? Why now? Why SNIS? SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Editorial Material ID EVIDENCE-BASED MEDICINE; QUALITY IMPROVEMENT GUIDELINES; CERVICAL CAROTID ANGIOPLASTY; OF-INTERVENTIONAL-RADIOLOGY; SYSTEMATIC REVIEWS; THERAPEUTIC-NEURORADIOLOGY; AMERICAN-SOCIETY; STENT PLACEMENT; COLLABORATIVE PANEL; PERFORMANCE C1 [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Meyers, Philip M.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Barr, John] Scripps Inst, San Diego, CA USA. [Jensen, Mary E.] Univ Virginia Hlth Syst, Dept Radiol, Charlottesville, VA USA. [Jensen, Mary E.] Univ Virginia Hlth Syst, Dept Neurosurg, Charlottesville, VA USA. [Derdeyn, Collin] Washington Univ, Sch Med, Ctr Stroke & Cerebrovasc Dis, St Louis, MO USA. [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRB 2, Boston, MA 02114 USA. EM hirsch@snisonline.org OI Derdeyn, Colin/0000-0002-5932-2683 NR 27 TC 7 Z9 7 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD JUL PY 2009 VL 1 IS 1 BP 5 EP 7 DI 10.1136/jnis.2009.000679 PG 3 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 601IO UT WOS:000278052000003 PM 21994097 ER PT J AU Hirsch, JA Yoo, AJ Nogueira, RG Verduzco, LA Schwamm, LH Pryor, JC Rabinov, JD Gonzalez, RG AF Hirsch, J. A. Yoo, A. J. Nogueira, R. G. Verduzco, L. A. Schwamm, L. H. Pryor, J. C. Rabinov, J. D. Gonzalez, R. G. TI Case volumes of intra-arterial and intravenous treatment of ischemic stroke in the USA SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID THROMBOLYTIC THERAPY; RECANALIZATION; INTERVENTION; REGISTRY; TRIAL; TIME AB Background and purpose: Ischemic stroke is a major cause of disability and death in the USA. Intravenous tissue plasminogen activator (t-PA) remains underutilized. With the development of newer intra-arterial reperfusion therapies, there is increased opportunity to address the more devastating large-vessel occlusions. We seek to identify the numbers of patients with stroke treated with intravenous and intra-arterial therapies, as well as to estimate the potential number of intra-arterial cases in the foreseeable future. Methods: We performed a literature search to determine case volumes of intravenous t-PA use. We extrapolated the current case volume of intra-arterial stroke therapies from the numbers of cases in which the Merci retrieval device was used. In order to estimate the potential numbers of intra-arterial stroke cases, we characterized the percentage of patients with stroke who received intra-arterial therapy at two leading stroke centers. We applied these percentages to the numbers of patients with stroke seen at the top 100, 200 and 500 stroke centers by volume. Results: The rate of intravenous t-PA use is 2.4-3.6%, resulting in 15 000-22 000 cases/year in the USA. The estimated case volume of intra-arterial therapies is 3500-7200 in 2006. Based on data from St. Luke's Brain and Stroke Institute and Massachusetts General Hospital, approximately 5-20% of patients with ischemic stroke can be treated with intra-arterial therapies. Extrapolating this to the top 500 stroke centers by volume, the potential number of intra-arterial cases in the USA is 10 400-41 500/ year. Conclusion: Based on the current numbers of intra-arterial cases, our theoretical model identifies a potential for significant growth of this stroke therapy. C1 [Hirsch, J. A.; Yoo, A. J.; Verduzco, L. A.; Rabinov, J. D.; Gonzalez, R. G.] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Hirsch, J. A.; Yoo, A. J.; Nogueira, R. G.; Pryor, J. C.; Rabinov, J. D.] Massachusetts Gen Hosp, Dept Intervent Neuroradiol, Boston, MA 02114 USA. [Nogueira, R. G.; Schwamm, L. H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Yoo, AJ (reprint author), Massachusetts Gen Hosp, Dept Neuroradiol, 55 Fruit St,Gray 241, Boston, MA 02114 USA. EM ajyoo@partners.org OI Schwamm, Lee/0000-0003-0592-9145 FU Neuroradiology Education and Research Foundation; Howard Hughes Medical Institute FX Funding: AY was the 2007 recipient of the Neuroradiology Education and Research Foundation/Boston Scientific Fellowship in Cerebrovascular Disease Research. LAV was a 2007 recipient of the Howard Hughes Medical Institute Research Training Fellowships for Medical Students. NR 23 TC 39 Z9 39 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD JUL PY 2009 VL 1 IS 1 BP 27 EP 31 DI 10.1136/jnis.2009.000166 PG 5 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 601IO UT WOS:000278052000007 PM 21994101 ER PT J AU Mckee, AC Cantu, RC Nowinski, CJ Hedley-Whyte, ET Gavett, BE Budson, AE Santini, VE Lee, HS Kubilus, CA Stern, RA AF McKee, Ann C. Cantu, Robert C. Nowinski, Christopher J. Hedley-Whyte, E. Tessa Gavett, Brandon E. Budson, Andrew E. Santini, Veronica E. Lee, Hyo-Soon Kubilus, Caroline A. Stern, Robert A. TI Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy After Repetitive Head Injury SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Review DE Athletes; Concussion; Dementia; Encephalopathy; Neurodegeneration; Tau protein; Traumatic brain injury ID AMYLOID PRECURSOR PROTEIN; NEUROFIBRILLARY TANGLE FORMATION; APOLIPOPROTEIN-E EPSILON-4; EXPERIMENTAL BRAIN-INJURY; FOOTBALL-LEAGUE PLAYER; ALZHEIMERS-DISEASE; DEMENTIA-PUGILISTICA; BETA-PROTEIN; SUPRANUCLEAR PALSY; AXONAL DAMAGE AB Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 professional athletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology. C1 [McKee, Ann C.; Budson, Andrew E.] Bedford Vet Adm Med Ctr, Geriatr Res Educ Clin Ctr, Bedford, MA 01730 USA. [McKee, Ann C.; Gavett, Brandon E.; Budson, Andrew E.; Santini, Veronica E.; Lee, Hyo-Soon; Kubilus, Caroline A.; Stern, Robert A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [McKee, Ann C.; Cantu, Robert C.; Nowinski, Christopher J.; Stern, Robert A.] Boston Univ, Sch Med, Ctr Study Traumat Encephalopathy, Boston, MA 02118 USA. [Cantu, Robert C.; Nowinski, Christopher J.] Sports Legacy Inst, Waltham, MA USA. [Cantu, Robert C.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Cantu, Robert C.] Emerson Hosp, Dept Neurosurg, Concord, MA USA. [Hedley-Whyte, E. Tessa] Harvard Univ, Sch Med, Dept Pathol, CS Kubik Lab Neuropathol,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Mckee, AC (reprint author), Bedford Vet Adm Med Ctr, Geriatr Res Educ Clin Ctr, 200 Springs Rd 182-B, Bedford, MA 01730 USA. EM amckee@bu.edu OI Stern, Robert/0000-0002-5008-077X; Gavett, Brandon/0000-0003-1938-1854 FU Boston University Alzheimer's Disease Center [NIA P30 AG 13846]; National Operating Committee on Standards for Athletic Equipment (NOCSAE); Department of Veterans' Affairs FX This work was supported by the Boston University Alzheimer's Disease Center NIA P30 AG 13846, supplement 0572063345-5, National Operating Committee on Standards for Athletic Equipment (NOCSAE), and by the Department of Veterans' Affairs. NR 120 TC 716 Z9 720 U1 47 U2 252 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUL PY 2009 VL 68 IS 7 BP 709 EP 735 PG 27 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 465CB UT WOS:000267557400001 PM 19535999 ER PT J AU de Calignon, A Spires-Jones, TL Pitstick, R Carlson, GA Hyman, BT AF de Calignon, Alix Spires-Jones, Tara L. Pitstick, Rose Carlson, George A. Hyman, Bradley T. TI Tangle-Bearing Neurons Survive Despite Disruption of Membrane Integrity in a Mouse Model of Tauopathy SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE In vivo imaging; 2-Photon microscopy; Propidium iodide; Tangles; Tauopathy ID PROPIDIUM IODIDE; NEURODEGENERATIVE DISORDERS; CASPASE ACTIVATION; IN-VIVO; ABNORMALITIES; DISSOCIATION AB Neurofibrillary tangles (NFTs) are associated with neuronal loss and correlate with cognitive impairment in Alzheimer disease, but how NFTs relate to neuronal death is not clear. We studied cell death in Tg4510 mice that reversibly express P301L mutant human tau and accumulate NFTs using in vivo multiphoton imaging of neurofibrillary pathology, propidium iodide (PI) incorporation into cells, caspase activation, and DNA labeling. We first observed that in live trice, a minority of neurons were labeled with the caspase probe or with PI fluorescence. These markers of cell stress were localized in the same cells and appeared specifically within NFT-bearing neurons. Contrary to expectations, the PI-stained neurons did not die during a day of observation; the presence of Hoechst-positive nuclei in them on the subsequent day indicated that the NFT-associated membrane disruption, as suggested by PI staining, and caspase activation do not lead to immediate death of neurons in this tauopathy model. This unique combination of in vivo multiphoton imaging with markers of cell death and pathological alteration is a powerful tool for investigating neuronal damage associated with neurofibrillary pathology. C1 [de Calignon, Alix; Spires-Jones, Tara L.; Hyman, Bradley T.] Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [de Calignon, Alix] Univ Paris 06, Ecole Doctorale B2M, Paris, France. [Pitstick, Rose; Carlson, George A.] McLaughlin Res Inst, Great Falls, MT USA. RP Hyman, BT (reprint author), Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org FU National Institutes of Health [AG026249, AG08487] FX This study was supported by grants AG026249 and AG08487 from the National Institutes of Health. NR 15 TC 29 Z9 29 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUL PY 2009 VL 68 IS 7 BP 757 EP 761 PG 5 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 465CB UT WOS:000267557400004 PM 19535996 ER PT J AU Seo, DW Lopez-Meraz, ML Allen, S Wasterlain, CG Niquet, J AF Seo, Dae-Won Lopez-Meraz, Maria-Leonor Allen, Suni Wasterlain, Claude Guy Niquet, Jerome TI Contribution of a Mitochondrial Pathway to Excitotoxic Neuronal Necrosis SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE glutamate; mitochondrial swelling; cytochrome c; caspase-3; primary cortical culture ID TRANSIENT CEREBRAL-ISCHEMIA; GLUTAMATE-INDUCED APOPTOSIS; CYTOCHROME-C RELEASE; CEREBROCORTICAL NEURONS; EQUINE ESTROGENS; CORTICAL-NEURONS; INDUCED SEIZURES; CELL-DEATH; CASPASE; ACTIVATION AB It is traditionally thought that excitotoxic necrosis is a passive mechanism that does not require the activation of a cell death program. In this study, we examined the contribution of the cytochrome c-dependent mitochondrial death pathway to excitotoxic neuronal necrosis, induced by exposing cultured cortical neurons to 1 mM glutamate for 6 hr and blocked by the NMDA antagonist, dizocilpine. Glutamate treatment induced early cytochrome c release, followed by activation of caspase-9 and caspase-3. Preincubation with the caspase-9 inhibitor z-LEHD-fmk, the caspase-3 inhibitor z-DEVD-fmk, or the specific pan-caspase inhibitor Q-VD-oph decreased the percentage of propidium iodide-positive neurons (52.5% +/- 3.1%, 39.4% +/- 3.5%, 44.6% +/- 3%, respectively, vs. 65% +/- 3% in glutamate + vehicle). EM studies showed mitochondrial release of cytochrome c in neurons in the early stages of necrosis and cleaved caspase-3 immunoreactivity in morphologically necrotic neurons. These results suggest that an active mechanism contributes to the demise of a sub-population of excitotoxic necrotic neurons. (C) 2009 Wiley-Liss, Inc. C1 [Lopez-Meraz, Maria-Leonor; Wasterlain, Claude Guy; Niquet, Jerome] Vet Affairs Greater Los Angeles Healthcare Syst 1, Epilepsy Res Labs, Los Angeles, CA USA. [Seo, Dae-Won; Lopez-Meraz, Maria-Leonor; Allen, Suni; Wasterlain, Claude Guy; Niquet, Jerome] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Seo, Dae-Won] Sungkyunkwan Univ, Samsung Med Ctr, Seoul, South Korea. [Wasterlain, Claude Guy] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. RP Niquet, J (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Epilepsy Res Lab 151, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jniquet@ucla.edu FU Veterans Health Administration; NINDS, National Institutes of Health [RO1 NS13515] FX Contract grant sponsor: Research Service of the Veterans Health Administration; Contract grant sponsor: NINDS, National Institutes of Health; Contract grant number: RO1 NS13515. NR 35 TC 10 Z9 10 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUL PY 2009 VL 87 IS 9 BP 2087 EP 2094 DI 10.1002/jnr.22035 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 451KE UT WOS:000266468300013 PM 19235896 ER PT J AU Bollo, RJ Berliner, JL Fischer, I Miles, DK Thiele, EA Zagzag, D Weiner, HL AF Bollo, Robert J. Berliner, Jonathan L. Fischer, Ingeborg Miles, Daniel K. Thiele, Elizabeth A. Zagzag, David Weiner, Howard L. TI Extraventricular subependymal giant cell tumor in a child with tuberous sclerosis complex Case report SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Article DE epilepsy; tuberous sclerosis; subependymal giant cell tumor ID SPECIAL EMPHASIS; ASTROCYTOMA; EPILEPSY; TSC2 AB Subependymal giant cell tumors (SGCTs) are observed in 5-20% of patients with tuberous sclerosis complex (TSC) but account for similar to 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and Surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period. (DOI: 10.3171/2009.3.PEDS08225) C1 [Bollo, Robert J.] NYU, Dept Neurosurg, Langone Med Ctr, New York, NY 10016 USA. [Bollo, Robert J.; Berliner, Jonathan L.; Weiner, Howard L.] NYU, Sch Med, Dept Neurosurg, New York, NY 10016 USA. [Fischer, Ingeborg; Zagzag, David] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Miles, Daniel K.] NYU, Sch Med, Dept Neurol, Comprehens Epilepsy Ctr, New York, NY 10016 USA. [Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Pediat Epilepsy Serv, Boston, MA 02114 USA. RP Bollo, RJ (reprint author), NYU, Dept Neurosurg, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. EM robert.bollo@nyumc.org NR 35 TC 8 Z9 8 U1 0 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 J9 J NEUROS-PEDIATR JI J. Neurosurg.-Pediatr. PD JUL PY 2009 VL 4 IS 1 BP 85 EP 90 DI 10.3171/2009.3.PEDS08225 PG 6 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA 462VB UT WOS:000267384000021 PM 19569916 ER PT J AU Stevens, EA Powers, AK Sweasey, TA Tatter, SB Ojemann, RG AF Stevens, E. Andrew Powers, Alexander K. Sweasey, Thomas A. Tatter, Stephen B. Ojemann, Robert G. TI Simplified harvest of autologous pericranium for duraplasty in Chiari malformation Type I Technical note SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE duraplasty; Chiari I malformation; pericranial graft; dural closure ID DURAL SUBSTITUTE; GRAFT; DECOMPRESSION; EXPERIENCE; SURGERY; CLOSURE; DERMIS AB The authors describe a method of harvesting autologous pericranium for duraplasty in patients with Chiari malformation Type I (CM-I) that avoids excessive exposure or a second incision. Nonautologous dural grafts have been associated with numerous complications including hemorrhage, bacteria and virus transmission, fatal Creutzfeldt-Jakob disease transmission, foreign body reaction, systemic immune response, excessive scarring. slower healing, premature graft dissolution, and wound dehiscence. Autogenous tissues have the advantage of being nonimmunogenic, nontoxic, readily available, and inexpensive. Pericranium is a preferred substrate because it is flexible, strong, and easily Sutured for a watertight closure. Current literature supports the use of autogenous pericranium for dural grafting in CM-I procedures, but has heretofore failed to provide a method of harvest that avoids the complications associated with a larger exposure or second incision. The authors offer a simple alternative technique for using local pericranium in duraplasty for CM-I or other posterior fossa abnormalities. (DOI:10.3171/2009.3.SPINE08196) C1 [Stevens, E. Andrew; Powers, Alexander K.; Sweasey, Thomas A.; Tatter, Stephen B.] Wake Forest Univ, Baptist Med Ctr, Dept Neurosurg, Winston Salem, NC 27157 USA. [Ojemann, Robert G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg Serv, Boston, MA USA. RP Stevens, EA (reprint author), Wake Forest Univ, Baptist Med Ctr, Dept Neurosurg, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM easteven@wfubmc.edu NR 21 TC 9 Z9 9 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD JUL PY 2009 VL 11 IS 1 BP 80 EP 83 DI 10.3171/2009.3.SPINE08196 PG 4 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 462VC UT WOS:000267384100017 PM 19569946 ER PT J AU Hattori, N Swan, M Stobbe, GA Uomoto, JM Minoshima, S Djang, D Krishnananthan, R Lewis, DH AF Hattori, Naoya Swan, Megan Stobbe, Gary A. Uomoto, Jay M. Minoshima, Satoshi Djang, David Krishnananthan, Ruben Lewis, David H. TI Differential SPECT Activation Patterns Associated with PASAT Performance May Indicate Frontocerebellar Functional Dissociation in Chronic Mild Traumatic Brain Injury SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE traumatic brain injury; cognitive fatigue; SPECT; activation study; PASAT ID SERIAL ADDITION TEST; WORKING-MEMORY; HEAD-INJURY; RECOVERY; MODERATE; FATIGUE; DISEASE; TASK; FMRI AB Patients with mild traumatic brain injury (TBI) often complain of cognitive fatigue during the chronic recovery phase. The Paced Auditory Serial Addition Test (PASAT) is a complex psychologic measure that may demonstrate subtle deficiencies in higher cognitive functions. The purpose of this study was to investigate the brain activation of regional cerebral blood flow (rCBF) with PASAT in patients with mild TBI to explore mechanisms for the cognitive fatigue. Methods: Two groups consisting of 15 patients with mild TBI and 15 healthy control subjects underwent (99m)Tc-ethylene cysteine dimer SPECT at rest and during PASAT on a separate day. Cortical rCBF was extracted using a 3-dimensional stereotactic surface projection and statistically analyzed to identify areas of activation, which were compared with PASAT performance scores. Results: Image analysis demonstrated a difference in the pattern of activation between patients with mild TBI and healthy control subjects. Healthy control subjects activated the superior temporal cortex (Brodmann area [BA] 22) bilaterally, the precentral gyrus (BA 9) on the left, and the precentral gyrus (BA 6) and cerebellum bilaterally. Patients with mild TBI demonstrated a larger area of supratentorial activation (BAs 9, 10, 13, and 46) but a smaller area of activation in the cerebellum, indicating frontocerebellar dissociation. Conclusion: Patients with mild TBI and cognitive fatigue demonstrated a different pattern of activation during PASAT. Frontocerebellar dissociation may explain cognitive impairment and cognitive fatigue in the chronic recovery phase of mild traumatic brain injury. C1 [Hattori, Naoya; Minoshima, Satoshi; Krishnananthan, Ruben; Lewis, David H.] Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. [Swan, Megan] Seattle Pacific Univ, Dept Psychol, Seattle, WA 98119 USA. [Stobbe, Gary A.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA. [Uomoto, Jay M.] VA Puget Sound Hlth Care Syst, Ctr Polytrauma Care, Dept Neuropsychol, Seattle, WA USA. [Djang, David] Seattle Nucl Med, Dept Nucl Med, Seattle, WA USA. RP Hattori, N (reprint author), Univ Washington, Sch Med, Dept Radiol, Box 356113,1959 NE Pacific St, Seattle, WA 98195 USA. EM nhattori@u.washington.edu RI Hattori, Naoya/G-2298-2012 NR 28 TC 16 Z9 16 U1 1 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUL PY 2009 VL 50 IS 7 BP 1054 EP 1061 DI 10.2967/jnumed.108.060368 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 529VO UT WOS:000272547100015 PM 19525460 ER PT J AU El Fakhri, G Kardan, A Sitek, A Dorbala, S Abi-Hatem, N Lahoud, Y Fischman, A Coughlan, M Yasuda, T Di Carli, MF AF El Fakhri, Georges Kardan, Arash Sitek, Arkadiusz Dorbala, Sharmila Abi-Hatem, Nathalie Lahoud, Youmna Fischman, Alan Coughlan, Martha Yasuda, Tsunehiro Di Carli, Marcelo F. TI Reproducibility and Accuracy of Quantitative Myocardial Blood Flow Assessment with (82)Rb PET: Comparison with (13)N-Ammonia PET SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE myocardial blood flow; PET; (82)Rb; (13)N-ammonia ID POSITRON-EMISSION-TOMOGRAPHY; GENERATOR-PRODUCED RB-82; NONINVASIVE QUANTIFICATION; N-13 AMMONIA; PERFUSION; NITROGEN-13-AMMONIA; TRANSFORMATION; AGREEMENT; HEART; MODEL AB (82)Rb cardiac PET allows the assessment of myocardial perfusion with a column generator in clinics that lack a cyclotron. There is evidence that the quantitation of myocardial blood flow (MBF) and coronary flow reserve (CFR) with dynamic (82)Rb PET is feasible. The objectives of this study were to determine the accuracy and reproducibility of MBF estimates from dynamic (82)Rb PET by using our methodology for generalized factor analysis (generalized factor analysis of dynamic sequences [GFADS]) and compartment analysis. Methods: Reproducibility was evaluated in 22 subjects undergoing dynamic rest and dipyridamole stress (82)Rb PET studies at a 2-wk interval. The inter-and intraobserver variability of MBF quantitation with dynamic (82)Rb PET was assessed with 4 repeated estimations by each of 4 observers. Accuracy was evaluated in 20 subjects undergoing dynamic rest and dipyridamole stress PET studies with (82)Rb and (13)N-ammonia, respectively. The left ventricular and right ventricular blood pool and left ventricular tissue time-activity curves were estimated by GFADS. MBF was estimated by fitting the blood pool and tissue time-activity curves to a 2-compartment kinetic model for (82)Rb and to a 3-compartment model for (13)N-ammonia. CFR was estimated as the ratio of peak MBF to baseline MBF. Results: The reproducibility of the MBF estimates in repeated (82)Rb studies was very good at rest and during peak stress (R(2) = 0.935), as was the reproducibility of the CFR estimates (R(2) = 0.841). The slope of the correlation line was very close to one for the estimation of MBF (0.986) and CFR (0.960) in repeated (82)Rb studies. The intraobserver reliability was less than 3% for the estimation of MBF at rest and during peak stress as well as for the estimation of CFR. The interobserver reliabilities were 0.950 at rest and 0.975 at peak stress. The correlation between myocardial flow estimates obtained at rest and those obtained during peak stress in (82)Rb and (13)N-ammonia studies was very good (R(2) = 0.857). Bland-Altman plots comparing CFR estimated with (82)Rb and CFR estimated with (13)N-ammonia revealed an underestimation of CFR with (82)Rb compared with (13)N-ammonia; the underestimation was within 61.96 SD. Conclusion: MBF quantitation with GFADS and dynamic (82)Rb PET demonstrated excellent reproducibility as well as intra- and inter-observer reliability. The accuracy of the absolute quantitation of MBF with factor and compartment analyses and dynamic (82)Rb PET was very good, compared with that achieved with (13)N-ammonia, for MBF of up to 2.5 mL/g/min. C1 [El Fakhri, Georges; Kardan, Arash; Abi-Hatem, Nathalie; Yasuda, Tsunehiro] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging,Sch Med, Boston, MA 02114 USA. [Sitek, Arkadiusz; Dorbala, Sharmila; Coughlan, Martha; Di Carli, Marcelo F.] Brigham & Womens Hosp, Dept Radiol, Div Nucl Med, Boston, MA 02115 USA. [Dorbala, Sharmila; Di Carli, Marcelo F.] Brigham & Womens Hosp, Cardiovasc Imaging Program, Boston, MA 02115 USA. [Abi-Hatem, Nathalie; Lahoud, Youmna] Holy Spirit Univ Kaslik, Fac Med, Mt Lebanon, Lebanon. [Fischman, Alan] Shriners Hosp Children, Boston, MA USA. RP El Fakhri, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging,Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM elfakhri@pet.mgh.harvard.edu OI Sitek, Arkadiusz/0000-0002-0677-4002 FU National Institutes of Health [RO1-EB005876]; American Heart Association [GIA-655909T] FX This work was supported in part by grants from the National Institutes of Health (RO1-EB005876) and the American Heart Association (GIA-655909T) and by an unrestricted educational Bracco Diagnostics grant. The contents of this article are the responsibility of the authors and do not represent the views of the National Institutes of Health or the American Heart Association. NR 31 TC 99 Z9 100 U1 1 U2 5 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUL PY 2009 VL 50 IS 7 BP 1062 EP 1071 DI 10.2967/jnumed.104.007831 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 529VO UT WOS:000272547100016 PM 19525467 ER PT J AU Ulrich, BT Buerhaus, PI Donelan, K Norman, L Dittus, R AF Ulrich, Beth T. Buerhaus, Peter I. Donelan, Karen Norman, Linda Dittus, Robert TI Magnet Status and Registered Nurse Views of the Work Environment and Nursing as a Career SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article ID RECOGNITION PROGRAM; SATISFACTION; HOSPITALS; MORTALITY; BURNOUT; RNS AB Objectives: To compare how registered nurses view the work environment and the nursing shortage based on the Magnet status of their organizations. Background: The upsurge in organizations pursuing and obtaining Magnet recognition provides increased opportunities to investigate whether and how registered nurses who are employed in Magnet organizations and organizations pursuing Magnet status perceive differences in the nursing shortage, hospitals' responses to the shortage, characteristics of the work environment, and professional relationships. Methods: A nationally representative sample of registered nurses licensed to practice in the United States was surveyed. The views of registered nurses who worked in Magnet organizations, organizations in the process of applying for Magnet status, and non-Magnet organizations were analyzed as independent groups. Results: Significant differences were found. Although there is a clear Magnet difference, there are also identifiable differences that occur during the pursuit of Magnet recognition. Conclusion: Many organizations in the process of applying for Magnet status rated higher than Magnet organizations, indicating that there is much to do to maintain the comparative advantages for Magnet hospitals. C1 [Ulrich, Beth T.] Gannett Healthcare Grp Nursing Spectrum NurseWeek, Houston, TX USA. [Buerhaus, Peter I.] Vanderbilt Univ, Sch Nursing, Inst Med & Publ Hlth, Ctr Interdisciplinary Hlth Workforce Studies, Nashville, TN 37240 USA. [Donelan, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ulrich, BT (reprint author), Gannett Healthcare Grp Nursing Spectrum NurseWeek, 2655 Villa Creek Dr,Suite 250, Dallas, TX 75234 USA. EM BUlrich@GannettHG.com FU Nursing Spectrum and Johnson Johnson FX This study was funded by grants from Nursing Spectrum and Johnson & Johnson. NR 17 TC 4 Z9 4 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-0443 J9 J NURS ADMIN JI J. Nurs. Adm. PD JUL-AUG PY 2009 VL 39 IS 7-8 BP S54 EP S62 PG 9 WC Nursing SC Nursing GA 478PM UT WOS:000268600200007 PM 19641440 ER PT J AU Weingart, SN Price, J Duncombe, D Connor, M Conley, K Conlin, GJ Sullivan, AM Powell, M Ponte, PR Bierer, BE AF Weingart, Saul N. Price, Jessica Duncombe, Deborah Connor, Maureen Conley, Karen Conlin, Genevieve J. Sullivan, Amy M. Powell, Mark Ponte, Patricia Reid Bierer, Barbara E. TI Enhancing Safety Reporting in Adult Ambulatory Oncology With a Clinician Champion A Practice Innovation SO JOURNAL OF NURSING CARE QUALITY LA English DT Article DE incident reporting; medical errors; safety culture; service quality ID PATIENT SAFETY; HEALTH-CARE; SERVICE QUALITY; ADVERSE EVENTS; HOSPITALS; CULTURE; SYSTEM; UNIT AB This article examines whether a patient safety "champion" on an ambulatory, chemotherapy infusion unit can increase reporting of adverse events and close calls. Reporting rates increased substantially oil both intervention and control units. It was accompanied by more reports of medical errors and conditions that worried staff and fewer reports of service quality incidents. The facilitated reporting method described here is a novel approach to incident reporting, complements the spontaneous reporting systems used in hospitals and some ambulatory care settings, and may help to build a safety culture. By identifying errors and worrisome conditions, it may help managers identify problems before they lead to harm. C1 [Weingart, Saul N.; Sullivan, Amy M.; Ponte, Patricia Reid; Bierer, Barbara E.] Dana Farber Canc Inst, Ctr Patient Safety, Boston, MA 02115 USA. [Powell, Mark] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Weingart, Saul N.; Bierer, Barbara E.] Harvard Univ, Sch Med, Boston, MA USA. [Conley, Karen] S Shore Hosp, Weymouth, MA USA. [Bierer, Barbara E.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Weingart, SN (reprint author), Dana Farber Canc Inst, Ctr Patient Safety, 44 Binney St, Boston, MA 02115 USA. EM saul_weingart@dfci.harvard.edu FU AHRQ HHS [1 K08 HS 11644] NR 33 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1057-3631 J9 J NURS CARE QUAL JI J. Nurs. Care Qual. PD JUL-SEP PY 2009 VL 24 IS 3 BP 203 EP 210 PG 8 WC Nursing SC Nursing GA 464KQ UT WOS:000267504200007 PM 19525761 ER PT J AU Corless, IB Michel, TH Nicholas, M Jameson, D Purtilo, R Dirkes, AMA AF Corless, Inge B. Michel, Theresa H. Nicholas, Marjorie Jameson, Deborah Purtilo, Ruth Dirkes, Angelique M. A. TI Educating Health Professions Students About the Issues Involved in Communicating Effectively: A Novel Approach SO JOURNAL OF NURSING EDUCATION LA English DT Article ID ONLINE; EXPERIENCES; MEDICINE AB The Schwartz Center Educational Rounds, the first Schwartz Center Rounds held at an educational institution, emphasize the overall theme of difficult conversations faced by students and professionals with patients, families, and other members of the health care team. Students in the health care professions do not have sufficient opportunities to practice the communication and decision making skills integral to compassionate caregiving. Such practice enhances communication with patients and families, as well as with other members of the interdisciplinary team. This article presents the underlying assumptions for this change-oriented project and describes the development, implementation, and evaluation of the Rounds for an interdisciplinary group of graduate students during a 4-year period. C1 [Corless, Inge B.] MGH Inst Hlth Profess, Grad Program Nursing, Boston, MA 02129 USA. [Michel, Theresa H.] MGH Inst Hlth Profess, Grad Program Phys Therapy, Boston, MA 02129 USA. [Nicholas, Marjorie] MGH Inst Hlth Profess, Grad Program Commun Sci & Disorders, Boston, MA 02129 USA. [Jameson, Deborah] Massachusetts Gen Hosp, Treadwell Lib, Boston, MA 02114 USA. [Dirkes, Angelique M. A.] Partners Home Care, Waltham, MA USA. RP Corless, IB (reprint author), MGH Inst Hlth Profess, Grad Program Nursing, CNY 36 1st Ave, Boston, MA 02129 USA. EM Icorless@MGHIHP.edu OI Corless, Inge/0000-0003-0438-2037 NR 28 TC 3 Z9 3 U1 3 U2 4 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0148-4834 J9 J NURS EDUC JI J. Nurs. Educ. PD JUL PY 2009 VL 48 IS 7 BP 367 EP 373 DI 10.3928/01484834-20090615-03 PG 7 WC Nursing SC Nursing GA 463RI UT WOS:000267449200003 PM 19634261 ER PT J AU Halpern, LR Parry, BA Hayward, G Peak, D Dodson, TB AF Halpern, Leslie R. Parry, Blair A. Hayward, Gregory Peak, David Dodson, Thomas B. TI A Comparison of 2 Protocols to Detect Intimate Partner Violence SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID DOMESTIC VIOLENCE; EMERGENCY-DEPARTMENT; WOMEN; INJURIES; MARKERS; ABUSE; AGE AB Purpose: Intimate partner violence (IPV) frequently results in maxillofacial injuries. The purpose of this study is to compare 2 protocols to identify women who self-report IPV-related injuries. Materials and Methods: Using a cross-sectional study design, we enrolled a sample of injured women who presented to the emergency department (ED) for evaluation and treatment. The predictor variable was the protocol used to identify injury etiology, that is, an innovative diagnostic protocol (DP) or the ED's standard operating procedure (SOP). The outcome variable was self-reported injury etiology categorized as IPV or other. Descriptive and bivariate statistics were Computed. Sensitivity, specificity, positive predictive value, negative predictive value, and odds ratios were Computed (with P <= .05 being considered statistically significant). Results: The sample was composed of 286 women with a mean age of 45.8 years. The self-reported prevalence of IPV-related injuries was 11.5% and 5% for the DP and SOP, respectively (P = .03). The diagnostic statistics for the DP and SOP, respectively, were as follows: sensitivities, 94% and 50%; specificities, 76% and 95%; positive predictive values, 34% and 50%; and negative predictive values, 98% and 95%. In the adjusted model the women evaluated with the DP had a 38-fold increased likelihood of reporting IPV (P < .01) when compared with the SOP. Conclusions: These results suggest that the proposed DP is associated with an increased frequency of self-reported IPV-related injuries when compared with the ED's SOP. (C) 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:1453-1459, 2009 C1 [Halpern, Leslie R.; Dodson, Thomas B.] Massachusetts Gen Hosp, Ctr Appl Clin Invest, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Halpern, Leslie R.] Harvard Univ, Sch Med, Boston, MA USA. [Parry, Blair A.; Hayward, Gregory; Peak, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02115 USA. RP Halpern, LR (reprint author), Massachusetts Gen Hosp, Ctr Appl Clin Invest, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren Bldg,Suite 1201, Boston, MA 02114 USA. EM lhalpern1@partners.org NR 30 TC 6 Z9 6 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD JUL PY 2009 VL 67 IS 7 BP 1453 EP 1459 DI 10.1016/j.joms.2009.03.003 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 467CH UT WOS:000267713600015 PM 19531417 ER PT J AU Varadarajan, KM Gill, TJ Freiberg, AA Rubash, HE Li, GA AF Varadarajan, Kartik M. Gill, Thomas J. Freiberg, Andrew A. Rubash, Harry E. Li, Guoan TI Gender Differences in Trochlear Groove Orientation and Rotational Kinematics of Human Knees SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE gender difference; trochlear orientation; knee kinematics; fluoroscopy; magnetic resonance imaging ID INTERCONDYLAR NOTCH WIDTH; PATELLAR TRACKING; JOINT KINEMATICS; ARTHROPLASTY; INJURIES; DESIGN; FORCES; FEMUR; DIMORPHISM; STIFFNESS AB Knowledge of the morphology and kinematics of the male and female knees is important for understanding gender-related dimorphism in knee pathology and improvement of related surgical treatments. Twelve male and 12 female subjects with healthy knees were recruited, and each subject performed a single leg lunge while images of the knee were recorded by two fluoroscopes. Tibiolentoral joint, motion was then reproduced using bony models matched to the fluoroscopic images. Femoral trochlear groove orientation was also measured in each knee. While many of the measured parameters were Found to be similar between the genders, a few interesting differences were also noted. Females showed greater external tibial rotation at 0 degrees flexion (-5.4 degrees vs. -1.3, p = 0.03), smaller internal rotation at 30 degrees flexion (1.7 vs. 6.49 degrees, p = 0.04) and greater range of tibial rotation (18.2 degrees vs. 12.4 degrees, p = 0.01) compared to males. Female knees also had a more medially oriented proximal trochlear groove (10.0 degrees vs. 4.5 degrees, p = 0.04). These gender differences in rotational kinematics and trochlear groove orientation may warrant further studies to determine implications for Surgical treatments such as total knee arthroplasty, and gender-related dimorphism in certain knee injuries and pathologies, like anterior cruciate ligament injury and patellofemoral problems. (C) 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:871-878, 2009 C1 [Varadarajan, Kartik M.; Gill, Thomas J.; Freiberg, Andrew A.; Rubash, Harry E.; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Varadarajan, Kartik M.; Gill, Thomas J.; Freiberg, Andrew A.; Rubash, Harry E.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Varadarajan, Kartik M.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU NIAMS NIH HHS [R21-AR05107, R01-AR052408, R01 AR052408, R01 AR052408-03] NR 38 TC 31 Z9 32 U1 0 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2009 VL 27 IS 7 BP 871 EP 878 DI 10.1002/jor.20844 PG 8 WC Orthopedics SC Orthopedics GA 457LU UT WOS:000266931000005 PM 19127520 ER PT J AU Blinderman, CD Homel, P Billings, JA Tennstedt, S Portenoy, RK AF Blinderman, Craig D. Homel, Peter Billings, J. Andrew Tennstedt, Sharon Portenoy, Russell K. TI Symptom Distress and Quality of Life in Patients with Advanced Chronic Obstructive Pulmonary Disease SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Chronic obstructive pulmonary disease; symptom distress; quality of life; MSAS ID ELDERLY-PATIENTS; PALLIATIVE CARE; HEART-FAILURE; IMPACT; PREVALENCE; DEPRESSION; OUTCOMES; CANCER; ADULTS; END AB Although chronic obstructive pulmonary disease (COPD) is a highly prevalent and disabling illness, few empirical studies have evaluated the impact of the disease on symptom distress, functional status, and quality of life. These outcomes were explored in a prospective survey of 100 patients with advanced COPD. Patients were recruited from two academic centers. The mean forced expiratory volume in 1 second (EEV1) was 24.4% (standard deviation = 3.9). Validated instruments were used to assess symptom distress (Memorial Symptom Assessment Scale [MSAS]), mental health (Mental Health Inventory [MHI]-5), functional status (Sickness Impact Profile [SIPI), quality of life (Multidimensional Index of Life Quality [MILQ]), spirituality (Functional Assessment of Chronic Illness Therapy [FACIT] Spirituality Scale), and comorbid conditions (Charlson Comorbidity Index). The most prevalent symptoms were dyspnea (94%), fatigue (71%), xerostomia (60%), coughing (56%), and anxiety (51%). Other symptoms with high prevalence were drowsiness (47%), irritability (42%), feeling nervous (40%), and wheezing (40%). Significant pain was reported in about. one-third of patients. Patients reported relatively high levels of overall functional impairment (SIP median = 24.0) and modest impairment in overall quality of life (MILQ median = 52). Overall, psychological well-being was relatively unimpaired, (median = 24.5), and the comfort derived from faith was intact (FACIT median = 2.5). Impairment in quality of life was strongly associated with symptom distress (MSAS-GDI; r = -0.74, P < 0.001), functional impairment (SIP total; r = -0.59, P < 0.001), female sex (r = -0.26, P = 0.01), and poor psychological well-being (MHI-5; r = 0.68, P < 0.001). In multivariate analyses, poor quality of life was strongly correlated with higher total. symptom distress, sickness-related dysfunction, and lower levels of psychological well-being (R(2) = 0.66). In addition, two specific psychological symptoms-worrying and feeling irritable-were independently predictive of poor quality of life. Patients with advanced COPD have multiple distressing symptoms and a high prevalence of disturbances in mood, functional status, and quality of life. A focus on ameliorating prevalent physical symptoms and psychological distress may lead to an improvement in the overall quality of life in this patient population. J Pain Symptom Manage 2009;38:115-123. (c) 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Blinderman, Craig D.; Billings, J. Andrew] Massachusetts Gen Hosp, Palliat Care Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Ctr Palliat Care, Boston, MA USA. [Homel, Peter; Portenoy, Russell K.] Beth Israel Deaconess Med Ctr, Dept Pain Med & Palliat Care, New York, NY 10003 USA. [Tennstedt, Sharon] New England Res Inst, Watertown, MA 02172 USA. RP Blinderman, CD (reprint author), Massachusetts Gen Hosp, Palliat Care Serv, Founders 600,55 Fruit St, Boston, MA 02114 USA. EM cblinderman@partners.org FU National Institute of Nursing Research, National Institutes of Health [NR05154] FX This study was supported by grant #NR05154 from the National Institute of Nursing Research, National Institutes of Health to Dr. Sharon Tennstedt. NR 24 TC 101 Z9 105 U1 4 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD JUL PY 2009 VL 38 IS 1 BP 115 EP 123 DI 10.1016/j.jpainsymman.2008.07.006 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 481BG UT WOS:000268780900017 PM 19232893 ER PT J AU Snyder, EL Sandstrom, DJ Law, K Fiore, C Sicinska, E Brito, J Bailey, D Fletcher, JA Loda, M Rodig, SJ Dal Cin, P Fletcher, CDM AF Snyder, Eric L. Sandstrom, Deborah J. Law, Kenneth Fiore, Christopher Sicinska, Ewa Brito, Joseph Bailey, Dyane Fletcher, Jonathan A. Loda, Massimo Rodig, Scott J. Dal Cin, Paola Fletcher, Christopher D. M. TI c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programme SO JOURNAL OF PATHOLOGY LA English DT Article DE c-Jun; liposarcoma; dedifferentiation ID COMPARATIVE GENOMIC HYBRIDIZATION; MALIGNANT FIBROUS HISTIOCYTOMAS; CHROMOSOMES; IMBALANCES; AMPLICON; SARCOMAS; TUMORS; GAINS; FISH; CGH AB Genomic amplification of c-Jun and its upstream kinases have been implicated as a mechanism of progression from well-differentiated to dedifferentiated liposarcoma. To further define the role of c-Jun in liposarcoma progression, we performed immunohistochemistry for c-Jun and its activating kinase ASK1 on a series of liposarcomas (n = 81). We. correlated the results with fluorescence in situ hybridization to detect c-Jun amplification. We also derived new cell lines from dedifferentiated liposarcomas with c-Jun amplification. c-Jun protein is expressed in the majority of dedifferentiated liposarcomas (91%) and their well-differentiated components (59%), but only in the minority of pure well-differentiated liposarcomas (27%). When c-Jun is amplified in dedifferentiated liposarcoma, it is interspersed with amplified MDM2 on ring and giant marker chromosomes. MDM2 amplification is one of the earliest events in liposarcoma development, and these results suggest that c-Jun was amplified at a similar time in the evolution of the tumour. In addition, shRNA to c-Jun in c-Jun-amplified liposarcoma cells reduces cell number in vitro and inhibits tumour formation in vivo without an observable effect on the differentiation state of the liposarcoma cells. Thus, c-Jun amplification is oncogenic in liposarcomas but not always sufficient for inhibition of adipocytic differentiation. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Snyder, Eric L.; Sandstrom, Deborah J.; Law, Kenneth; Fletcher, Jonathan A.; Loda, Massimo; Rodig, Scott J.; Dal Cin, Paola; Fletcher, Christopher D. M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Snyder, Eric L.; Fiore, Christopher; Sicinska, Ewa; Brito, Joseph; Bailey, Dyane; Loda, Massimo] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Snyder, Eric L.; Fiore, Christopher; Sicinska, Ewa; Brito, Joseph; Bailey, Dyane; Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. RP Fletcher, CDM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM cfletcher@partners.org NR 20 TC 37 Z9 38 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD JUL PY 2009 VL 218 IS 3 BP 292 EP 300 DI 10.1002/path.2564 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA 465UL UT WOS:000267613300002 PM 19449367 ER PT J AU Thiagalingam, S Jakobiec, FA Chen, T Michaud, N Colby, KA Walton, DS AF Thiagalingam, Sureka Jakobiec, Frederick A. Chen, Teresa Michaud, Norman Colby, Kathryn A. Walton, David S. TI Corneal Anomalies in Newborn Primary Congenital Glaucoma SO JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS LA English DT Article ID PENETRATING KERATOPLASTY; OPAQUE CORNEAS; TRANSPLANTATION; INFANTS; BUPHTHALMOS; CHILDREN; EYES AB This report describes the corneal pathology in an infant with newborn primary congenital glaucoma and discusses whether these findings could be due to a developmental anomaly. The corneal specimen of a 4-month-old infant with newborn primary congenital glaucoma and cloudy corneas who had undergone penetrating keratoplasty was evaluated by light and electron microscopy. Light microscopy showed a thinned epithelium, areas of thickened Bowman's layer (approximately 27 pm thick) interspersed with nuclei, and a thickened and disorganized stroma. Descemet's membrane was intact, and the endothelium was mildly attenuated. The corneal changes seen in this patient may be specific to primary congenital glaucoma and may contribute to the corneal clouding seen so frequently in these patients. [J Pediatr Ophthalmol Strabismus 2009;46:241-244.] C1 [Thiagalingam, Sureka; Jakobiec, Frederick A.; Chen, Teresa; Michaud, Norman; Colby, Kathryn A.; Walton, David S.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Thiagalingam, Sureka; Jakobiec, Frederick A.; Chen, Teresa; Colby, Kathryn A.; Walton, David S.] Harvard Univ, Sch Med, Boston, MA USA. RP Walton, DS (reprint author), 2 Longfellow Pl,Suite 201, Boston, MA 02114 USA. NR 20 TC 4 Z9 4 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0191-3913 J9 J PEDIAT OPHTH STRAB JI J. Pediatr. Ophthalmol. Strabismus. PD JUL-AUG PY 2009 VL 46 IS 4 BP 241 EP 244 DI 10.3928/01913913-20090706-14 PG 4 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 472FB UT WOS:000268113900013 PM 19645407 ER PT J AU Peshkin, BN DeMarco, TA Garber, JE Valdimarsdottir, HB Patenaude, AF Schneider, KA Schwartz, MD Tercyak, KP AF Peshkin, Beth N. DeMarco, Tiffani A. Garber, Judy E. Valdimarsdottir, Heiddis B. Patenaude, Andrea F. Schneider, Katherine A. Schwartz, Marc D. Tercyak, Kenneth P. TI Brief Assessment of Parents Attitudes Toward Testing Minor Children for Hereditary Breast/Ovarian Cancer Genes: Development and Validation of the Pediatric BRCA1/2 Testing Attitudes Scale (P-TAS) SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE bioethics; children; counseling; genetic cancer; genetic counseling; genetic testing; parents ID BREAST-OVARIAN CANCER; ADULT-ONSET CONDITIONS; PSYCHOLOGICAL DISTRESS; SUSCEPTIBILITY; ADOLESCENTS; MUTATIONS; STATEMENT; FAMILIES; WOMEN; RISK AB Objective Predictive genetic testing for hereditary breast/ovarian cancer risk (BRCA1/2 testing) is not recommended for minor children due to its lack of immediate medical benefit and potential psychological risk. Yet, tested mothers are often interested in learning about their childrens cancer risks via pediatric BRCA1/2 testing, raising a host of bioethical concerns. However, no reliable or valid tool exists to formally gauge parents interest in such testing. The aim of this study was to develop and evaluate a new measure for use in genetic research and consultation, known as the Pediatric BRCA1/2 Testing Attitudes Scale (P-TAS). Methods After pretest genetic counseling and provision of a blood sample for BRCA1/2 testing, the P-TAS was administered to 187 mothers of children between 8- and 21-years-old. The measure was also given to 96 of the mothers nontested co-parents. Analyses of the factor structure and psychometric properties of the measure were performed in mothers and confirmed in their co-parents. Results The two factors of the P-TAS, labeled Attitudes and Beliefs (Factor 1) and Decision Making and Communication (Factor 2), accounted for 62.9 of the variance and were reliable (Cronbachs coefficient alpha s = .70 and.90, respectively); the structure and properties were largely confirmed among co-parents. Validity was indicated through its convergence with related constructs. Conclusions This new tool may be integrated into genetic counseling research to better assess parents attitudes and interests in pediatric BRCA1/2 testing. Such information may help guide ongoing discussions about the appropriateness of testing in adolescent or young adult children. C1 [Tercyak, Kenneth P.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Control Program, Washington, DC 20007 USA. [Garber, Judy E.; Patenaude, Andrea F.; Schneider, Katherine A.] Dana Farber Canc Inst, Boston, MA USA. [Valdimarsdottir, Heiddis B.] Mt Sinai Sch Med, New York, NY USA. RP Tercyak, KP (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Control Program, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM tercyakk@georgetown.edu FU NCI NIH HHS [CA091831, CA082346, CA108933, K07 CA091831, R01 CA082346, R01 CA108933]; NHGRI NIH HHS [HG002686, R01 HG002686] NR 52 TC 19 Z9 19 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD JUL PY 2009 VL 34 IS 6 BP 627 EP 638 DI 10.1093/jpepsy/jsn033 PG 12 WC Psychology, Developmental SC Psychology GA 460XK UT WOS:000267225300005 PM 18385162 ER PT J AU Nicoucar, K Giger, R Pope, HG Jaecklin, T Dulguerov, P AF Nicoucar, Keyvan Giger, Roland Pope, Harrison G., Jr. Jaecklin, Thomas Dulguerov, Pavel TI Management of congenital fourth branchial arch anomalies: a review and analysis of published cases SO JOURNAL OF PEDIATRIC SURGERY LA English DT Review DE Congenital; Infection; Neck; Thyroiditis; Pyriform; Piriform; Sinus; Fistula; Branchial region ID ACUTE SUPPURATIVE THYROIDITIS; PIRIFORM SINUS FISTULA; PYRIFORM SINUS; POUCH SINUS; EIKENELLA-CORRODENS; CHILDREN; CLEFT; DIAGNOSIS; MALFORMATIONS; CAUTERIZATION AB Background/Purpose: Congenital fourth branchial arch anomalies are uncommon entities, heretofore described only in case reports, affecting primarily children, and typically presenting as a cervical inflammatory process. The aim of the study was to collect appropriate data on the diagnosis, treatment, and outcome of this condition and to suggest guidelines for its management. Methods: We conducted a structured review of the literature for cases explicitly identified as congenital fourth branchial arch anomalies or meeting anatomical criteria for this condition. We computed descriptive statistics and performed several post hoc 2-way comparisons of subgroups of cases. Results: We located and critically evaluated 526 cases. Fourth arch anomalies were usually located on the left (94%) and generally presented as acute suppurative thyroiditis (45%) or recurrent neck abscess (42%). Barium swallow and direct laryngoscopy were the most useful diagnostic tools. Treatment options differed mainly in recurrence rates: incision and drainage, 89%. open neck surgery and tract excision, 15%; endoscopic cauterization of the sinus tract opening, 15%; and open neck surgery with partial thyroidectomy, 8%. Complications after surgery occurred primarily in children 8 years or younger. Conclusion: Fourth arch anomalies are more common than once thought. Treatment of these disorders with repeated incision and drainage yields high rates of recurrence; thus, complete excision of the entire fistula tract during a quiescent period appears preferable. Combining this surgery with partial thyroidectomy may further decrease recurrence rates. Complications can likely be minimized by using antibiotic treatment of acute infections or endoscopic cauterization in children 8 years or younger, and delaying open neck surgery. (C) 2009 Elsevier Inc. All rights reserved. C1 [Nicoucar, Keyvan; Giger, Roland; Dulguerov, Pavel] Univ Hosp Geneva, Dept Otolaryngol Head & Neck Surg, CH-1211 Geneva, Switzerland. [Pope, Harrison G., Jr.] Harvard Univ, Sch Med, McLean Hosp, Belmont, MA 02478 USA. [Jaecklin, Thomas] Univ Hosp Geneva, Pediat Intens Care Unit, CH-1211 Geneva, Switzerland. RP Nicoucar, K (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. EM keyvan_nicoucar@meei.harvard.edu RI Dulguerov, Pavel/I-7325-2015 OI Dulguerov, Pavel/0000-0001-5863-3933 NR 40 TC 44 Z9 56 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 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD JUL PY 2009 VL 44 IS 7 BP 1432 EP 1439 DI 10.1016/j.jpedsurg.2009.12.001 PG 8 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 469ZD UT WOS:000267939600024 PM 19573674 ER PT J AU Hammerness, P Wilens, T Mick, E Spencer, T Doyle, R McCreary, M Becker, J Biederman, J AF Hammerness, Paul Wilens, Timothy Mick, Eric Spencer, Thomas Doyle, Robert McCreary, Michelle Becker, Judith Biederman, Joseph TI Cardiovascular Effects of Longer-Term, High-Dose OROS Methylphenidate in Adolescents with Attention Deficit Hyperactivity Disorder SO JOURNAL OF PEDIATRICS LA English DT Article ID SALTS EXTENDED-RELEASE; AMERICAN-HEART-ASSOCIATION; CONGENITAL CARDIAC DEFECTS; SCHOOL-AGED CHILDREN; DEFICIT/HYPERACTIVITY DISORDER; BLOOD-PRESSURE; STIMULANT-DRUGS; ADHD; MEDICATIONS; PREVALENCE AB Objective To examine the effects of high doses of extended-release methylphenidate (OROS MPH) on cardiovascular variables in adolescents with attention deficit hyperactivity disorder (ADHD). Study design ECG indices plus systolic blood pressure (SBP), diastolic BP (DBP) and heart rate (HR) were assessed during an open-label study of OROS MPH in 114 adolescents with ADHD (doses up to 1.5 mg/kg/d), Cardiovascular parameters were assessed at 6 weeks and 6 months. Results Small but statistically significant changes in DBP and HR were observed at 6 weeks, without further increases up to 6 months' follow-up. A small but statistically significant increase in SBP was observed over time. Twenty-nine percent of patients had isolated elevations in BP readings prior to study entry, and 14% had > 3 consecutive visits at which elevated BP were observed during OROS MPH treatment. No clinically significant changes in ECG parameters were observed. No serious cardiovascular adverse events occurred. Conclusions Treatment with relatively high doses of OROS MPH was associated with small but statistically significant mean increases in BP and HR, primarily during the first 6 weeks of treatment, without clinically meaningful changes in ECG. These observations are consistent with previous reports using lower doses. (J Pediatr 2009;155:84-9). C1 [Hammerness, Paul; Wilens, Timothy; Mick, Eric; Spencer, Thomas; Doyle, Robert; McCreary, Michelle; Becker, Judith] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Biederman, Joseph] Massachusetts Gen Hosp, Dept Pediat Cardiol, Cambridge, MA 02138 USA. RP Hammerness, P (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, 185 Alewife Brook Pkwy,Suite 2000, Cambridge, MA 02138 USA. EM phammerness@partners.org OI Mick, Eric/0000-0001-8505-8145 NR 29 TC 22 Z9 22 U1 5 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2009 VL 155 IS 1 BP 84 EP 89 DI 10.1016/j.jpeds.2009.02.008 PG 6 WC Pediatrics SC Pediatrics GA 466OU UT WOS:000267672600023 PM 19394037 ER PT J AU Friedewald, VE Kornman, KS Beck, JD Genco, R Goldfine, A Libby, P Offenbacher, S Ridker, PM Van Dyke, TE Roberts, WC AF Friedewald, Vincent E. Kornman, Kenneth S. Beck, James D. Genco, Robert Goldfine, Allison Libby, Peter Offenbacher, Steven Ridker, Paul M. Van Dyke, Thomas E. Roberts, William C. TI The American Journal of Cardiology and Journal of Periodontology Editors' Consensus: Periodontitis and Atherosclerotic Cardiovascular Disease SO JOURNAL OF PERIODONTOLOGY LA English DT Editorial Material ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; ALVEOLAR BONE LOSS; DENSITY-LIPOPROTEIN CHOLESTEROL; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INDUCED GINGIVAL HYPERPLASIA; NUTRITION EXAMINATION SURVEY; PERIPHERAL ARTERIAL-DISEASE; DEPENDENT DIABETES-MELLITUS; CALCIUM-CHANNEL BLOCKERS C1 [Friedewald, Vincent E.] Univ Notre Dame, Notre Dame, IN 46556 USA. [Friedewald, Vincent E.] Univ Texas Med Sch Houston, Dept Internal Med, Houston, TX USA. [Kornman, Kenneth S.] Interleukin Genet, Waltham, MA USA. [Beck, James D.; Offenbacher, Steven] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Genco, Robert] SUNY Buffalo, Dept Oral Biol, Amherst, NY USA. [Genco, Robert] SUNY Buffalo, Dept Microbiol, Amherst, NY USA. [Ridker, Paul M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Goldfine, Allison] Joslin Diabet Ctr, Boston, MA 02215 USA. [Van Dyke, Thomas E.] Boston Univ, Clin Res Ctr, Goldman Sch Dent Med, Boston, MA 02215 USA. [Roberts, William C.] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Waco, TX 76798 USA. [Roberts, William C.] Baylor Hlth Care Syst, A Webb Roberts Ctr Continuing Med Educ, Dallas, TX USA. RP Friedewald, VE (reprint author), Univ Notre Dame, Notre Dame, IN 46556 USA. EM vfriedew@nd.edu NR 122 TC 102 Z9 112 U1 2 U2 13 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD JUL PY 2009 VL 80 IS 7 BP 1021 EP 1032 DI 10.1902/jop.2009.097001 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 471FT UT WOS:000268042100002 PM 19563277 ER PT J AU Cappelli, D Steffen, MJ Holt, SC Ebersole, JL AF Cappelli, D. Steffen, M. J. Holt, S. C. Ebersole, J. L. TI Periodontitis in Pregnancy: Clinical and Serum Antibody Observations From a Baboon Model of Ligature-Induced Disease SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Antibody; bacteria; periodontitis; pregnancy; primate studies; serum ID NONHUMAN PRIMATE MODEL; ACUTE-PHASE REACTANTS; LOW-BIRTH-WEIGHT; PORPHYROMONAS-GINGIVALIS; MACACA-FASCICULARIS; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; REFRACTORY PERIODONTITIS; EXPERIMENTAL GINGIVITIS; DIABETES-MELLITUS; CYNOMOLGUS MONKEY AB Background: Chronic oral infections that elicit host responses leading to periodontal disease are linked with various sequelae of systemic diseases. This report provides seminal information on the clinical and adaptive immunologic characteristics of a baboon model of ligature-induced periodontitis during pregnancy. Methods: Female Papio anubis were evaluated for periodontal health at baseline. Ligatures were tied around selected teeth to initiate oral inflammation and periodontitis. Then the animals were bred. At midpregnancy (similar to 90 days), a clinical evaluation was performed, and additional ligatures were tied on teeth in the contralateral quadrants to maintain progressing periodontitis throughout pregnancy. A final clinical evaluation was done for all experimental teeth after delivery, and ligatures were removed. Serum was collected at all sampling intervals for the determination of antibody levels to a group of 20 oral bacteria. Unligated animals served as controls. Results: At baseline, 16% of animals exhibited minimal plaque and gingival inflammation without periodontal disease. The remaining baboons demonstrated varying levels of inflammation/bleeding, and similar to 20% of the population had periodontal pocketing (>3 mm). Ligated animals expressed increased levels of inflammation and increased probing depths and clinical attachment loss (AL) and could be stratified into multiple subsets postligation based upon changes in clinical parameters at midpregnancy and at delivery. Baboons were categorized into disease susceptibility groups (periodontal disease susceptibility 1 through 4) that described the extent/severity of induced disease during pregnancy. Control animals showed minimal periodontal changes during gestation. Significant differences in serum antibody to multiple oral bacteria were found in animals presenting with periodontitis at baseline and during the 6 months of ligature-induced disease. A significant correlation to antibody to P. gingivalis, which was sustained throughout ligation and pregnancy, was observed with disease presentation. Conclusions: The clinical presentation at baseline, reflecting the natural history of oral disease in these animals, suggests individual variation that is reflected in the characteristics of the adaptive immune responses to oral bacteria. The variability in the response to ligation with resulting periodontal disease provides a model to document prospectively the relationship between oral and systemic health outcomes. J Periodontol 2009,80:1154-1165. C1 [Steffen, M. J.; Ebersole, J. L.] Univ Kentucky, Coll Dent, Ctr Oral Hlth Res, Lexington, KY 40536 USA. [Cappelli, D.] Univ Texas Hlth Sci Ctr San Antonio, Sch Dent, San Antonio, TX 78229 USA. [Holt, S. C.] Forsyth Inst, Boston, MA USA. RP Ebersole, JL (reprint author), Univ Kentucky, Coll Dent, Ctr Oral Hlth Res, HSRB422 Bosomworth Bldg, Lexington, KY 40536 USA. EM jleber2@uky.edu FU National Institute for Dental and Craniofacial Research, Bethesda Maryland [DE013598]; Southwest National Primate Research Center [13986] FX This work was supported by United States Public Health Service (USPHS) grant DE013598 from the National Institute for Dental and Craniofacial Research, Bethesda Maryland. The authors thank Drs. Lianrui Chu, Scott Eddy, and Robert Ayala, Department of Community Dentistry, University of Texas Health Science Center at San Antonio, and Lakshmyya Kesavalu and Malini Bharadwaj, University of Kentucky, for technical support in developing and managing these data. We acknowledge the crucial contribution of Drs. Kathleen Brasky and Karen Rice and the scientific and technical staff at the Southwest Foundation for Biomedical Research and the contribution from USPHS grant 13986 in support of the Southwest National Primate Research Center at the foundation. We also thank Dr. M.J. Novak, Center for Oral Health Research, University of Kentucky, for the critical review of the manuscript. The authors report no conflicts of interest related to this study. NR 79 TC 10 Z9 10 U1 0 U2 0 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD JUL PY 2009 VL 80 IS 7 BP 1154 EP 1165 DI 10.1902/jop.2009.080199 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 471FT UT WOS:000268042100021 PM 19563297 ER PT J AU Morinelli, TA Kendall, RT Luttrell, LM Walker, LP Ullian, ME AF Morinelli, Thomas A. Kendall, Ryan T. Luttrell, Louis M. Walker, Linda P. Ullian, Michael E. TI Angiotensin II-Induced Cyclooxygenase 2 Expression in Rat Aorta Vascular Smooth Muscle Cells Does Not Require Heterotrimeric G Protein Activation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID SURAMIN ANALOGS; KINASE CASCADE; AT(1) RECEPTOR; TRANSCRIPTION; ENDOCYTOSIS; MASTOPARAN; BRAIN AB Angiotensin II (AngII) initiates cellular effects via its G protein-coupled angiotensin 1 (AT(1)) receptor (AT(1)R). Previously, we showed that AngII-induced expression of the prostanoid-producing enzyme cyclooxygenase 2 (COX-2) was dependent upon nuclear trafficking of activated AT(1)R. In the present study, mastoparan (an activator of G proteins), suramin (an inhibitor of G proteins), 1-[6-[[17 beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122; a specific inhibitor of phospholipase C), and sarcosine(1)-Ile(4)-Ile(8)-AngII (SII-AngII; a G protein-independent AT(1)R agonist) were used to determine the involvement of G proteins and AT(1A)R trafficking in AngII-stimulated COX-2 protein expression in human embryonic kidney-293 cells stably expressing AT(1A)/green fluorescent protein receptors and cultured vascular smooth muscle cells, respectively. Mastoparan alone stimulated release of intracellular calcium and increased COX-2 expression. Preincubation with mastoparan inhibited AngII-induced calcium signaling without altering AngII-induced AT(1A)R trafficking, p42/44 extracellular signal-regulated kinase (ERK) activation, or COX-2 expression. Suramin or U73122 had no significant effect on their own; they did not inhibit AngII-induced AT(1A)R trafficking, p42/44 ERK activation, or COX-2 expression; but they did inhibit AngII-induced calcium responses. SII-AngII stimulated AT(1A)R trafficking and increased COX-2 protein expression without activating intracellular calcium release. These data suggest that G protein activation results in increased COX-2 protein expression, but AngII-induced COX-2 expression seems to occur independently of G protein activation. C1 [Morinelli, Thomas A.; Walker, Linda P.; Ullian, Michael E.] Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. [Kendall, Ryan T.; Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Div Endocrinol, Charleston, SC 29425 USA. [Morinelli, Thomas A.; Luttrell, Louis M.; Ullian, Michael E.] Ralph H Johnson Vet Adm Hosp, Charleston, SC USA. RP Morinelli, TA (reprint author), Med Univ S Carolina, Dept Med, Div Nephrol, 829 Clin Sci Bldg,96 Jonathan Lucas St, Charleston, SC 29425 USA. EM morinelt@musc.edu FU Dialysis Clinic Incorporated [C-2342A]; Department of Veteran's Affairs Research Enhancement Award Program [0013] FX This work was supported by Dialysis Clinic Incorporated [Grant C-2342A] (research awards); and the Department of Veteran's Affairs Research Enhancement Award Program [Grant 0013]. NR 23 TC 9 Z9 11 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL PY 2009 VL 330 IS 1 BP 118 EP 124 DI 10.1124/jpet.109.151829 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 461PL UT WOS:000267280300013 PM 19351865 ER PT J AU Chambers, MA Moylan, JS Smith, JD Goodyear, LJ Reid, MB AF Chambers, Melissa A. Moylan, Jennifer S. Smith, Jeffrey D. Goodyear, Laurie J. Reid, Michael B. TI Stretch-stimulated glucose uptake in skeletal muscle is mediated by reactive oxygen species and p38 MAP-kinase SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID ACTIVATED PROTEIN-KINASE; GLUT4 TRANSLOCATION; 3T3-L1 ADIPOCYTES; HYDROGEN-PEROXIDE; L6 MYOTUBES; TRANSPORT; CONTRACTION; INSULIN; STRESS; EXERCISE AB Alternatives to the canonical insulin-stimulated pathway for glucose uptake are exercise- and exogenous reactive oxygen species (ROS)-stimulated glucose uptake. We proposed a model wherein mechanical loading, i.e. stretch, stimulates production of ROS to activate AMP-activated kinase (AMPK) to increase glucose uptake. Immunoblotting was used to measure protein phosphorylation; the fluorochrome probe 2'7'-dichlorofluorescin diacetate was used to measure cytosolic oxidant activity and 2-deoxy-d[1,2-(3)H]glucose was used to measure glucose uptake. The current studies demonstrate that stretch increases ROS, AMPK alpha phosphorylation and glucose transport in murine extensor digitorum longus (EDL) muscle (+121%, +164% and +184%, respectively; P < 0.05). We also demonstrate that stretch-induced glucose uptake persists in transgenic mice expressing an inactive form of the AMPK alpha 2 catalytic subunit in skeletal muscle (+173%; P < 0.05). MnTBAP, a superoxide dismutase (SOD) mimetic, N-acteyl cysteine (NAC), a non-specific antioxidant, ebselen, a glutathione mimetic, or combined SOD plus catalase (ROS-selective scavengers) all decrease stretch-stimulated glucose uptake (P < 0.05) without changing basal uptake (P > 0.16). We also demonstrate that stretch-stimulated glucose uptake persists in the presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294001 (P < 0.05) but is diminished by the p38-MAPK inhibitors SB203580 and A304000 (P > 0.99). These data indicate that stretch-stimulated glucose uptake in skeletal muscle is mediated by a ROS- and p38 MAPK-dependent mechanism that appears to be AMPK alpha 2- and PI3-K-independent. C1 [Chambers, Melissa A.; Moylan, Jennifer S.; Smith, Jeffrey D.; Reid, Michael B.] Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA. [Goodyear, Laurie J.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP Chambers, MA (reprint author), Univ Kentucky, Dept Physiol, 800 Rose St,Room MN-633, Lexington, KY 40536 USA. EM masmit8@uky.edu FU Flexcell [FX-3000]; NIH [DK066232, AR42238]; American Heart Association [AHA0615263B] FX We thank Dr Karyn Esser for the use of the Flexcell (FX-3000) device for the cell culture studies. This research was supported by grants from the NIH (DK066232) and (AR42238) and the American Heart Association (AHA0615263B). NR 48 TC 59 Z9 59 U1 2 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUL 1 PY 2009 VL 587 IS 13 BP 3363 EP 3373 DI 10.1113/jphysiol.2008.165639 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 464WO UT WOS:000267540500037 PM 19403598 ER PT J AU Henderson, DC Fan, XD Sharma, B Copeland, PM Borba, CPC Freudenreich, O Cather, C Evins, AE Goff, DC AF Henderson, David C. Fan, Xiaoduo Sharma, Bikash Copeland, Paul M. Borba, Christina P. C. Freudenreich, Oliver Cather, Corinne Evins, A. Eden Goff, Donald C. TI Waist Circumference Is the Best Anthropometric Predictor for Insulin Resistance in Nondiabetic Patients with Schizophrenia Treated with Clozapine But Not Olanzapine SO JOURNAL OF PSYCHIATRIC PRACTICE LA English DT Article DE schizophrenia; waist circumference; insulin resistance; glucose metabolism; metabolic syndrome; diabetes mellitus; second-generation (atypical) antipsychotic; clozapine; olanzapine ID BODY-MASS INDEX; VISCERAL ADIPOSE-TISSUE; DISEASE RISK-FACTORS; DENSITY-LIPOPROTEIN CHOLESTEROL; ATYPICAL ANTIPSYCHOTIC-DRUGS; CORONARY-HEART-DISEASE; GLUCOSE-TOLERANCE TEST; MINIMAL MODEL ANALYSIS; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE AB Objective. The goal of this study was to evaluate which anthropometric measure (human body measurement) best predicts insulin resistance measured by the insulin sensitivity index (SI) and the homeostasis model of assessment of insulin resistance (HOMA-IR) in nondiabetic patients with schizophrenia treated with clozapine or olanzapine. Methods. We conducted a cross-sectional study of nondiabetic subjects with schizophrenia being treated with olanzapine or clozapine using a frequently sampled intravenous glucose tolerance test, nutritional assessment, and anthropometric measures, to assess the relationship between anthropometric measures and insulin resistance. Results. No difference was found between the groups treated with clozapine and olanzapine in age, gender, race, body mass index (BMI), waist circumference (WC), lipid levels, HOMA-IR, or SI. The disposition index (SI x the acute insulin response to glucose), which measures how the body compensates for insulin resistance to maintain a normal glucose level, was significantly lower in the group treated with clozapine than in the group treated with olanzapine (1067 1390 vs. 2521 2805; p = 0.013), suggesting that the subjects treated with clozapine had a reduced compensatory response to IR compared with the subjects treated with olanzapine. In the clozapine group, both higher WC and BMI were significantly associated with elevated HOMA-IR and lower SI; however, WC was a stronger correlate of IR than BMI, as measured by SI (-0.50 vs. -0.40). In the olanzapine group, neither WC nor BMI was significantly associated with any measure of glucose metabolism. Conclusions. In this study, WC was the single best anthropometric surrogate for predicting IR in patients treated with clozapine but not olanzapine. The results suggest that WC may be a valuable screening tool for predicting IR in patients with schizophrenia being treated with clozapine who are at relatively higher risk of developing the metabolic syndrome, type 2 diabetes mellitus, and associated cardiovascular disease. (Journal of Psychiatric Practice 2009;15:251-261) C1 [Henderson, David C.; Fan, Xiaoduo; Sharma, Bikash; Borba, Christina P. C.; Freudenreich, Oliver; Cather, Corinne; Evins, A. Eden; Goff, Donald C.] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Henderson, David C.; Fan, Xiaoduo; Copeland, Paul M.; Freudenreich, Oliver; Cather, Corinne; Evins, A. Eden; Goff, Donald C.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Goff, DC (reprint author), Freedom Trail Clin, 25 Staniford St, Boston, MA 02114 USA. EM dchenderson@partners.org FU Stanley Foundation, (DCH); National Institute of Health (NIH/NCRR) [5MO1RR01066-24]; NARSAD New Investigator Award (DCH); Pfizer, GlaxoSmithKline; National Institute on Drug Abuse (NIDA) CDDC FX This study was supported by Stanley Foundation, (DCH); National Institute of Health (NIH/NCRR) Grant 5MO1RR01066-24 (General Clinical Research Center), and a NARSAD New Investigator Award (DCH). Study sponsors were not involved in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the report for publication. The authors have listed the following disclosures: Dr. Henderson has received honoraria or research support over the past year from Takeda, Bristol-Myers Squibb, Pfizer, Solvay, Janssen, and COVANCE. Dr. Goff has received honoraria or research support over the past year from Wyeth, Eli Lilly, Pfizer, Novartis, Indevus, Lundbeck, and Schering-Plough. Dr. Copeland has received an honorarium from Eli Lilly. Dr. Fan has received research support from Eli Lilly. Dr. Freudenreich has received research support from Cephalon. Dr. Evins has received research support from Pfizer, GlaxoSmithKline, and National Institute on Drug Abuse (NIDA) CDDC. Dr. Cather, Dr. Sharma and Ms. Borba report no disclosures. NR 75 TC 8 Z9 9 U1 5 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1527-4160 J9 J PSYCHIATR PRACT JI J. Psychiatr. Pract. PD JUL PY 2009 VL 15 IS 4 BP 251 EP 261 PG 11 WC Psychiatry SC Psychiatry GA 477KE UT WOS:000268517200002 PM 19625881 ER PT J AU Ehrlich, S Salbach-Andrae, H Eckart, S Merle, JV Burghardt, R Pfeiffer, E Franke, L Uebelhack, R Lehmkuhl, U Hellweg, R AF Ehrlich, Stefan Salbach-Andrae, Harriet Eckart, Sarah Merle, Julia V. Burghardt, Roland Pfeiffer, Ernst Franke, Leonora Uebelhack, Ralf Lehmkuhl, Ulrike Hellweg, Rainer TI Serum brain-derived neurotrophic factor and peripheral indicators of the serotonin system in underweight and weight-recovered adolescent girls and women with anorexia nervosa SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Article ID BODY-MASS INDEX; RAT-BRAIN; EATING DISORDER; BULIMIA-NERVOSA; FEMALE-PATIENTS; HUMAN PLATELETS; BLOOD-LEVELS; FACTOR BDNF; DEPRESSION; CHILDREN AB Background: Brain-derived neurotrophic factor (BDNF) mutant mice show hyperphagia and hyperleptinemia. Animal and cell-culture experiments suggest multiple interrelations between BDNF and the serotonin (5-HT) system. We studied serum BDNF in patients with anorexia nervosa and its associations with peripheral indicators of the 5-HT system. To control for secondary effects of acute malnutrition, we assessed acutely underweight patients with anorexia nervosa (acAN) in comparison to long-term weight-recovered patients with the disorder (recAN) and healthy controls. Methods: We determined serum BDNF, platelet 5-HT content and platelet 5-HT uptake in 33 patients in the acAN group, 20 patients in the recAN group and 33 controls. Plasma leptin served as an indicator of malnutrition. Results: Patients in the acAN group were aged 14-29 years and had a mean body mass index (BMI) of 14.9 (standard deviation [SD] 1.4) kg/m(2). Those in the recAN group were aged 15-29 years and had a mean BMI of 20.5 (SD 1.3) kg/m(2) and the controls were aged 15-26 years and had a BMI of 21.4 (SD 2.1) kg/m(2). The mean serum BDNF levels were significantly increased in the recAN group compared with the acAN group (8820, SD 3074 v. 6161, SD 2885 pg/mL, U= 154.5, p = 0.001). There were no significant associations between BDNF and either platelet 5-HT content or platelet 5-HT uptake. Among patients with anorexia nervosa, we found significant positive linear relations between BDNF and BMI (r = 0.312, p = 0.023) and between BDNF and leptin (r = 0.365, p = 0.016). Limitations: We measured the signal proteins under study in peripheral blood. Conclusion: Serum BDNF levels in patients with anorexia nervosa depend on the state of illness and the degree of hypoleptinemia. Upregulation of BDNF in weight-recovered patients with anorexia nervosa could be part of a regenerative process after biochemical and molecular neuronal injury due to prolonged malnutrition. Associations between the BDNF and the 5-HT system in humans remain to be established. C1 [Ehrlich, Stefan; Eckart, Sarah; Franke, Leonora; Uebelhack, Ralf; Hellweg, Rainer] Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany. [Ehrlich, Stefan; Salbach-Andrae, Harriet; Merle, Julia V.; Burghardt, Roland; Pfeiffer, Ernst; Lehmkuhl, Ulrike] Charite Univ Med Berlin, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-13353 Berlin, Germany. RP Ehrlich, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Athinoula A Martinos Ctr Biomed Imaging,Med Sch, Bldg 149,13th St,Room 2311, Charlestown, MA 02129 USA. EM stefan@nmr.mgh.harvard.edu NR 55 TC 2 Z9 2 U1 1 U2 2 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 1180-4882 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD JUL PY 2009 VL 34 IS 4 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 462CV UT WOS:000267324500009 ER PT J AU Visvanathan, S Wagner, C Rojas, J Kay, J Dasgupta, B Matteson, EL Mack, M Baker, DG Rahman, MU AF Visvanathan, Sudha Wagner, Carrie Rojas, Jeannie Kay, Jonathan Dasgupta, Bhaskar Matteson, Eric L. Mack, Michael Baker, Daniel G. Rahman, Mahboob U. TI E-selectin, Interleukin 18, Serum Amyloid A, and Matrix Metalloproteinase 9 Are Associated with Clinical Response to Golimumab plus Methotrexate in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE GOLIMUMAB; RHEUMATOID ARTHRITIS; BIOMARKERS; INFLAMMATION; BONE TURNOVER ID NECROSIS-FACTOR-ALPHA; TNF-ALPHA; MONOCLONAL-ANTIBODY; INFLIXIMAB; CYTOKINES; EXPRESSION; INHIBITORS; REDUCTION; EFFICACY; TISSUE AB Objective. To assess the effect Of golimumab (human monoclonal antibody to tumor necrosis factor-alpha) plus methotrexate (MTX) on selected inflammatory biomarkers, and to determine if these effects predict clinical response in rheumatoid arthritis (RA). Methods. Sera from adults with active RA despite MTX therapy. who received subcutaneous injections of placebo + MTX (MTX alone, n = 34) or golimumab 50 or 100 mg every 2 or 4 weeks + MTX (n = 137). were analyzed for levels of C-reactive protein (CRP), Serum amyloid A (SAA), interleukin 18 (IL-18). E-selectin, matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinase I (TIMP-I). Results. Golimumab + MTX treatment significantly decreased serum CRP SAA. IL-18, E-selectin, TIMP-1, and MMP-9 levels (median percent changes of -4.1% to -74.3% across treatment groups) versus MTX alone (-5.8% to 9.7%) when first measured at Week 4: decreases were sustained through Week 16. Larger magnitudes of decrease in all biomarkers were observed for clinical responders Versus nonresponders. For golimumab + MTX. regression analyses including all biomarkers and select clinical measures showed that reductions ill levels of several markers (SAA, E-selectin, MMP-9) as early as Week 4 correlated significantly with improvement in swollen joint Count (SJC) at Week 16, as did reductions in E-selectin with improvement in tender joint count at Week 16. After accounting for the biomarkers, however, treatment group was no longer significant for SJC. Conclusion. Significant decreases in several inflammatory biomarkers were associated with golimumab + MTX therapy. Decreases in serum levels of SAA, E-selectin. and MMP-9 Lit Week 4 may be useful in predicting clinical response at Week 16. (First Release June 1 2009: J Rheumatol 2009:36:1371-9; doi: 10.3899/jrheum.080755) C1 Centocor Res & Dev Inc, Malvern, PA USA. [Kay, Jonathan] Massachusetts Gen Hosp, Rheumatol Unit, Boston, MA 02114 USA. Southend Univ, Dept Rheumatol, Westcliff On Sea, Essex, England. [Matteson, Eric L.] Mayo Clin, Dept Rheumatol, Coll Med, Rochester, MN USA. [Rahman, Mahboob U.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Kay, Jonathan] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Visvanathan, S (reprint author), Centocor Res & Dev Inc, 145 King Purssia Rd,Room 2511, Radnor, PA 19406 USA. EM Svisvana@eits.jnj.com OI Kay, Jonathan/0000-0002-8970-4260 NR 20 TC 15 Z9 17 U1 0 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUL PY 2009 VL 36 IS 7 BP 1371 EP 1379 DI 10.3899/jrheum.080755 PG 9 WC Rheumatology SC Rheumatology GA 468UG UT WOS:000267847700006 PM 19487269 ER PT J AU Mohamed, OA Hamed, HA Roaiah, MF Helmy, T Mahran, A Bennett, CJ AF Mohamed, Osama A. Hamed, Hamed A. Roaiah, Mohamed Farid Helmy, Tarek Mahran, Ali Bennett, Carol J. TI Vascular Risk Factors as Predictors of Sexual Function Following Coronary Artery Bypass Graft SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Cardiovascular Risk Factors; Coronary Artery Bypass Grafting; Sexual Function Following Coronary Artery Bypass Grafting ID ERECTILE DYSFUNCTION; OFF-PUMP; DISEASE; EPIDEMIOLOGY; IMPOTENCE; SURGERY AB Introduction. A strong association between cardiovascular risk factors and erectile dysfunction (ED) was suggested. Coronary artery bypass grafting (CABG) is the gold standard for surgical myocardial revascularization. Aim. We herein evaluate the impact of vascular risk factors on postoperative sexual functions in patients undergo CABG. Main Outcome Measures. ED severity by the International Index of Erectile Function (IIEF-5) and penile duplex study. Methods. The present study included 100 patients who underwent CABG. The patients were evaluated by an abridged form of the IIEF-5 questionnaire, followed by CABG. Six months after surgery the erectile function of all patients was revaluated utilizing the IIEF-5. Results. Number of risk factors was significantly associated with postoperative change in IIEF-5 score (P = 0.02). A post hoc analysis of the association revealed that patients with one risk factor were significantly more likely to have increased IIEF-5 scores (N = 18), whereas those with two or more risk factors were significantly more likely to have decreased IIEF-5 scores (N = 21, P < 0.05). Furthermore, those with no risk factors were significantly more likely to be stable (N = 8) compared with those with more than two risk factors, who were more likely to have decreased scores (P < 0.05). The hierarchical logistic regression results showed that when examining all risk factors simultaneously, because of multicollinearity, only hyperlipidemia was significantly associated with postoperative ED (odds ratio [OR] = 11.33, confirdence interval [CI] = 1.25, 102.82). Frequency of intercourse was also significantly associated with postoperative ED after controlling for risk factors (OR = 0.71, CI = 0.52, 0.97). Conclusions. This data clearly shows that the number of cardiovascular risk factors is an essential predictive factor for sexual function following surgery. Only hyperlipidemia may play a predictive role for the future sexual function of patients undergo CABG. Mohamed OA, Hamed HA, Roaiah MF, Helmy T, Mahran A, and Bennett CJ. Vascular risk factors as predictors of sexual function following coronary artery bypass graft. J Sex Med 2009;6:2017-2023. C1 [Mohamed, Osama A.] Baylor Coll Med, Scott Dept Urol, Houston, TX 77025 USA. [Hamed, Hamed A.; Roaiah, Mohamed Farid] Cairo Univ, Fac Med, Androl Dept, Cairo, Egypt. [Helmy, Tarek] Cairo Univ, Fac Med, Cardiothorac Dept, Cairo, Egypt. [Mahran, Ali] Asyut Univ, Androl Dept, Fac Med, Asyut, Egypt. [Bennett, Carol J.] Greater Los Angeles VA Med Syst, Los Angeles, CA USA. [Bennett, Carol J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Mohamed, OA (reprint author), Baylor Coll Med, Scott Dept Urol, 7490 Bromton Rd, Houston, TX 77025 USA. EM azimusama@gamil.com NR 22 TC 4 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1743-6095 J9 J SEX MED JI J. Sex. Med. PD JUL PY 2009 VL 6 IS 7 BP 2017 EP 2023 DI 10.1111/j.1743-6109.2009.01268.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 462QA UT WOS:000267369500025 PM 19453877 ER PT J AU Monuteaux, MC Biederman, J Doyle, AE Mick, E Faraone, SV AF Monuteaux, Michael C. Biederman, Joseph Doyle, Alysa E. Mick, Eric Faraone, Stephen V. TI Genetic Risk for Conduct Disorder Symptom Subtypes in an ADHD Sample: Specificity to Aggressive Symptoms SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; conduct disorder; genetics; aggression ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; FAMILY-BASED ASSOCIATION; ANTISOCIAL-BEHAVIOR; OPPOSITIONAL DEFIANT; ENVIRONMENTAL-INFLUENCES; CANDIDATE GENES; BIRTH-WEIGHT; CHILDREN; SEROTONIN; CHILDHOOD AB Objective: Recent studies have suggested an association between candidate genes (i.e., COMT, SLC6A4) and conduct disorder (CD). However, it is not clear if these relations extend to CD within the context of attention-deficit/hyperactivity disorder (ADHD). Also, it is uncertain whether the risk is specific to aggressive symptoms or is a risk for CD generally. The aim of this study was to examine the role of the COMT and SLC6A4 genes in the risk for CD and its symptomatic subtypes in the context of ADHD. Method: We examined subjects with ADHD (n = 444, age range 6-55 years) aggregated across four completed studies. Psychiatric diagnoses were determined by structured interviews. We tested the association between genotype and the diagnosis of CD and aggressive and covert symptom counts. Results: There was no significant association between variations in functional polymorphisms of either the COMT gene or the SLC6A4 gene and the risk for CD. The COMT gene was associated with increased aggressive CD symptoms but not covert CD symptoms. The SLC6A4 gene was not associated with either symptom subtype. Conclusions: These findings contribute to our understanding of the genetic basis of antisocial behavior in the ADHD population and provide additional support for the notion that aggressive and covert CD symptom subtypes are etiologically distinct. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(7):757-764. C1 [Monuteaux, Michael C.] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY USA. RP Monuteaux, MC (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM mmonuteaux@partners.org OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIH [R01HD37694, R01HD37999, R01MH66877] FX Financial support: NIH grants R01HD37694, R01HD37999, and R01MH66877 to S.F NR 51 TC 43 Z9 44 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2009 VL 48 IS 7 BP 757 EP 764 DI 10.1097/CHI.0b013e3181a5661b PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 460ZA UT WOS:000267230700012 PM 19465875 ER PT J AU Aram, SS Russel, KS Potter, MP AF Aram, Sepideh S. Russel, Kristin S. Potter, Mona P. TI Eclipse (The Twilight Saga, Book 3). SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review C1 [Aram, Sepideh S.; Russel, Kristin S.; Potter, Mona P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Aram, SS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM saram@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2009 VL 48 IS 7 BP 771 EP 773 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 460ZA UT WOS:000267230700019 ER PT J AU Aram, SS Russel, KS Potter, MP AF Aram, Sepideh S. Russel, Kristin S. Potter, Mona P. TI Breaking Dawn (The Twilight Saga, Book 4). SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review C1 [Aram, Sepideh S.; Russel, Kristin S.; Potter, Mona P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Aram, SS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM saram@partners.org NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2009 VL 48 IS 7 BP 771 EP 773 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 460ZA UT WOS:000267230700020 ER PT J AU Aram, SS Russel, KS Potter, MP AF Aram, Sepideh S. Russel, Kristin S. Potter, Mona P. TI New Moon (The Twilight Saga, Book 2). SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review C1 [Aram, Sepideh S.; Russel, Kristin S.; Potter, Mona P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Aram, SS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM saram@partners.org NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2009 VL 48 IS 7 BP 771 EP 773 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 460ZA UT WOS:000267230700018 ER PT J AU Aram, SS Russel, KS Potter, MP AF Aram, Sepideh S. Russel, Kristin S. Potter, Mona P. TI Twilight. SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review C1 [Aram, Sepideh S.; Russel, Kristin S.; Potter, Mona P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Aram, SS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM saram@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2009 VL 48 IS 7 BP 771 EP 773 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 460ZA UT WOS:000267230700017 ER PT J AU Asgari, MA Tang, J Epstein, EH Chren, MM Warton, EM Quesenberry, CP Go, AS Friedman, GD AF Asgari, Maryam A. Tang, Jean Epstein, Ervin H., Jr. Chren, Mary-Margaret Warton, E. Margaret Quesenberry, Charles P., Jr. Go, Alan S. Friedman, Gary D. TI Statin use and risk of basal cell carcinoma SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE basal cell carcinoma; pharmacoepidemiology; skin cancer; statin ID NONMELANOMA SKIN-CANCER; FOLLOW-UP; CLINICAL-TRIALS; CHOLESTEROL; POPULATION; METAANALYSIS; PREVENTION; LOVASTATIN; SIMVASTATIN; REGRESSION AB Objective: We examined the association between statin use and basal cell carcinoma (BCC) risk. Methods: We identified all members of a large integrated health care delivery system with a diagnosis of a histologically proven BCC in 1997. Subsequent BCCs were identified through 2006 from health plan electronic pathology records. Longitudinal exposure to statins and other lipid-lowering agents was determined from automated pharmacy records. We used extended Cox regression to examine the independent association between receipt of statin therapy (ever vs never, cumulative duration) and risk of subsequent BCC. To minimize confounding by indication, we conducted sensitivity analyses in the subset of individuals considered eligible for lipid-lowering therapy based on national guidelines. Results: Among 12,123 members given a diagnosis of BCC who had no prior statin exposure, 6381 developed a subsequent BCC during follow-up. Neither "ever use of statins" (adjusted hazard ratio 1.02, 95% confidence interval: 0.92-1.12) or Cumulative duration of statin (adjusted hazard ratio 1.02/year, 95% confidence interval: 0.99-1.11) was associated With subsequent BCC after adjustment for age, sex, and health care use. Risk estimates did not change appreciably when the analysis was limited to the Subset of individuals who met eligibility criteria for initiating statin therapy. There was also no significant association between use of non-statin antilipemics and subsequent BCC (adjusted hazard ratio 1.10, 95% confidence interval: 0.76-1-58). Limitations: No information was available for BCC risk factors, Such as sun sensitivity and sun exposure. Conclusions: Among a large cohort of individuals with BCC, statin therapy was not significantly associated with risk of subsequent BCC. (J Am Acad Dermatol 2009;61:66-72.) C1 [Asgari, Maryam A.; Warton, E. Margaret; Quesenberry, Charles P., Jr.; Go, Alan S.; Friedman, Gary D.] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Asgari, Maryam A.; Tang, Jean; Chren, Mary-Margaret] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Biostat Epidemiol & Med, San Francisco, CA 94143 USA. [Chren, Mary-Margaret] San Francisco VA Med Ctr, Hlth Serv Res Enhancement Award Program, San Francisco, CA USA. [Tang, Jean; Epstein, Ervin H., Jr.] Childrens Hosp, Oakland Res Inst, Oakland, CA USA. [Friedman, Gary D.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Asgari, MA (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM maryam.m.asgari@kp.org RI Asgari, Maryam/O-4947-2016 FU National Institute of Arthritis Musculoskeletal and Skin Diseases [K23 AR 051037, K24 AR 052667]; National Cancer Institute [R01 CA 098838] FX Supported in part by the National Institute of Arthritis Musculoskeletal and Skin Diseases (K23 AR 051037 to Dr Asgari, K24 AR 052667 to Dr Chren) and by the National Cancer Institute (R01 CA 098838 to Dr Friedman). NR 31 TC 7 Z9 7 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2009 VL 61 IS 1 BP 66 EP 72 DI 10.1016/j.jaad.2009.02.011 PG 7 WC Dermatology SC Dermatology GA 462DA UT WOS:000267325000010 PM 19464071 ER PT J AU Park, JM Tsao, H Tsao, S AF Park, Jong Min Tsao, Hensin Tsao, Sandy TI Acquired bilateral nevus of Ota-like macules (Hori nevus): Etiologic and therapeutic considerations SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review ID SWITCHED RUBY-LASER; ND-YAG LASER; DERMAL MELANOCYTOSIS; ALEXANDRITE LASER; COMBINATION AB Background: Acquired bilateral nevus Of Ota-like macules (ABNOM), also known as Hori nevus, is one of the most commonly acquired dermal facial melanocytoses among people with dark skin, especially Asian women. Objective: The goals of this article were to review published work on ABNOM; address controversies about pathogenesis and therapeutic approach; and inspire further study. Methods: Articles in the literature related to the description of ABNOM were extracted and summarized. Results: Clinically, ABNOM occurs predominantly on the face of middle-aged women. Histologically, it is characterized by irregularly shaped, bipolar melanocytes dispersed through the mid to papillary dermis. Therapeutically, various pigment-targeting lasers have emerged as the major mode of treatment. Limitations: There is a notable absence of both biological insight into the cause of ABNOM and robust trials to effectively define a standardized therapy. The scattered reports in the literature preclude a more rigorous meta-analytical approach. Conclusion: Although there have been many reports on ABNOM since 1984, the pathogenesis still remains unclear and controversial, and treatment of ABNOM is still challenging. (J Am Acad Dermatol 2009;61:88-93.) C1 [Tsao, Sandy] Massachusetts Gen Hosp, Dept Dermatol, MGH Dermatol Laser & Cosmet Ctr, Boston, MA 02114 USA. RP Tsao, S (reprint author), Massachusetts Gen Hosp, Dept Dermatol, MGH Dermatol Laser & Cosmet Ctr, Bartlett 622,55 Fruit St, Boston, MA 02114 USA. NR 31 TC 12 Z9 12 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2009 VL 61 IS 1 BP 88 EP 93 DI 10.1016/j.jaad.2008.10.054 PG 6 WC Dermatology SC Dermatology GA 462DA UT WOS:000267325000013 PM 19539841 ER PT J AU Parchman, ML Munoz, A AF Parchman, Michael L. Munoz, Abel TI Risk Factors for Methicillin-Resistant Staphylococcal aureus Skin and Soft Tissue Infections Presenting in Primary Care: A South Texas Ambulatory Research Network (STARNet) Study SO JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE LA English DT Article ID UNITED-STATES; MRSA AB Purpose: To examine skin and soft tissue infections presenting at 4 primary care clinics and assess if historical risk factors and examination findings were associated with a positive methicillin-resistant Staphylococcus aureus (MRSA) culture. Methods: During the 10-month observational study (April 2007 through January 2008), physicians in 5 practices across South Texas collected history, physical examination findings, culture results, and antibiotic( s) prescribed for all patients presenting with a skin or soft tissue infection. Analyses were conducted to determine the relationship between historical indicators, location of lesions, and examination findings with a positive MRSA culture. Results: Across 4 practices, 164 cases of skin and soft tissue infections were collected during 10 months. Of the 94 with a culture, 63 (67%) were MRSA positive. Patients working in or exposed to a health care setting were more likely to have a culture positive for MRSA, as were those presenting with an abscess. MRSA-positive lesions were also significantly smaller in size. Conclusions: Because of the high prevalence of MRSA skin and soft tissue infections among patients presenting to family physicians, presumptive treatment for MRSA may be indicated. However, increasing levels of resistance to current antibiotics is concerning and warrants development of alternative management strategies. (J Am Board Fam Med 2009;22:375-9.) C1 [Parchman, Michael L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Family & Community Med, San Antonio, TX 78229 USA. [Parchman, Michael L.] S Texas Vet Hlth Care Syst, VERDICT Hlth Serv Res Program, Austin, TX USA. [Munoz, Abel] Munoz Family Med Clin, Austin, TX USA. RP Parchman, ML (reprint author), S Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM parchman@uthscsa.edu OI Parchman, Michael/0000-0001-7129-2889 NR 11 TC 22 Z9 22 U1 0 U2 0 PU AMER BOARD FAMILY MEDICINE PI LEXINGTON PA 2228 YOUNG DR, LEXINGTON, KY 40505 USA SN 1557-2625 J9 J AM BOARD FAM MED JI J. Am. Board Fam. Med. PD JUL-AUG PY 2009 VL 22 IS 4 BP 375 EP 379 DI 10.3122/jabfm.2009.04.090003 PG 5 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 468OK UT WOS:000267828700008 PM 19587251 ER PT J AU Shuja, F Tabbara, M Li, YQ Liu, BL Butt, MU Velmahos, GC deMoya, M Alam, HB AF Shuja, Fahad Tabbara, Malek Li, Yongqing Liu, Baoling Butt, Muhammad Umar Velmahos, George C. deMoya, Marc Alam, Hasan B. TI Profound Hypothermia Decreases Cardiac Apoptosis Through Akt Survival Pathway SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article; Proceedings Paper CT 94th Annual Clinical Congress of the American-College-of-Surgeons/63rd Annual Sessions of the Owen H Wangensteen Forum on Fundamental Surgical Problems CY OCT 12-16, 2008 CL San Francisco, CA SP Amer Coll Surg ID SPINAL-CORD-INJURY; SWINE MODEL; LETHAL HEMORRHAGE; CARDIOPULMONARY BYPASS; ARREST; ISCHEMIA; SHOCK; RATS; EXSANGUINATION; RESUSCITATION AB BACKGROUND: Hypothermia increases the tolerable ischemia time for myocardium in hemorrhagic shock, but precise mechanisms are not clearly established. Here we studied activation of Akt cell survival pathway in a rodent model of emergency preservation and delayed resuscitation. STUDY DESIGN: Wistar-Kyoto rats underwent 40% blood volume arterial hemorrhage during 10 minutes and were randomized into 2 groups based on core body temperatures (n = 7/group): hypothermia (15 degrees C) and normothermia (37 degrees C). Hypothermia was induced by infusing cold isotonic solution using cardiopulmonary bypass (CPB) setup. After reaching target body temperature, low-flow state (CPB flow rate of 20 mL/kg/min) was maintained for 60 minutes. Hypothermic rats were rewarmed to baseline temperature; all rats were resuscitated on CPB and monitored for 3 hours. The normothermia group underwent identical CPB management. Sham rats (no hemorrhage, no instrumentation) were used as controls (n = 7). Tissues were harvested at the end of experiment. RESULTS: Induction of hypothermia increased survival rates (100% versus 0% in normothermia group). Western blot analysis of cardiac tissue revealed increased levels of phospho-Akt (active) in hypothermia and sham groups compared with the normothermia group (p < 0.05). Among downstream targets of Akt, phospho-GSK-3 beta (inactive), phospho-Bad (inactive), beta-catenin, and Bcl-2 were considerably elevated in the hypothermia group compared with the normothermia group. Hypothermia also showed decreased activity of caspase-3 protein compared with normothermia (p < 0.05), suggesting decreased apoptosis. CONCLUSIONS: Profound hypothermia increases survival in a rodent model of hemorrhagic shock and prolonged low-flow state. Hypothermia preserves Akt signaling pathway in cardiomyocytes with a concurrent decrease in cardiac apoptosis. (J Am Coll Surg 2009;209:89-99. (C) 2009 by the American College of Surgeons) C1 [Shuja, Fahad; Tabbara, Malek; Li, Yongqing; Liu, Baoling; Butt, Muhammad Umar; Velmahos, George C.; deMoya, Marc; Alam, Hasan B.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Alam, HB (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Ste 810, Boston, MA 02114 USA. OI Tabbara, Malek/0000-0003-1046-7803 NR 41 TC 26 Z9 32 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD JUL PY 2009 VL 209 IS 1 BP 89 EP 99 DI 10.1016/j.jamcollsurg.2009.03.010 PG 11 WC Surgery SC Surgery GA 470CT UT WOS:000267952300012 PM 19651068 ER PT J AU Vagefi, PA Kwolek, CJ Wicky, S Watkins, MT AF Vagefi, Parsia A. Kwolek, Christopher J. Wicky, Stephan Watkins, Michael T. TI Congestive Heart Failure from Traumatic Arteriovenous Fistula SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Editorial Material C1 [Vagefi, Parsia A.; Kwolek, Christopher J.; Wicky, Stephan; Watkins, Michael T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Vagefi, PA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD JUL PY 2009 VL 209 IS 1 BP 150 EP 150 DI 10.1016/j.jamcollsurg.2008.11.021 PG 1 WC Surgery SC Surgery GA 470CT UT WOS:000267952300022 PM 19651078 ER PT J AU Herman, AD Johnson, TM Ritchie, CS Parmelee, PA AF Herman, Adam D. Johnson, Theodore M., II Ritchie, Christine S. Parmelee, Patricia A. TI Pain Management Interventions in the Nursing Home: A Structured Review of the Literature SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE pain management; nursing home; review; healthcare quality ID RANDOMIZED CONTROLLED-TRIAL; LONG-TERM-CARE; LOW-BACK PAIN; QUALITY-IMPROVEMENT; NONMALIGNANT PAIN; ELDERLY-PATIENTS; RESIDENTS; PREVALENCE; DEMENTIA; HEALTH AB Residents in nursing homes (NHs) experience pain that is underrecognized and undertreated. This pain contributes to a decline in quality of life. Although descriptive studies of pain assessment and management have been conducted, few have been published that critically evaluate interventions to improve pain management. Identification of the strengths and gaps in the current literature is required. A literature search was conducted of clinical trials that evaluated prospective interventions to improve pain management. Information on the intervention type, resident sample and setting, endpoints, and study design were extracted. Studies were classified based on a modification of Donabedian's model of healthcare quality. Four categories of interventions were identified: actor, decision support, treatment, and systems. The search strategy and selection criteria yielded 21 articles. Eleven studies used an actor intervention; of these, eight also employed a systems intervention, and one also used a treatment intervention. Two studies used a decision support intervention, seven used a treatment intervention, and one used a systems intervention. The overall quality of research was uneven in several areas: research design-nine studies were quasi-experimental in nature, endpoints measures were not consistent-three did not perform statistical analysis, and characteristics of the resident samples varied dramatically. In conclusion, the number of high-quality studies of pain management in NHs remains limited. Process endpoints are used as surrogate measures for resident endpoints. Systematic approaches are needed to understand how each type of intervention improves the quality of pain management at the resident level. C1 [Herman, Adam D.; Johnson, Theodore M., II] Emory Univ, Div Geriatr Med & Gerontol, Atlanta, GA 30322 USA. [Parmelee, Patricia A.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Herman, Adam D.; Johnson, Theodore M., II; Parmelee, Patricia A.] Atlanta Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Decatur, GA USA. [Ritchie, Christine S.] Univ Alabama, Div Gerontol Geriatr & Palliat Care, Birmingham, AL USA. [Ritchie, Christine S.] Birmingham Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. RP Herman, AD (reprint author), 1841 Clifton Rd NE, Atlanta, GA 30329 USA. EM adherma@emory.edu NR 50 TC 31 Z9 31 U1 3 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2009 VL 57 IS 7 BP 1258 EP 1267 DI 10.1111/j.1532-5415.2009.02315.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 464WI UT WOS:000267539800017 PM 19558481 ER PT J AU Williams, BA Lindquist, K Hill, T Baillargeon, J Mellow, J Greifinger, R Walter, LC AF Williams, Brie A. Lindquist, Karla Hill, Terry Baillargeon, Jacques Mellow, Jeff Greifinger, Robert Walter, Louise C. TI Caregiving Behind Bars: Correctional Officer Reports of Disability in Geriatric Prisoners SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Geriatrics-Society CY APR 30-MAY 04, 2008 CL Washington, DC SP Amer Geriatr Soc DE prisoners; disability; geriatric ID LIVING OLDER PERSONS; FUNCTIONAL IMPAIRMENT; MENTAL-HEALTH; CARE AB Despite increasing numbers of geriatric prisoners, little is known about geriatric disability or health care in prison. Although correctional officers often act as a liaison between prisoners and the healthcare system, the role of officers in recognizing geriatric disability has not been characterized. The goals of this study were to assess officers' assessment of disability in their assigned geriatric prisoners and to contrast their views with reports from the California Department of Corrections and Rehabilitation (CDCR). Questionnaires were given to 71 officers assigned to 618 randomly selected geriatric prisoners in 11 prisons. Information about 41 additional prisoners identified by correctional officers as "high risk" was also analyzed. Prisoner disability and health were determined through correctional officer questionnaires (activity of daily living (ADL) impairment, geriatric syndromes, level of care), chart review (medical diagnoses), and CDCR data (demographics, disability designation). Overall, 211 (34.1%) geriatric prisoners were unknown to their officer. Of the 407 known prisoners, officers reported that 5.0% had ADL impairment and 3.1% were unsafe. Discordance between officer and CDCR reports of disability was common, with officers reporting higher disability rates. The 41 high-risk prisoners were more likely to have ADL impairment (22.0% vs 5.2%, P <.01) and geriatric syndromes such as falls and incontinence than the random sample. Overall, nearly one-third of geriatric prisoners were unknown to their assigned officer. Officers identified more disability than the CDCR, and prisoners they identified as high risk had nursing home-level functional impairments. Significant improvement in disability assessment is needed for officers and the CDCR. C1 [Williams, Brie A.; Lindquist, Karla; Walter, Louise C.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Williams, Brie A.; Walter, Louise C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Hill, Terry] Calif Prison Receivership, Sacramento, CA USA. [Baillargeon, Jacques] Univ Texas Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX USA. [Mellow, Jeff] CUNY John Jay Coll Criminal Justice, Dept Law Police Sci & Criminal Justice Adm, New York, NY 10019 USA. [Greifinger, Robert] CUNY John Jay Coll Criminal Justice, Criminal Justice Res & Evaluat Ctr, New York, NY 10019 USA. RP Williams, BA (reprint author), 4150 Clement St,Box 181-G, San Francisco, CA 94121 USA. EM brie.williams@ucsf.edu NR 29 TC 11 Z9 12 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2009 VL 57 IS 7 BP 1286 EP 1292 DI 10.1111/j.1532-5415.2009.02286.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 464WI UT WOS:000267539800021 PM 19582902 ER PT J AU Flaherty, JH Shay, K Weir, C Kamholz, B Boockvar, KS Shaughnessy, M Shapiro, R Gordon, S Stein, J Rudolph, JL AF Flaherty, Joseph H. Shay, Kenneth Weir, Charlene Kamholz, Barbara Boockvar, Kenneth S. Shaughnessy, Marianne Shapiro, Rita Gordon, Sharon Stein, Joan Rudolph, James L. CA VA Delirium Working Grp TI The Development of a Mental Status Vital Sign for Use Across the Spectrum of Care SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Mental Status; vital sign; delirium ID HOSPITALIZED OLDER PATIENTS; AGITATION-SEDATION SCALE; DELIRIUM; RELIABILITY; UNIT; RECOGNITION; INPATIENTS; POSTACUTE; VALIDITY; ICU C1 [Flaherty, Joseph H.] St Louis Univ, Sch Med, Div Geriatr, St Louis VA Med Ctr,GRECC, St Louis, MO 63104 USA. [Shay, Kenneth] US Dept Vet Affairs, Off Geriatr & Extended Care, Ann Arbor, MI USA. [Weir, Charlene] Salt Lake City VA Med Ctr, GRECC, Salt Lake City, UT USA. [Kamholz, Barbara] Duke Univ, Durham, NC USA. [Kamholz, Barbara] Durham VA Med Ctr, GRECC, Durham, NC USA. [Boockvar, Kenneth S.] James J Peters VA Med Ctr, GRECC, Bronx, NY USA. [Boockvar, Kenneth S.] Mt Sinai Sch Med, New York, NY USA. [Boockvar, Kenneth S.] Jewish Home Lifecare, New York, NY USA. [Shaughnessy, Marianne] Univ Maryland, Sch Nursing, Baltimore VA Med Ctr, GRECC, Baltimore, MD 21201 USA. [Shapiro, Rita] VA Chicago Hlth Care Syst, Chicago, IL USA. [Gordon, Sharon] VA Ann Arbor Hlth Care Syst, Ann Arbor, MI USA. [Stein, Joan] Tennessee Valley VA, GRECC, Nashville, TN USA. [Stein, Joan] Ctr Hlth Serv Res Vanderbilt, Nashville, TN USA. [Rudolph, James L.] Harvard Univ, Brigham & Womens Hosp, Dept Med, VA Boston Hlth Care Syst,Div Aging,GRECC, Boston, MA 02115 USA. RP Flaherty, JH (reprint author), St Louis Univ, Sch Med, Div Geriatr, St Louis VA Med Ctr,GRECC, 1402 S Grand Blvd,M238, St Louis, MO 63104 USA. EM flaherty@slu.edu OI Boockvar, Kenneth/0000-0003-1165-5558 NR 20 TC 35 Z9 35 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD JUL PY 2009 VL 10 IS 6 BP 379 EP 380 DI 10.1016/j.jamda.2009.04.001 PG 2 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 477ZL UT WOS:000268557400004 PM 19560714 ER PT J AU Ishii, S Weintraub, N Mervis, JR AF Ishii, Shinya Weintraub, Nancy Mervis, James R. TI Apathy: A Common Psychiatric Syndrome in the Elderly SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Review DE Apathy; dementia; cognition disorders; mood disorders ID MILD COGNITIVE IMPAIRMENT; TRAUMATIC BRAIN-INJURY; SUBTHALAMIC NUCLEUS STIMULATION; NURSING-HOME RESIDENTS; PROGRESSIVE SUPRANUCLEAR PALSY; PARAMETRIC MAPPING ANALYSIS; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; NEUROPSYCHIATRIC SYMPTOMS; BEHAVIORAL DISTURBANCES AB Apathy, or a lack of motivation, has been increasingly recognized as a distinct psychiatric syndrome. Apathy is primarily a dysfunction of the frontal-subcortical circuit and is associated with various neuropsychiatric disorders including Alzheimer's disease. Apathy is associated with a number of adverse outcomes, including apparent cognitive impairment, decreased daily function, poor insight into one's own functional and cognitive impairment, and poor outcome from rehabilitation treatment. Furthermore, the degree of caregiver's burden in these patients is significant. This article reviews the definition of apathy, prevalence and associated adverse outcomes, causation, the approach to patients with apathy, and available treatment options with particular attention to studies conducted in a nursing home setting. The purpose of this article is to increase the recognition of apathy by physicians working in the nursing home. (J Am Med Dir Assoc 2009; 10: 381-393) C1 [Ishii, Shinya] Vet Affairs Greater Los Angeles Healthcare Syst, GRECC, Los Angeles, CA 90073 USA. [Weintraub, Nancy; Mervis, James R.] Sepulveda Campus Greater Los Angeles Vet Affairs, Los Angeles, CA 90073 USA. [Weintraub, Nancy; Mervis, James R.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Ishii, S (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, GRECC, 11301 Wilshire Blvd,Bldg 220,Room 302, Los Angeles, CA 90073 USA. EM sishii@mednet.ucla.edu NR 178 TC 48 Z9 52 U1 3 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD JUL PY 2009 VL 10 IS 6 BP 381 EP 393 DI 10.1016/j.jamda.2009.03.007 PG 13 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 477ZL UT WOS:000268557400005 PM 19560715 ER PT J AU Shea, S Weinstock, RS Teresi, JA Palmas, W Starren, J Cimino, JJ Lai, AM Field, L Morin, PC Goland, R Izquierdo, RE Ebner, S Silver, S Petkova, E Kong, J Eimicke, JP AF Shea, Steven Weinstock, Ruth S. Teresi, Jeanne A. Palmas, Walter Starren, Justin Cimino, James J. Lai, Albert M. Field, Lesley Morin, Philip C. Goland, Robin Izquierdo, Roberto E. Ebner, Susana Silver, Stephanie Petkova, Eva Kong, Jian Eimicke, Joseph P. CA IDEATel Consortium TI A Randomized Trial Comparing Telemedicine Case Management with Usual Care in Older, Ethnically Diverse, Medically Underserved Patients with Diabetes Mellitus: 5 Year Results of the IDEATel Study SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID COLUMBIA-UNIVERSITY INFORMATICS; INTENSIVE GLYCEMIC CONTROL; BLOOD-PRESSURE CONTROL; TREATMENT PANEL-III; CARDIOVASCULAR-DISEASE; MICROVASCULAR COMPLICATIONS; COST-EFFECTIVENESS; GLUCOSE CONTROL; ELDERLY PEOPLE; HEALTH-CARE AB Context: Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions and lower access to care. Objectives: To examine the effectiveness of a telemedicine intervention to achieve clinical management goals in older, ethnically diverse, medically underserved patients with diabetes. Design, Setting, and Patients: A randomized controlled trial was conducted, comparing telemedicine case management to usual care, with blinded outcome evaluation, in 1,665 Medicare recipients with diabetes, aged 55 years, residing in federally designated medically underserved areas of New York State. Interventions: Home telemedicine unit with nurse case management versus usual care. Main Outcome Measures: The primary endpoints assessed over 5 years of follow-up were hemoglobin A1c (HgbA1c), low density lipoprotein (LDL) cholesterol, and blood pressure levels. Results: Intention-to-treat mixed models showed that telemedicine achieved net overall reductions over five years of follow-up in the primary endpoints (HgbA1c, p = 0.001; LDL, p < 0.001; systolic and diastolic blood pressure, p = 0.024; p < 0.001). Estimated differences (95% CI) in year 5 were 0.29 (0.12, 0.46)% for HgbA1c, 3.84 (-0.08, 7.77) mg/dL for LDL cholesterol, and 4.32 (1.93, 6.72) mm Hg for systolic and 2.64 (1.53, 3,74) mm Hg for diastolic blood pressure. There were 176 deaths in the intervention group and 169 in the usual care group (hazard ratio 1.01 [0.82, 1.24]). Conclusions: Telemedicine case management resulted in net improvements in HgbA1c, LDL-cholesterol and blood pressure levels over 5 years in medically underserved Medicare beneficiaries. Mortality was not different between the groups, although power was limited. C1 [Shea, Steven; Palmas, Walter; Field, Lesley; Goland, Robin; Ebner, Susana] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Joseph Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Shea, Steven; Cimino, James J.] Columbia Univ, Dept Biomed Informat, New York, NY USA. [Teresi, Jeanne A.] Columbia Univ, Stroud Ctr, New York, NY USA. [Goland, Robin; Ebner, Susana] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY USA. [Weinstock, Ruth S.; Morin, Philip C.; Izquierdo, Roberto E.] SUNY Upstate Med Univ, Joslin Diabet Ctr, Syracuse, NY USA. [Weinstock, Ruth S.; Morin, Philip C.; Izquierdo, Roberto E.] SUNY Upstate Med Univ, Div Endocrinol Diabet & Metab, Syracuse, NY USA. [Weinstock, Ruth S.] VA Med Ctr, Dept Vet Affairs, Syracuse, NY USA. [Teresi, Jeanne A.; Silver, Stephanie; Kong, Jian; Eimicke, Joseph P.] Res Div Hebrew Home Riverdale, Bronx, NY USA. [Teresi, Jeanne A.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [Starren, Justin] Marshfield Clin Fdn Med Res & Educ, Marshfield, MN USA. [Cimino, James J.] Natl Inst Hlth Clin Ctr, Lab Informat Dept, Bethesda, MD USA. [Lai, Albert M.] Ohio State Univ, Columbus, OH 43210 USA. [Petkova, Eva] NYU, Sch Med, Div Biostat, Dept Child & Adolescent Psychiat, New York, NY USA. RP Shea, S (reprint author), Div Gen Med, 630 W 168th St, New York, NY 10032 USA. EM ss35@columbia.edu RI Lai, Albert/E-3453-2011; OI Lai, Albert/0000-0002-9241-2656; Petkova, Eva/0000-0001-5129-9442; Cimino, James/0000-0003-4101-1622 NR 47 TC 131 Z9 134 U1 4 U2 28 PU HANLEY & BELFUS-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 446 EP 456 DI 10.1197/jamia.M3157 PG 11 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 470QZ UT WOS:000267995500003 PM 19390093 ER PT J AU Wang, CJ Patel, MH Schueth, AJ Bradley, M Wu, SY Crosson, JC Glassman, PA Bell, DS AF Wang, C. Jason Patel, Mihir H. Schueth, Anthony J. Bradley, Melissa Wu, Shinyi Crosson, Jesse C. Glassman, Peter A. Bell, Douglas S. TI Perceptions of Standards-based Electronic Prescribing Systems as Implemented in Outpatient Primary Care: A Physician Survey SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article; Proceedings Paper CT Annual Conference of the Agency-for-Healthcare-Research-and-Quality CY SEP 26-28, 2007 CL Bethesda, MD SP Agcy Healthcare Res & Qual ID CLINICAL DECISION-SUPPORT; ORDER ENTRY SYSTEMS; AMBULATORY-CARE; NATIONAL-SURVEY; HEALTH RECORDS; DRUG ALERTS; EXPERIENCES; TECHNOLOGY; ACCEPTANCE; ADOPTION AB Objective: To compare the experiences of e-prescribing users and nonusers regarding prescription safety and workload and to assess the use of information from two e-prescribing standards (for medication history and formulary and benefit information), as they are implemented. Design: Cross-sectional survey of physicians who either had installed or were awaiting installation of one of two commercial e-prescribing systems. Measurements: Perceptions about medication history and formulary and benefit information among all respondents, and among e-prescribing users, experiences with system usability, job performance impact, and amount of e-prescribing. Results: Of 395 eligible physicians, 228 (58%) completed the survey. E-prescribers (n = 139) were more likely than non-e-prescribers (n = 89) to perceive that they could identify clinically important drug-drug interactions (83 versus 67%, p = 0.004) but not that they could identify prescriptions from other providers (65 versus 60%, p = 0.49). They also perceived no significant difference in calls about drug coverage problems (76 versus 71% reported getting 10 or fewer such calls per week; p = 0.43). Most e-prescribers reported high satisfaction with their systems, but 17% had stopped using the system and another 46% said they sometimes reverted to handwriting for prescriptions that they could write electronically. The volume of e-prescribing was correlated with perceptions that it enhanced job performance, whereas quitting was associated with perceptions of poor usability. Conclusions: E-prescribing users reported patient safety benefits but they did not perceive the enhanced benefits expected from using standardized medication history or formulary and benefit information. Additional work is needed for these standards to have the desired effects. C1 [Wang, C. Jason] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Wang, C. Jason; Bradley, Melissa; Wu, Shinyi; Glassman, Peter A.; Bell, Douglas S.] RAND Hlth, Santa Monica, CA USA. [Wang, C. Jason] Boston Univ, Sch Publ Hlth, Dept Maternal & Child Hlth, Boston, MA 02118 USA. [Patel, Mihir H.] MedImpact Healthcare Syst Inc, Hackensack, NJ USA. [Schueth, Anthony J.] Point of Care Partners LLC, Boston, MA USA. [Wu, Shinyi] Univ So Calif, Daniel J Epstein Dept Ind & Syst Engn, Los Angeles, CA USA. [Crosson, Jesse C.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Family Med, Div Res, New Brunswick, NJ USA. [Glassman, Peter A.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Excellence Study Healthcare Provider, Los Angeles, CA USA. [Glassman, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Bell, Douglas S.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med, Los Angeles, CA 90095 USA. RP Wang, CJ (reprint author), Boston Univ, Sch Med, Dept Pediat, 88 E Newto St,Vose 3, Boston, MA 02118 USA. EM jason.wang@bmc.org RI Bell, Douglas/G-6702-2013 OI Bell, Douglas/0000-0002-5063-8294 FU AHRQ HHS [1U18HS016391-01, U18 HS016391]; NEI NIH HHS [1K23EY018668-01, K23 EY018668] NR 41 TC 35 Z9 35 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 493 EP 502 DI 10.1197/jamia.M2998 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 470QZ UT WOS:000267995500009 PM 19390106 ER PT J AU Zai, AH Farr, KM Grant, RW Mort, E Ferris, TG Chueh, HC AF Zai, Adrian H. Farr, Kit M. Grant, Richard W. Mort, Elizabeth Ferris, Timothy G. Chueh, Henry C. TI Queuing Theory to Guide the Implementation of a Heart Failure Inpatient Registry Program SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article; Proceedings Paper CT Spring Congress of the American-Medical-Informatics-Association CY MAY 29-31, 2008 CL Phoenix, AZ SP Amer Med Informat Assoc ID ROOM STAFFING NEEDS; HOSPITAL READMISSION; ELDERLY PATIENTS; CARE; MANAGEMENT; HOME; RISK; SYSTEM; INTERVENTION; ASSOCIATION AB Objective: The authors previously implemented an electronic heart failure registry at a large academic hospital to identify heart failure patients and to connect these patients with appropriate discharge services. Despite significant improvements in patient identification and connection rates, time to connection remained high, with an average delay of 3.2 days from the time patients were admitted to the time connections were made. Our objective for this current study was to determine the most effective solution to minimize time to connection. Design: We used a queuing theory model to simulate 3 different potential solutions to decrease the delay from patient identification to connection with discharge services. Measurements: The measures included average rate at which patients were being connected to the post discharge heart failure services program, average number of patients in line, and average patient waiting time. Results: Using queuing theory model simulations, we were able to estimate for our current system the minimum rate at which patients need to be connected (262 patients/mo), the ideal patient arrival rate (174 patients/mo) and the maximal patient arrival rate that could be achieved by adding 1 extra nurse (348 patients/mo). Conclusions: Our modeling approach was instrumental in helping us characterize key process parameters and estimate the impact of adding staff on the time between identifying patients with heart failure and connecting them with appropriate discharge services. C1 [Zai, Adrian H.; Grant, Richard W.; Chueh, Henry C.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. [Mort, Elizabeth; Ferris, Timothy G.] Massachusetts Gen Hosp, Massachusetts Gen Phys Org, Boston, MA 02114 USA. [Mort, Elizabeth; Chueh, Henry C.] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Farr, Kit M.] Newton Wellesley Hosp, Cardiovasc Hlth Ctr, Boston, MA USA. [Mort, Elizabeth; Ferris, Timothy G.] Partners Healthcare, Boston, MA USA. RP Zai, AH (reprint author), Massachusetts Gen Hosp, Comp Sci Lab, 50 Staniford St,Suite 750, Boston, MA 02114 USA. EM azai@partners.org OI Zai, Adrian/0000-0002-2972-6839; Grant, Richard/0000-0002-6164-8025 NR 48 TC 6 Z9 6 U1 1 U2 2 PU HANLEY & BELFUS-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 516 EP 523 DI 10.1197/jamia.M2977 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 470QZ UT WOS:000267995500012 PM 19390108 ER PT J AU Douglas, PS DeCara, JM Devereux, RB Duckworth, S Gardin, JM Jaber, WA Morehead, AJ Oh, JK Picard, MH Solomon, SD Wei, K Weissman, NJ AF Douglas, Pamela S. DeCara, Jeanne M. Devereux, Richard B. Duckworth, Shelly Gardin, Julius M. Jaber, Wael A. Morehead, Annitta J. Oh, Jae K. Picard, Michael H. Solomon, Scott D. Wei, Kevin Weissman, Neil J. TI Echocardiographic Imaging in Clinical Trials: American Society of Echocardiography Standards for Echocardiography Core Laboratories Endorsed by the American College of Cardiology Foundation SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID REPRODUCIBILITY; RELIABILITY; PERFORMANCE; AGREEMENT; MASS C1 [Douglas, Pamela S.; Duckworth, Shelly] Duke Univ, Med Ctr, Durham, NC USA. [DeCara, Jeanne M.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Devereux, Richard B.] New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. [Gardin, Julius M.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Gardin, Julius M.] Touro Univ, Coll Med, Hackensack, NJ USA. [Jaber, Wael A.; Morehead, Annitta J.] Cleveland Clin, Cleveland, OH 44106 USA. [Oh, Jae K.] Mayo Clin, Rochester, MN USA. [Picard, Michael H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Solomon, Scott D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Wei, Kevin] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Weissman, Neil J.] Washington Hosp Ctr, Washington, DC 20010 USA. RP Douglas, PS (reprint author), Amer Soc Echocardiog, 2100 Gateway Ctr Blvd,Suite 310, Morrisville, NC 27560 USA. EM ase@asecho.org RI Solomon, Scott/I-5789-2013; OI Picard, Michael/0000-0002-9264-3243 NR 21 TC 78 Z9 80 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD JUL PY 2009 VL 22 IS 7 BP 755 EP 765 DI 10.1016/j.echo.2009.05.020 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465KG UT WOS:000267582100003 PM 19560654 ER PT J AU Martin, NM Picard, MH AF Martin, Nicole M. Picard, Michael H. TI Two Years of Appropriateness Criteria for Echocardiography: What Have We Learned and What Else Do We Need to Do? SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Editorial Material C1 [Picard, Michael H.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Boston, MA 02114 USA. [Martin, Nicole M.; Picard, Michael H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Picard, MH (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Yawkey 5E,55 Fruit St, Boston, MA 02114 USA. EM mhpicard@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 11 TC 9 Z9 9 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD JUL PY 2009 VL 22 IS 7 BP 800 EP 802 DI 10.1016/j.echo.2009.05.024 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465KG UT WOS:000267582100008 PM 19560658 ER PT J AU Wang, YX John, R Chen, JL Richardson, JA Shelton, JM Bennett, M Zhou, XJ Nagami, GT Zhang, Y Wu, QQ Lu, CY AF Wang, Yanxia John, Reji Chen, Jianlin Richardson, James A. Shelton, John M. Bennett, Michael Zhou, Xin J. Nagami, Glenn T. Zhang, Ying Wu, Qing Qing Lu, Christopher Y. TI IRF-1 Promotes Inflammation Early after Ischemic Acute Kidney Injury SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-of-Nephrology/Annual Renal Week CY NOV 04-09, 2008 CL Philadelphia, PA SP Amer Soc Nephrol ID ACUTE-RENAL-FAILURE; REGULATORY FACTOR-I; ACUTE TUBULAR-NECROSIS; REPERFUSION INJURY; TRANSCRIPTION FACTORS; ISCHEMIA/REPERFUSION INJURY; DOCOSAHEXAENOIC ACID; EPITHELIAL-CELLS; TNF-ALPHA; T-CELL AB Acute renal ischemia elicits an inflammatory response that may exacerbate acute kidney injury, but the regulation of the initial signals that recruit leukocytes is not well understood. Here, we found that IFN regulatory factor 1 (IRF-1) was a critical, early proinflammatory signal released during ischemic injury in vitro and in vivo. Within 15 min of reperfusion, proximal tubular cells of the S3 segment produced IRF-1, which is a transcription factor that activates proinflammatory genes. Transgenic knockout of IRF-1 ameliorated the impairment of renal function, morphologic injury, and inflammation after acute ischemia. Bone marrow chimera experiments determined that maximal ischemic injury required IRF-1 expression by both leukocytes and radioresistant renal cells, the latter identified as S3 proximal tubule cells in the outer medulla by in situ hybridization and immunohistochemistry. In vitro, reactive oxygen species, generated during ischemia/reperfusion injury, stimulated expression of IRF-1 in an S3 proximal tubular cell line. Taken together, these data suggest that IRF-1 gene activation by reactive oxygen species is an early signal that promotes inflammation after ischemic renal injury. C1 [Richardson, James A.; Shelton, John M.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Richardson, James A.; Shelton, John M.; Bennett, Michael; Zhou, Xin J.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Lu, Christopher Y.] Univ Texas SW Med Ctr Dallas, Grad Program Immunol, Dallas, TX 75390 USA. [Nagami, Glenn T.] VA Greater Los Angeles, Nephrol Sect, Los Angeles, CA USA. [Nagami, Glenn T.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Lu, CY (reprint author), Univ Texas SW Med Sch, Dept Internal Med Nephrol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM christopher.lu@utsouthwestern.edu FU NIDDK NIH HHS [P30DK079328, P30 DK079328, R01DK06963303] NR 62 TC 23 Z9 25 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2009 VL 20 IS 7 BP 1544 EP 1555 DI 10.1681/ASN.2008080843 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 467XC UT WOS:000267775400019 PM 19443641 ER PT J AU Gundiah, N Ratcliffe, MB Pruitt, LA AF Gundiah, Namrata Ratcliffe, Mark B. Pruitt, Lisa A. TI The biomechanics of arterial elastin SO JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS LA English DT Article ID STRAIN-ENERGY FUNCTION; MECHANICAL-PROPERTIES; CONSTITUTIVE RELATION; PASSIVE MYOCARDIUM; LAMELLAR UNIT; DEFORMATION; PROTEINS; BEHAVIOR; SOLIDS AB Uniaxial mechanical experiments have shown that a neo-Hookean/Gaussian model is suitable to describe the mechanics of arterial elastin networks [Gundiah, N., Ratcliffe, M.B., Pruitt, L.A., 2007. Determination of strain energy function for arterial elastin: Experiments using histology and mechanical tests. J. Biomech. 40, 586-594]. Based on the three-dimensional elastin architecture in arteries, we have proposed an orthotropic material symmetry for arterial elastin consisting of two orthogonally oriented and symmetrically placed families of mechanically equivalent fibers. In this study, we use these results to describe the strain energy function for arterial elastin, with dependence on a reduced subclass of invariants, as W = W(I(1), I(4)). We use previously published equations for this dependence [Humphrey, J.D., Strumpf, R.K., Yin, F.C.P., 1990a. Determination of a constitutive relation for passive myocardium: I. A new functional form. J. Biomech. Eng. 112, 333-339], in combination with a theoretical guided Rivlin-Saunders framework [Rivlin, R.S., Saunders, D.W, 1951. Large elastic deformations of isotropic materials VII. Experiments on the deformation of rubber. Phil. Trans. R. Soc. A 243, 251-288] and biaxial mechanical experiments, to obtain the form of this dependence. Using mechanical equivalence of elastin in the circumferential and longitudinal directions, we add a term in 16 to W that is similar to the form in 14. We propose a semi-empirical model for arterial elastin given by W = c(0) (I(1) - 3) + c(1) (I(4) - 1)(2) + c(2) (I(6) - 1)(2), where c(0), c(1) and c(3) are unknown coefficients. we used the Levenberg-Marquardt algorithm to fit theoretically calculated and experimentally determined stresses from equibiaxial experiments on autoclaved elastin tissues and obtain c(0) = 73.96 +/- 22.51 kPa, c(1) = 1.18 +/- 1.79 kPa and c(2) = 0.8 +/- 1.26 kPa. Thus, the entropic contribution to the strain energy function, represented by c(0), is a dominant feature of elastin mechanics. Because there are no significant differences in the coefficients corresponding to invariants 14 and 16, we surmise that there is an equal distribution of fibers in the circumferential and axial directions. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Gundiah, Namrata; Pruitt, Lisa A.] Univ Calif Berkeley, Dept Mech Engn, Berkeley, CA 94720 USA. [Pruitt, Lisa A.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Ratcliffe, Mark B.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Ratcliffe, Mark B.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Pruitt, LA (reprint author), Univ Calif Berkeley, Dept Mech Engn, 5134 Etcheverry Hall,Mailstop 1740, Berkeley, CA 94720 USA. EM lpruitt@me.berkeley.edu FU NHLBI NIH HHS [R01 HL063348, 2R01 HL06334805] NR 34 TC 24 Z9 24 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1751-6161 J9 J MECH BEHAV BIOMED JI J. Mech. Behav. Biomed. Mater. PD JUL PY 2009 VL 2 IS 3 BP 288 EP 296 DI 10.1016/j.jmbbm.2008.10.007 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 430SO UT WOS:000265009000008 PM 19627833 ER PT J AU DeCaprio, JA AF DeCaprio, James A. TI Does Detection of Merkel Cell Polyomavirus in Merkel Cell Carcinoma Provide Prognostic Information? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP DeCaprio, JA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Mayer 440,44 Binney St, Boston, MA 02115 USA. EM james_decaprio@dfci.harvard.edu FU NCI NIH HHS [R01 CA173023] NR 12 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 1 PY 2009 VL 101 IS 13 BP 905 EP 907 DI 10.1093/jnci/djp162 PG 3 WC Oncology SC Oncology GA 466MS UT WOS:000267666900003 PM 19535772 ER PT J AU Burstein, HJ AF Burstein, Harold J. TI Quality Measures, Clinical Practice, NCCN, and McAllen, Texas SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Burstein, Harold J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA USA. [Burstein, Harold J.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Burstein, HJ (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2009 VL 7 IS 7 BP 695 EP 695 PG 1 WC Oncology SC Oncology GA 499ZJ UT WOS:000270265300001 PM 19635224 ER PT J AU Clark, OH Ajani, JA Benson, AB Berlin, JD Blaszkowsky, LS Byrd, D Choti, MA Doherty, GM Engstrom, PF Gibbs, JF Heslin, MJ Kandeel, F Kessinger, A Kulke, MH Kunz, P Kvols, L Olson, JA Ratliff, TW Salem, R Saltz, L Schteingart, DE Shah, MH Shibata, S AF Clark, Orlo H. Ajani, Jaffer A. Benson, Al B., III Berlin, Jordan D. Blaszkowsky, Lawrence S. Byrd, David Choti, Michael A. Doherty, Gerard M. Engstrom, Paul F. Gibbs, John F. Heslin, Martin J. Kandeel, Fouad Kessinger, Anne Kulke, Matthew H. Kunz, Pamela Kvols, Larry Olson, John A., Jr. Ratliff, Thomas W. Salem, Riad Saltz, Leonard Schteingart, David E. Shah, Manisha H. Shibata, Stephen TI Neuroendocrine Tumors SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE NCCN Clinical Practice Guidelines; neuroendocrine tumors; carcinoma; multiple endocrine neoplasia; MEN-1; MEN-2; pheochromocytoma; islet cell cancer ID SPORADIC ADRENOCORTICAL TUMORS; ADRENAL-CORTICAL CARCINOMA; ISLET-CELL-CARCINOMA; PHASE-II TRIAL; ENDOCRINE GASTROENTEROPANCREATIC TUMORS; HEPATIC ARTERIAL CHEMOEMBOLIZATION; SOMATOSTATIN-RECEPTOR SCINTIGRAPHY; LAPAROSCOPIC THERMAL ABLATION; MALIGNANT PHEOCHROMOCYTOMA; CHROMOGRANIN-A C1 [Ajani, Jaffer A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Benson, Al B., III; Salem, Riad] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Blaszkowsky, Lawrence S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Byrd, David] Seattle Canc Care Alliance, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Choti, Michael A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sidney, BC, Canada. [Doherty, Gerard M.; Schteingart, David E.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Heslin, Martin J.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Kessinger, Anne] Univ Nebraska Med Ctr, Eppley Canc Ctr, Omaha, NE USA. [Ratliff, Thomas W.] Univ Tennessee, Inst Canc, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. OI Saltz, Leonard/0000-0001-8353-4670 NR 114 TC 50 Z9 55 U1 0 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2009 VL 7 IS 7 BP 712 EP 747 PG 36 WC Oncology SC Oncology GA 499ZJ UT WOS:000270265300003 PM 19635226 ER PT J AU Klein, MM Downs, HM Oaklander, AL AF Klein, M. M. Downs, H. M. Oaklander, A. L. TI BEST TEST? COMPARISON OF DISTAL-LEG SKIN BIOPSY, AUTONOMIC FUNCTION TESTING, BLOOD-FLOW, AND AXON FLARE MEASUREMENTS FOR DIAGNOSIS OF SMALL-FIBER POLYNEUROPATHY (SFPN) SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Annual Meeting of the Peripheral-Nerve-Society CY JUL 04-08, 2009 CL Wurzburg, GERMANY SP Peripheral Nerve Soc C1 [Klein, M. M.; Downs, H. M.; Oaklander, A. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD JUL PY 2009 VL 14 BP 76 EP 76 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 490TE UT WOS:000269527000175 ER PT J AU Korngut, L Che, M Martinez, JA Toth, CC Woolf, CJ Zochodne, DW AF Korngut, L. Che, Ma Martinez, J. A. Toth, C. C. Woolf, C. J. Zochodne, D. W. TI EARLY PROTECTION FROM SENSORY ABNORMALITIES IN DIABETIC MICE WITH OVEREXPRESSION OF HUMAN HEAT SHOCK PROTEIN 27 SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Annual Meeting of the Peripheral-Nerve-Society CY JUL 04-08, 2009 CL Wurzburg, GERMANY SP Peripheral Nerve Soc C1 [Korngut, L.; Martinez, J. A.; Toth, C. C.; Zochodne, D. W.] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Calgary, AB, Canada. [Che, Ma; Woolf, C. J.] Harvard Univ, Sch Med, Dept Anaesthesia & Crit Care, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD JUL PY 2009 VL 14 BP 79 EP 79 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 490TE UT WOS:000269527000182 ER PT J AU Oaklander, AL AF Oaklander, A. L. TI INITIAL CHARACTERIZATION OF ACQUIRED JUVENILE-ONSET SMALL-FIBER POLYNEUROPATHY (SFPN): EVIDENCE FOR ORGAN-SPECIFIC AUTOIMMUNITY SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Annual Meeting of the Peripheral-Nerve-Society CY JUL 04-08, 2009 CL Wurzburg, GERMANY SP Peripheral Nerve Soc C1 [Oaklander, A. L.] Harvard Univ, Sch Med, Boston, MA USA. [Oaklander, A. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD JUL PY 2009 VL 14 BP 112 EP 113 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 490TE UT WOS:000269527000256 ER PT J AU Moukarbel, GV Jneid, H Walker, JD Garasic, JM Wang, TJ AF Moukarbel, George V. Jneid, Hani Walker, Jennifer D. Garasic, Joseph M. Wang, Thomas J. TI Aortic pseudoaneurysm compressing the left coronary artery SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 [Moukarbel, George V.; Jneid, Hani; Garasic, Joseph M.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Walker, Jennifer D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cardiac Surg, Boston, MA 02114 USA. RP Moukarbel, GV (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, GRB-800,55 Fruit St, Boston, MA 02114 USA. EM moukarbel.george@mgh.harvard.edu NR 6 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JUL PY 2009 VL 138 IS 1 BP 236 EP 237 DI 10.1016/j.jtcvs.2008.02.077 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 466WQ UT WOS:000267695400040 PM 19577088 ER PT J AU Park, S Holmes-Tisch, AJ Cho, EY Shim, YM Kim, J Kim, HS Lee, J Park, YH Ahn, JS Park, K Janne, PA Ahn, MJ AF Park, Sarah Holmes-Tisch, Alison J. Cho, Eun Yoon Shim, Young Mog Kim, Jinkook Kim, Hyo Song Lee, Jeeyun Park, Yeon Hee Ahn, Jin Seok Park, Keunchil Jaenne, Pasi A. Ahn, Myung-Ju TI Discordance of Molecular Biomarkers Associated with Epidermal Growth Factor Receptor Pathway between Primary Tumors and Lymph Node Metastasis in Non-small Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Non-small cell lung cancer; EGFR; Mutation; Lymph node; Metastasis; DNA sequencing ID DISSECTION IMPROVES SURVIVAL; PREVIOUSLY TREATED PATIENTS; GENETIC-HETEROGENEITY; CLONAL EVOLUTION; EGFR MUTATIONS; BREAST-CANCER; STAGES II; GEFITINIB; ERLOTINIB; EXPRESSION AB Introduction: For the identification of the patients who most likely benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), molecular assays are considered to be of paramount importance. Given the heterogeneity of NSCLC at the molecular level, this study was conducted to determine the discrepancy in EGFR mutations between primary tumors and the corresponding lymph node metastasis. Patients and Methods: Surgically resected 101 paired primary NSCLC and metastatic lymph nodes were evaluated for the EGFR mutations by direct DNA sequencing and heteroduplex analysis. Results: EGFR mutation was detected in 29.7% (30 of 101) of the primary tumors and in 27.7% of lymph node metastases (28 of 101) by either direct sequencing or heteroduplex analysis, respectively. By direct sequencing, 12 cases (11.9%) showed discordance in EGFR mutations between primary tumors and metastasis. In 11 cases, EGFR mutations were detected only in the primary tumor, whereas 1 case only in lymph node metastases. By heteroduplex analysis, 17 cases (16.8%) were discordant. Ten cases were primary tumor positive and lymph node negative, whereas seven cases were lymph node positive and primary tumor negative. Conclusions: A considerable proportion of NSCLC showed discrepancy in EGFR Mutations between primary tumors and metastatic lymph nodes, suggesting tumor heterogeneity at the molecular level during the process of metastasis. C1 [Kim, Hyo Song; Lee, Jeeyun; Park, Yeon Hee; Ahn, Jin Seok; Park, Keunchil; Ahn, Myung-Ju] Sungkyunkwan Univ, Div Hematol Oncol, Dept Med, Samsung Med Ctr,Sch Med, Seoul 135710, South Korea. [Park, Sarah] Hallym Univ, Div Hematol Oncol, Dept Med, Hangang Sacred Heart Hosp,Sch Med, Seoul, South Korea. [Holmes-Tisch, Alison J.; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cho, Eun Yoon] Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Dept Pathol, Seoul 135710, South Korea. [Shim, Young Mog] Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Dept Thorac & Cardiovasc Surg, Seoul 135710, South Korea. RP Ahn, MJ (reprint author), Sungkyunkwan Univ, Div Hematol Oncol, Dept Med, Samsung Med Ctr,Sch Med, 50 Ilwon Dong, Seoul 135710, South Korea. EM pjanne@partners.org; silkahn@skku.edu RI Lee, Jee Yun/C-9646-2011; Kim, Jhingook/C-9663-2011; Lee, Jeeyun/I-7171-2015 FU Korean Health 21 RD Project; Ministry of Health and Welfare, and Republic of Korea [0405-MN01-0604-0007] FX Supported in part by a grant of the Korean Health 21 R&D Project, Ministry of Health and Welfare, and Republic of Korea (0405-MN01-0604-0007). NR 37 TC 89 Z9 96 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2009 VL 4 IS 7 BP 809 EP 815 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 462VR UT WOS:000267386000007 PM 19487967 ER PT J AU Chen, Z Shivdasani, RA AF Chen, Z. Shivdasani, R. A. TI Regulation of platelet biogenesis: insights from the May-Hegglin anomaly and other MYH9-related disorders SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article; Proceedings Paper CT 22nd Congress of the International-Society-on-Thrombosis-and-Haemostasis CY JUL 12-17, 2009 CL Boston, MD SP Int Soc Thrombos & Haemostas DE megakaryocyte May-Hegglin anomaly; myosin IIA; platelet ID MYOSIN HEAVY-CHAIN; RESTRICTED MYH9 INACTIVATION; PROPLATELET FORMATION; LEUKOCYTE INCLUSIONS; BONE-MARROW; NEGATIVE REGULATOR; FECHTNER-SYNDROME; MUTATIONS; MEGAKARYOCYTES; DISEASE AB Megakaryocyte (MK) maturation culminates in release of blood platelets through proplatelet extensions. MKs presumably delay elaborating proplatelets until synthesis of platelet constituents is complete. Recent insights from investigation of a classic human congenital macrothrombocytopenia, the May-Hegglin anomaly, and related MYH9-associated disorders shed new light on underlying mechanisms. The findings reviewed in this article implicate myosin IIA, the nonmuscle myosin heavy chain product of the MYH9 gene, in restraining proplatelet formation until MKs achieve terminal maturity. Loss of myosin IIA function, through dominant inhibitory mutations in humans, targeted gene disruption in mice, or manipulation of cultured MKs, seems to accelerate proplatelet formation. The resulting process is inefficient and produces platelets that vary widely in size, shape and content. Several lines of evidence suggest that the Rho-ROCK-myosin light chain pathway restrains proplatelet formation through myosin IIA. These findings illustrate that mammalian thrombopoiesis is complex and subject to both positive and negative regulation. C1 [Chen, Z.; Shivdasani, R. A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chen, Z.; Shivdasani, R. A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shivdasani, R. A.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Dana 720, Boston, MA 02115 USA. EM ramesh_shivdasani@dfci.harvard.edu FU NHLBI NIH HHS [R01HL63143] NR 34 TC 13 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2009 VL 7 BP 272 EP 276 DI 10.1111/j.1538-7836.2009.03425.x PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 470IY UT WOS:000267969600061 PM 19630815 ER PT J AU Diener, JL Lagasse, HAD Duerschmied, D Merhi, Y Tanguay, JF Hutabarat, R Gilbert, J Wagner, DD Schaub, R AF Diener, J. L. Lagasse, H. A. Daniel Duerschmied, D. Merhi, Y. Tanguay, J-F. Hutabarat, R. Gilbert, J. Wagner, D. D. Schaub, R. TI Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779 SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE aptamer; platelets; thrombosis; von Willebrand factor ID CORONARY-ARTERY THROMBOSIS; FACTOR A1 DOMAIN; ELEVATION-MYOCARDIAL-INFARCTION; HUMANIZED MONOCLONAL-ANTIBODY; GLYCOPROTEIN-IB; VONWILLEBRAND-FACTOR; CRYSTAL-STRUCTURE; ALPHA; DISEASE; VWF AB Background: von Willebrand factor (VWF) has a role in both hemostasis and thrombosis. Platelets adhere to damaged arteries by interactions between the VWF A1-domain and glycoprotein Ib receptors under conditions of high shear. This initial platelet binding event stimulates platelet activation, recruitment, and activation of the clotting cascade, promoting thrombus formation. Objective: To characterize the inhibitory activity of a VWF inhibitory aptamer. Methods: Using in vitro selection, aptamer stabilization, and conjugation to a 20-kDa poly(ethylene glycol), we generated a nuclease-resistant aptamer, ARC1779, that binds to the VWF A1-domain with high affinity (K(D) similar to 2 nm). The aptamer was assessed for inhibition of VWF-induced platelet aggregation. In vitro inhibition of platelet adhesion was assessed on collagen-coated slides and injured pig aortic segments. In vivo activity was assessed in a cynomolgus monkey carotid electrical injury thrombosis model. Results and Conclusion: ARC1779 inhibited botrocetin-induced platelet aggregation (IC(90) similar to 300 nm) and shear force-induced platelet aggregation (IC(95) similar to 400 nm). It reduced adhesion of platelets to collagen-coated matrices and formation of platelet thrombi on denuded porcine arteries. ARC1779 also inhibited the formation of occlusive thrombi in cynomolgus monkeys. We have discovered a novel anti-VWF aptamer that could have therapeutic use as an anti-VWF agent in the setting of VWF-mediated thrombosis. C1 [Hutabarat, R.; Gilbert, J.; Schaub, R.] Archemix Corp, Cambridge, MA 02142 USA. [Duerschmied, D.; Wagner, D. D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Duerschmied, D.; Wagner, D. D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Merhi, Y.; Tanguay, J-F.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. RP Schaub, R (reprint author), Archemix Corp, 300 3rd St, Cambridge, MA 02142 USA. EM bschaub@archemix.com FU National Heart, Lung and Blood Institute of the National Institutes of Health [HL095091] FX The authors wish to thank A. Makim, S. Lewis and T. McCauley for pharmacokinetic support, P. Wagner and M. Gilbert for assay support, and R. Boomer and J. Fraone for compound synthesis. This work was supported in part by a National Heart, Lung and Blood Institute of the National Institutes of Health grant HL095091 to D. D. Wagner and R. Schaub. NR 36 TC 63 Z9 66 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2009 VL 7 IS 7 BP 1155 EP 1162 DI 10.1111/j.1538-7836.2009.03459.x PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 463JA UT WOS:000267427000017 PM 19422452 ER PT J AU Duerschmied, D Canault, M Lievens, D Brill, A Cifuni, SM Bader, M Wagner, DD AF Duerschmied, D. Canault, M. Lievens, D. Brill, A. Cifuni, S. M. Bader, M. Wagner, D. D. TI Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17) SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE 5-HT2AR; GPIb alpha; platelet; serotonin; TACE ID VON-WILLEBRAND-FACTOR; THROMBUS FORMATION; 5-HT2A RECEPTOR; GPIB-IX; ACTIVATION; AGGREGATION; TRANSPORTER; PROLIFERATION; ANTAGONISTS; MEDICATION AB Background: Peripheral serotonin (5-hydroxytryptamine, 5-HT) is transported by platelets and released upon stimulation. In the platelet cytoplasm, 5-HT is transamidated to small GTPases, promoting alpha-granule release and primary hemostasis. Objective: We hypothesized that 5-HT could also stimulate platelet receptor shedding after binding to the membrane 5-HT receptor (5-HT2AR). Methods: Western blot and flow cytometry were used to determine levels of the adhesion receptor glycoprotein (GP)Ib alpha on platelets or its shed fragment glycocalicin in plasma and serum from wild-type mice, Tph1(-/-) mice lacking peripheral 5-HT, and mice lacking functional tumor necrosis factor-alpha-converting enzyme (TACE, ADAM17). Flow chamber experiments and intravital microscopy were used to examine the adhesive properties of platelets after stimulation of 5-HT2AR. Results: Glycocalicin was significantly reduced in Tph1(-/-) plasma and serum. In isolated platelets, 5-HT induced shedding of GPIb alpha, which was increased to 60% when 5-HT uptake was inhibited by the selective serotonin reuptake inhibitor fluoxetine. Specific 5-HT2AR agonism and antagonism suggested activation of this receptor. The shedding could not be induced in TACE(Delta Zn/Delta Zn) platelets, suggesting that activated TACE mediated the shedding of GPIb alpha. Intracellular signaling involved phosphorylation of p38 mitogen-activated protein kinase rather than G-protein signaling. 5-HT2AR stimulation decreased platelet adhesion to collagen-bound von Willebrand factor under arterial shear (1500 s(-1)) and incorporation into FeCl(3)-induced thrombi in mesenteric arterioles. Conclusions: Stimulation of 5-HT2AR on platelets induces TACE-mediated shedding of GPIb alpha, the key adhesion molecule under high shear conditions. Our observations demonstrate a new pathway through which 5-HT could modulate cardiovascular disease. C1 [Duerschmied, D.; Canault, M.; Lievens, D.; Brill, A.; Cifuni, S. M.; Wagner, D. D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Duerschmied, D.; Canault, M.; Brill, A.; Wagner, D. D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Duerschmied, D.] Univ Hosp Freiburg, Freiburg, Germany. [Bader, M.] Max Delbruck Ctr Mol Med, Berlin, Germany. RP Wagner, DD (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 3 Blackfan Circle,3rd Floor, Boston, MA 02115 USA. EM wagner@idi.harvard.edu RI Lievens, Dirk/D-6975-2011; Canault, Matthias/H-5128-2013; OI Canault, Matthias/0000-0002-7880-5250; Bader, Michael/0000-0003-4780-4164 FU National Institutes of Health [1 HL056949]; Fondation pour la Recherche Medicale, France FX We thank N. D. Horseman for kindly providing Tph1-/- mice and L. Cowan for proofreading the manuscript. This work was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health (grant PO 1 HL056949 to D. D. Wagner). M. Canault was supported by the Fondation pour la Recherche Medicale, France. NR 35 TC 21 Z9 21 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2009 VL 7 IS 7 BP 1163 EP 1171 DI 10.1111/j.1538-7836.2009.03476.x PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 463JA UT WOS:000267427000018 PM 19426283 ER PT J AU Hursting, MJ Jang, IK AF Hursting, Marcie J. Jang, Ik-Kyung TI Dosing patterns and outcomes in African American, Asian, and Hispanic patients with heparin-induced thrombocytopenia treated with argatroban SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Heparin-induced thrombocytopenia; Thrombosis; Race; Argatroban; Risk factors ID PERCUTANEOUS CORONARY INTERVENTION; RISK-FACTORS; CARDIOVASCULAR-DISEASE; RECOMBINANT HIRUDIN; RENAL-FAILURE; OPEN-LABEL; THROMBOSIS; ANTICOAGULATION; THERAPY; DYSFUNCTION AB We retrospectively evaluated dosing patterns and 37-day outcomes in argatroban-treated African American (n = 52), Asian (n = 13), and Hispanic (n = 14) patients with heparin-induced thrombocytopenia (HIT). The Asians required a lesser median dose (1.0 mu g/kg/min) than the other groups (1.9 mu g/kg/min, each) to achieve comparable activated partial thromboplastin times (medians: 61-69 s). Durations of therapy were similar (medians: 4.0-5.5 days). New thrombosis occurred in 11 (21%) African Americans, 1 (8%) Asian, and 1 (7%) Hispanic; of these 13 patients, 9 (69%) had baseline HIT-related thrombosis. Amputation occurred in 6 (12%) African Americans and 3 (21%) Hispanics; of these nine patients, 6 (67%) had diabetes. One (2%) African American and 1 (7%) Hispanic died from thrombosis. The composite of death due to thrombosis, amputation due to ischemic complications of HIT, or new thrombosis occurred in 14 (27%) African Americans, 1 (8%) Asian, and 4 (29%) Hispanics. Two (4%) African Americans and none others (0%) had major bleeding. These findings suggest that despite argatroban anticoagulation, African Americans and Hispanics may have worse outcomes in HIT than Asians. In minority patients with adverse HIT outcomes, baseline HIT-related thrombosis or diabetes is often present. C1 [Jang, Ik-Kyung] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jang, Ik-Kyung] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Hursting, Marcie J.] Clin Sci Consulting, Austin, TX USA. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, Bigelow 800,55 Fruit St, Boston, MA 02114 USA. EM ijang@partners.org FU GlaxoSmithKline FX MJH received consultancy fees from GlaxoSmithKline. IKJ has received grant support from GlaxoSmithKline. The authors have full control of all primary data and agree to allow the journal to review their data, if requested. NR 44 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD JUL PY 2009 VL 28 IS 1 BP 10 EP 15 DI 10.1007/s11239-008-0295-x PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 457ES UT WOS:000266911900003 PM 19016311 ER PT J AU Tigli, RS Ghosh, S Laha, MM Shevde, NK Daheron, L Gimble, J Gumusderelioglu, M Kaplan, DL AF Tigli, R. Seda Ghosh, Sourabh Laha, Michael M. Shevde, Nirupama K. Daheron, Laurence Gimble, Jeffrey Gumusderelioglu, Menemse Kaplan, David L. TI Comparative chondrogenesis of human cell sources in 3D scaffolds SO JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE LA English DT Article DE chondrocytes; stem cells; silk; chitosan; chrondrogenesis; scaffold ID MESENCHYMAL STEM-CELLS; HUMAN ARTICULAR CHONDROCYTES; BONE-MARROW; ADIPOSE-TISSUE; IN-VITRO; STROMAL CELLS; SILK SCAFFOLDS; NEOCARTILAGE FORMATION; CHITOSAN SCAFFOLDS; CARTILAGE DEFECTS AB Cartilage tissue can be engineered by starting from a diversity of cell sources, including stem-cell based and primary cell-based platforms. Selecting an appropriate cell source for the process of cartilage tissue engineering or repair is critical and challenging, due to the variety of cell options available. in this study, cellular responses of isolated human chondrocytes, human embryonic stem cells and mesenchymal stem cells (MSCs) derived from three sources, human embryonic stem cells, bone marrow and adipose tissue, were assessed for chondrogenic potential in 3D culture. All cell sources were characterized by FACS analysis to compare expression of some surface markers. The cells were differentiated in two different biomaterial matrices, silk and chitosan scaffolds, in the presence and absence of bone morphogenetic protein 6 (BMP6), along with the standard chondrogenic differentiating factors. Embryonic stem cells-derived MSCs showed unique characteristics, with preserved chondrogenic phenotype in both scaffolds with regard to chondrogenesis, as determined by real time RT-PCR, histological and microscopical analyses. After 4 weeks of cultivation, embryonic stem cells-derived MSCs were promising for chondrogenesis, particularly in the silk scaffolds with BMP6. The results suggest that cell source differences are important to consider with regard to chondrogenic outcomes, and among the variables addressed here the human embryonic stem cells-derived MSCs were the preferred cell source. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Tigli, R. Seda; Ghosh, Sourabh; Laha, Michael M.; Kaplan, David L.] Tufts Univ, Dept Biomed Engn, Medford, MA 02155 USA. [Tigli, R. Seda; Gumusderelioglu, Menemse] Hacettepe Univ, Dept Chem Engn, TR-06800 Beytepe, Turkey. [Shevde, Nirupama K.] WiCell Res Inst, Madison, WI 53707 USA. [Daheron, Laurence] Massachusetts Gen Hosp, Ctr Regenerat Med & Technol, Boston, MA 02114 USA. [Gimble, Jeffrey] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Kaplan, DL (reprint author), Tufts Univ, Dept Biomed Engn, 4 Colby St, Medford, MA 02155 USA. EM David.Kaplan@tufts.edu RI Ghosh, Sourabh/D-2942-2011 FU Turkish National Research Council (TuBiTAK); NIH [P41] FX R. Seda Tigh acknowledges a grant provided by the Turkish National Research Council (TuBiTAK). We thank the NIH P41 Tissue Engineering Resource Center for support of the studies. NR 63 TC 61 Z9 64 U1 3 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-6254 EI 1932-7005 J9 J TISSUE ENG REGEN M JI J. Tissue Eng. Regen. Med. PD JUL PY 2009 VL 3 IS 5 BP 348 EP 360 DI 10.1002/term.169 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Engineering, Biomedical SC Cell Biology; Biotechnology & Applied Microbiology; Engineering GA 473SA UT WOS:000268228000003 ER PT J AU Lindenhovius, ALC Fesch, Q Ring, D Kloen, P AF Lindenhovius, Anneluuk L. C. Fesch, Quinten Ring, David Kloen, Peter TI The Long-Term Outcome of Open Reduction and Internal Fixation of Stable Displaced Isolated Partial Articular Fractures of the Radial Head SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article DE Radial head fracture; Mason 2; Long term; Open reduction internal fixation ID MASON TYPE-II; FOLLOW-UP; NECK; ELBOW AB Background: Excellent long-term results have been reported for nonoperative treatment of stable isolated displaced partial articular (Mason 2) fractures of the radial head, suggesting that the role of operative treatment can be questioned. This investigation reports the long-term outcome of operatively treated Mason 2 radial head fractures. Methods: Sixteen patients with stable displaced partial articular (Mason 2) fractures of the radial head not associated with fracture or dislocation of the proximal forearm were evaluated an average of 22 years (range, 14-30 years) after open reduction and internal fixation with screws (I I patients) or a plate and screws (5 patients). Complications included two infections (I deep and I superficial), two patients with restriction of motion because of screws of excessive length, and one transient posterior interosseous nerve palsy. A second surgery for implant removal was routine (14 of 16 patients). Results: The average flexion arc was 129 degrees (range, 110-145 degrees) and the average forearm rotation arc was 166 degrees (range, 120-180 degrees). According to the Mayo Elbow Performance Index, elbow function was excellent in nine patients, good in four, fair in two, and poor in one patient. According to the classification system of Steinberg et al., there were three good, eight fair, and five poor results. The average score on the Disabilities of the Arm, Shoulder, and Hand questionnaire was 12 points (range, 0-52). Conclusion: The long-term results of operative treatment of stable isolated displaced partial articular (Mason 2) fractures of the radial head demonstrate no appreciable advantage over the long-term results of nonoperative treatment of these fractures published in prior reports. Moreover, the appeal of operative treatment is diminished by the potential complications. C1 [Ring, David] Harvard Univ, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Med Sch,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fesch, Quinten] Univ Amsterdam, Orthotrauma Res Ctr Amsterdam, Amsterdam, Netherlands. [Kloen, Peter] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. RP Ring, D (reprint author), Harvard Univ, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Med Sch,Massachusetts Gen Hosp, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 26 TC 26 Z9 30 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD JUL PY 2009 VL 67 IS 1 BP 143 EP 146 DI 10.1097/TA.0b013e31818234d6 PG 4 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 470CZ UT WOS:000267953100025 PM 19590324 ER EF