FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Klepeis, VE Deshpande, V Sohani, AR Ferry, JA AF Klepeis, V. E. Deshpande, V. Sohani, A. R. Ferry, J. A. TI Sclerosing Inflammatory Pseudotumor of the Orbit: An IgG4-Related Disease SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Klepeis, V. E.; Deshpande, V.; Sohani, A. R.; Ferry, J. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1371 BP 307A EP 307A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301387 ER PT J AU Nardi, V Abramson, JS Hasserjian, RP AF Nardi, V. Abramson, J. S. Hasserjian, R. P. TI Morphologic Dysplasia in Staging Marrow from High-Grade Non-Hodgkin's Lymphoma Patients: A Paraneoplastic Phenomenon Associated with Adverse Clinical Outcome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Nardi, V.; Abramson, J. S.; Hasserjian, R. P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1403 BP 314A EP 314A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301419 ER PT J AU Rodig, SJ Kutok, JL Paterson, JC Zhang, W Shipp, MA Grogan, T Pileri, SA Montes-Moreno, S Johnson, NA Ben-Neriah, S Farinha, P Piris, MA Gascoyne, R Marafioti, T AF Rodig, S. J. Kutok, J. L. Paterson, J. C. Zhang, W. Shipp, M. A. Grogan, T. Pileri, S. A. Montes-Moreno, S. Johnson, N. A. Ben-Neriah, S. Farinha, P. Piris, M. A. Gascoyne, R. Marafioti, T. TI VpreB3, a Pre-BCR Associated Protein, Is Expressed by a Subset of Mature, Germinal Center B Cells and a Biomarker of Burkitt Lymphoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Oxford, Oxford, England. Ventana Med Syst, Tucson, AZ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Arizona, Tucson, AZ USA. Univ Bologna, Sch Med, Bologna, Italy. Spanish Natl Canc Ctr CNIO, Madrid, Spain. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1424 BP 318A EP 319A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301440 ER PT J AU Ryan, RJH Zukerberg, L Sloan, JM Collins, B Ferry, J AF Ryan, R. J. H. Zukerberg, L. Sloan, J. M. Collins, B. Ferry, J. TI MALT Lymphoma with Associated Amyloid Deposition - A Clinico-Pathological Study of 18 Cases SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1430 BP 320A EP 320A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301446 ER PT J AU Wang, SA Abruzzo, LV Hasserjian, RP Medeiros, LJ Miranda, RN AF Wang, S. A. Abruzzo, L. V. Hasserjian, R. P. Medeiros, L. J. Miranda, R. N. TI Myelodysplastic Syndromes with Interstitial Deletions of 11q Lack Cryptic 11q23 Translocations and Exhibit Characteristic Clinicopathologic Features SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 UT MD Anderson, Houston, TX USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1460 BP 327A EP 327A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301476 ER PT J AU Louissaint, A Ferry, JA Harris, NL Zukerberg, LR AF Louissaint, A. Ferry, J. A. Harris, N. L. Zukerberg, L. R. TI Morphology and Immunophenotype of Infectious Mononucleosis Presenting in Axillary and Inguinal Lymph Nodes and Other Unusual Locations SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Louissaint, A.; Ferry, J. A.; Harris, N. L.; Zukerberg, L. R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1491 BP 334A EP 334A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301506 ER PT J AU Farris, AB Taheri, D Fazlollahi, L Iafrate, AJ Smith, RN Collins, AB Tolkoff-Rubin, N Spitzer, TR Kawai, T Cosimi, AB Sachs, DH Colvin, RB AF Farris, A. B. Taheri, D. Fazlollahi, L. Iafrate, A. J. Smith, R. N. Collins, A. B. Tolkoff-Rubin, N. Spitzer, T. R. Kawai, T. Cosimi, A. B. Sachs, D. H. Colvin, R. B. TI Distinctive Renal Biopsy Pathology in the Engraftment Syndrome: A Response to Combined Kidney and Bone Marrow Transplantation SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory U, Atlanta, GA USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1512 BP 339A EP 339A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301527 ER PT J AU Farris, AB Coban, I Klimstra, DS Kim, G Deshpande, V Ohike, N Adsay, N AF Farris, A. B. Coban, I. Klimstra, D. S. Kim, G. Deshpande, V. Ohike, N. Adsay, N. TI Necrotizing Arteritis Presenting as a Pancreatic Mass: A New Addition to the Immune-Related Tumoral Pancreatitides SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Emory U, Atlanta, GA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. UCSF, San Francisco, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1576 BP 354A EP 355A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301591 ER PT J AU Gupta, RK Genevay, M Johnson, NB Lauwers, GY Deshpande, V AF Gupta, R. K. Genevay, M. Johnson, N. B. Lauwers, G. Y. Deshpande, V. TI Is Autoimmune Pancreatitis Associated with an Increased Risk of Malignancy? A Retrospective and Comparative Study SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Univ Geneva, Geneva, Switzerland. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1584 BP 356A EP 357A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301599 ER PT J AU Lennerz, JK Chapman, WC Brunt, EM AF Lennerz, J. K. Chapman, W. C. Brunt, E. M. TI Epithelial-Mesenchymal Transition (EMT) of K19 Structures within the Stromal Compartment of HCV Cirrhosis Parallels Hepatocarcinogenesis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Washington Univ, St Louis, MO 63130 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1604 BP 361A EP 361A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301619 ER PT J AU Lisovsky, M Dresser, K Woda, B Mino-Kenudson, M AF Lisovsky, M. Dresser, K. Woda, B. Mino-Kenudson, M. TI Differentiation of Pancreatic Intraepithelial Neoplasia-3 (PanIN-3) and Ductal Adenocarcinoma of the Pancreas from Lower Grade PanINs Utilizing Immunohistochemistry for Cell Polarity Protein Lethal Giant Larva 2 (Igl2) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. UMassMem Med Ctr, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1615 BP 363A EP 363A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301630 ER PT J AU Nagata, K Lauwers, GY Murata, S Shimizu, M AF Nagata, K. Lauwers, G. Y. Murata, S. Shimizu, M. TI Gallbladder Intramural Papillary Mucinous Neoplasm: A New Entity Similar to IPMN of the Pancreas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Saitama Med Univ, Saitama Int Med Ctr, Hidaka, Saitama, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1628 BP 366A EP 366A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301643 ER PT J AU Shen, J Konstantinidis, I Ferrone, CR Deshpande, V AF Shen, J. Konstantinidis, I. Ferrone, C. R. Deshpande, V. TI Intrapancreatic Cholangiocarcinomas: A Clinicopathological and Immunohistochemical Analysis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Shen, J.; Konstantinidis, I.; Ferrone, C. R.; Deshpande, V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1651 BP 371A EP 371A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301666 ER PT J AU Xiao, HD Yamaguchi, H Dias-Santagata, D Kuboki, Y Akhavanfard, S Hatori, T Yamamoto, M Shiratori, K Kobayashi, M Shimizu, M Mino-Kenudson, M Furukawa, T AF Xiao, H. D. Yamaguchi, H. Dias-Santagata, D. Kuboki, Y. Akhavanfard, S. Hatori, T. Yamamoto, M. Shiratori, K. Kobayashi, M. Shimizu, M. Mino-Kenudson, M. Furukawa, T. TI Molecular Characteristics and Biological Behavior of Intraductal Papillary-Mucinous Neoplasm, Oncocytic Type (IPMN-O) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Saitama Med Univ, Saitama, Japan. Int Res & Educ Inst Integrated Med Sci, Tokyo, Japan. Tokyo Womens Med Univ, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1667 BP 374A EP 375A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301682 ER PT J AU Laury, AR Hornick, JL Piao, H Perets, R Barletta, J Chirieac, LR Krane, JF Lis, R Loda, M Drapkin, R Hirsch, MS AF Laury, A. R. Hornick, J. L. Piao, H. Perets, R. Barletta, J. Chirieac, L. R. Krane, J. F. Lis, R. Loda, M. Drapkin, R. Hirsch, M. S. TI PAX8 Is Highly Sensitive and Specific for Mullerian, Renal and Thyroid Neoplasms: A Study of 1500 Epithelial Tumors SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1730 BP 388A EP 388A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301745 ER PT J AU Cheng, L Janne, PA Jackman, DM Johnson, BE Joshi, VA Lindeman, NI AF Cheng, L. Janne, P. A. Jackman, D. M. Johnson, B. E. Joshi, V. A. Lindeman, N. I. TI Mutational Analysis of EGFR, KRAS, BRAF, PIK3CA, and ERBB2 in Non-Small-Cell Lung Carcinomas (NSCLC) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Mol Med Lab, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1783 BP 399A EP 399A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301798 ER PT J AU Klepeis, VE Mark, EG Dias-Santagata, D Iafrate, AJ Minto-Kenudson, M AF Klepeis, V. E. Mark, E. G. Dias-Santagata, D. Iafrate, A. J. Minto-Kenudson, M. TI Genotype-Phenotype Correlation in Lung Adenocarcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1812 BP 406A EP 406A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301827 ER PT J AU Hunt, JL Smith, MT Black-Schaffer, WS AF Hunt, J. L. Smith, M. T. Black-Schaffer, W. S. TI Joint Commission Standards for Ongoing and Focused Performance Evaluation in Anatomic Pathology: Current Trends in Practice SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Med Univ S Carolina, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1870 BP 418A EP 418A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301885 ER PT J AU Morgan, EA Oh, KY Waghorne, CG Neuberg, D Stevenson, K Kutok, JL AF Morgan, E. A. Oh, K. Y. Waghorne, C. G. Neuberg, D. Stevenson, K. Kutok, J. L. TI Flow Cytometry Underestimates the Bone Marrow CD34-Positive Blast Population Compared to Immunohistochemical and Morphologic Assessments SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1874 BP 419A EP 419A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301889 ER PT J AU Ryan, RJH Snuderl, M Black-Schaffer, WS Hunt, J AF Ryan, R. J. H. Snuderl, M. Black-Schaffer, W. S. Hunt, J. TI Improvements in Training and Credentialing of Residents for Independent Frozen Section Sign-Out Responsibility SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Ryan, R. J. H.; Snuderl, M.; Black-Schaffer, W. S.; Hunt, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2010 VL 90 SU 1 MA 1880 BP 421A EP 421A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 553AR UT WOS:000274337301895 ER PT J AU Corrales-Medina, VF Madjid, M Musher, DM AF Corrales-Medina, Vicente F. Madjid, Mohammad Musher, Daniel M. TI Role of acute infection in triggering acute coronary syndromes SO LANCET INFECTIOUS DISEASES LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; C-REACTIVE PROTEIN; RESPIRATORY-TRACT INFECTIONS; COMMUNITY-ACQUIRED PNEUMONIA; AMERICAN-HEART-ASSOCIATION; HEAVY PHYSICAL EXERTION; CARDIOVASCULAR-DISEASE; INFLUENZA VACCINATION; UNSTABLE ANGINA; ARTERY-DISEASE AB Acute coronary syndromes are a leading cause of morbidity and mortality worldwide. The mechanisms underlying the triggering of these events are diverse and include increased coronary and systemic inflammatory activity dominant prothrombotic conditions, increased biomechanical stress on coronary arteries, variations in the coronary arterial tone, disturbed haemodynamic homoeostasis, and altered myocardial metabolic balance. There is experimental evidence that acute infections can promote the development of acute coronary syndromes, and clinical data strongly support a role for acute infections in triggering these events. In our Review, we summarise the pathogenesis of coronary artery disease and present the evidence linking acute infections with the development of acute coronary syndromes. Greater awareness of this association is likely to encourage research into ways of protecting patients who are at high risk. C1 [Corrales-Medina, Vicente F.] Univ Ottawa, Dept Med, Div Infect Dis, Ottawa, ON K1N 6N5, Canada. [Madjid, Mohammad; Musher, Daniel M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Musher, Daniel M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Musher, Daniel M.] Baylor Coll Med, Infect Dis Sect, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Madjid, Mohammad] Univ Texas Hlth Sci Ctr Houston, Dept Med, Houston, TX USA. [Madjid, Mohammad] St Lukes Episcopal Hosp, Texas Heart Inst, Atherosclerosis Res Lab, Houston, TX USA. RP Musher, DM (reprint author), Baylor Coll Med, Infect Dis Sect, Michael E DeBakey Vet Affairs Med Ctr, Room 4B-370,2002 Holcombe Blvd, Houston, TX 77030 USA. EM Daniel.Musher@va.gov FU Department of Veterans Affairs; VFC-M FX We thank Karla Absi-Delgado for her invaluable contribution to the creation of the figures and the Medical Media Department of the Michael E DeBakey VA Medical Center for assisting with their preparation. This work was partly funded by the Department of Veterans Affairs through the Merit Review Program for DMM. Funds from this source were used for financial support of VFC-M in his role as Research Fellow at Baylor College of Medicine under the direction of DMM. NR 120 TC 88 Z9 95 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD FEB PY 2010 VL 10 IS 2 BP 83 EP 92 PG 10 WC Infectious Diseases SC Infectious Diseases GA 558DS UT WOS:000274721600014 PM 20113977 ER PT J AU Je, YJ Schutz, FAB Choueiri, TK AF Je, Youjin Schutz, Fabio A. B. Choueiri, Toni K. TI Risk of bleeding not increased by sorafenib or sunitinib Reply SO LANCET ONCOLOGY LA English DT Editorial Material C1 [Je, Youjin] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Schutz, Fabio A. B.; Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Je, YJ (reprint author), Harvard Univ, Sch Publ Hlth, Huntington Ave, Boston, MA 02215 USA. EM toni_choueiri@dfci.harvard.edu NR 1 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 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD FEB PY 2010 VL 11 IS 2 BP 113 EP 113 PG 1 WC Oncology SC Oncology GA 563SC UT WOS:000275152900011 ER PT J AU Goguen, LA Norris, CM Jaklitsch, MT Sullivan, CA Posner, MR Haddad, RI Tishler, RB Burke, E Annino, DJ AF Goguen, Laura A. Norris, Charles M. Jaklitsch, Michael T. Sullivan, Christopher A. Posner, Marshall R. Haddad, Robert I. Tishler, Roy B. Burke, Elaine Annino, Donald J., Jr. TI Combined Antegrade and Retrograde Esophageal Dilation for Head and Neck Cancer-Related Complete Esophageal Stenosis SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT 112th Annual Meeting of the Triological-Society/Combined Otolaryngology Spring Meeting CY MAY 28-31, 2009 CL Phoenix, AZ SP Triol Soc DE Esophageal stenosis; pharyngo esophageal stenosis; dysphagia; head and neck cancer; antegrade esophageal dilation; retrograde esophageal dilation; CARD ID SQUAMOUS-CELL CARCINOMA; ADVANCED LARYNGEAL-CANCER; LOCALLY ADVANCED HEAD; QUALITY-OF-LIFE; RADIATION-THERAPY; CONCURRENT CHEMORADIATION; ENDOSCOPIC MANAGEMENT; ORGAN PRESERVATION; CHEMOTHERAPY; DYSPHAGIA AB Objectives/Hypothesis: Assess the safety and efficacy of combined antegrade and retrograde esophageal dilation (CARD) for complete esopbageal stenosis following head and neck cancer (HNC) treatment. Review HNC dysphagia management. Study Design: Retrospective review of all patients undergoing CARD following HNC treatment between May 2001 and September 2008. Methods: Forty-five patients were identified for review. Parameters assessed included: ability to obtain intraoperative esophageal patency, complications, number of dilations required, diet, and gastric tube (GT) status. Factors associated with dilation failure were analyzed. Results: Intraoperative esophageal patency was obtained in 91% of patients. Median number of all dilations per patient was three. Median number of CARDs per patient was one. Resumption of oral intake occurred in 36/45 (80%). Diet results included: regular or soft diet 32/45 (71%), GT removal 27/45 (60%), and GT dependence with nothing by mouth 9/45 (20%). Laryngeal and pharyngeal stenosis, radionecrosis, tracheotomy dependence, and elongated stenosis were associated with dilation failure. Complications occurred in 18/63 (29%) CARD procedures: eight pneumomediastinum, seven GT site problems, two esophageal perforations, and one pharyngeal infection. All complications resolved spontaneously or with. minimal interventions. Conclusions: CARD was safe and effective. Intraoperative patency was achieved in 91% of patients. Eighty percent resumed oral intake. The majority of patients had their GTs removed and resumed a soft or regular diet. Dilation failure was associated with laryngeal, pharyngeal, and excessively long esophageal stenosis, often resulting from radionecrosis. Complications were minor. CARD should be considered before relegating patients with complete esophageal stenosis to chronic GT dependence or subjecting them to laryngopharyngo esophagectomy. C1 [Goguen, Laura A.; Norris, Charles M.; Sullivan, Christopher A.; Annino, Donald J., Jr.] Brigham & Womens Hosp, Div Otolaryngol, Dept Surg, Boston, MA 02115 USA. [Jaklitsch, Michael T.] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02115 USA. [Posner, Marshall R.; Haddad, Robert I.] Brigham & Womens Hosp, Dept Med Oncol, Boston, MA 02115 USA. [Tishler, Roy B.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Burke, Elaine] Brigham & Womens Hosp, Dept Rehabil Speech & Swallow Serv, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Goguen, LA (reprint author), Brigham & Womens Hosp, Div Otolaryngol, Dept Surg, 45 Francis St, Boston, MA 02115 USA. EM lgoguen@partners.org NR 43 TC 14 Z9 14 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2010 VL 120 IS 2 BP 261 EP 266 DI 10.1002/lary.20727 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 556QA UT WOS:000274605000009 PM 19998421 ER PT J AU Kumai, Y Kobler, JB Park, H Galindo, M Herrera, VLM Zeitels, SM AF Kumai, Yoshihiko Kobler, James B. Park, Hyoungshin Galindo, Marilyn Herrera, Victoria L. M. Zeitels, Steven M. TI Modulation of Vocal Fold Scar Fibroblasts By Adipose-Derived Stem/Stromal Cells SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT 112th Annual Meeting of the Triological-Society/Combined Otolaryngology Spring Meeting CY MAY 28-31, 2009 CL Phoenix, AZ SP Triol Soc DE Adipose-derived stem cells; scar fibroblast; coculture; hepatocyte growth factor; alpha-smooth muscle actin ID HEPATOCYTE GROWTH-FACTOR; MESENCHYMAL STEM-CELLS; STROMAL CELLS; EXTRACELLULAR-MATRIX; EXPRESSION; INJECTION; ACTIVATION; PREVENTION; MODEL AB Objectives/Hypothesis: To explore whether adipose-derived stem/stromal cells (ASCs) have therapeutic potential for treating scarred superficial lamina propria through the effects of secreted hepatocyte growth factor (HGF) on scar fibroblasts. Study Design: In vitro study using coculture system. Methods: Scar fibroblasts (SFs) were isolated from ferret vocal folds electrocauterized 2 weeks previously. ASCs were isolated from ferret lipoaspirated subcutaneous abdominal fat. For coculture experiments, the two cell types were combined in Transwell plates for 6 days, followed by 1 or 3 days of monoculture after removing the upper chamber. Assays were then performed on cells and media from the bottom chamber. We measured: 1) the production of hyaluronic acid (RA), collagen and HGF via enzyme-linked immunosorbent assays, 2) the expression of alpha-smooth muscle actin (alpha-SMA), 3) cell proliferation, and 4) apoptosis of SFs (2, 3, and 4 via flow cytometry). Other experiments examined the effects of HGF on SFs and the effects of HGF neutralization in the coculture system. Results: Coculture led to significant decreases in SF collagen production (P <.05), cell proliferation (P <.05), and a-SMA expression (P <.05), whereas HA production increased (P <.05). Coculture also increased HGF secretion from ASCs (P <.05). Neutralization of HGF abolished the inhibitory effects of ASCs on SF collagen synthesis (P <.05). Conclusions: ASCs influence SFs to adopt a less fibrotic profile. It appears that HGF is at least one of the soluble factors responsible for this effect. Implanted ASCs could potentially ameliorate vocal fold scar by acting as long-term, intrinsic sources of HGF. C1 [Kobler, James B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Surg, Ctr Laryngeal Surg & Voice Rehabil,Laryngeal Surg, Boston, MA 02114 USA. [Herrera, Victoria L. M.] Boston Univ, Sch Med, Dept Med, Sect Mol Med, Boston, MA 02118 USA. [Herrera, Victoria L. M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. RP Kobler, JB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Surg, Ctr Laryngeal Surg & Voice Rehabil,Laryngeal Surg, 55 Fruit St,620 Their, Boston, MA 02114 USA. EM jkobler@partners.org NR 28 TC 22 Z9 24 U1 1 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2010 VL 120 IS 2 BP 330 EP 337 DI 10.1002/lary.20753 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 556QA UT WOS:000274605000022 PM 20013848 ER PT J AU Jia, WC Sun, V Tran, N Choi, B Liu, SW Mihm, MC Phung, TL Nelson, JS AF Jia, Wangcun Sun, Victor Tran, Nadia Choi, Bernard Liu, Shaiw-wen Mihm, Martin C., Jr. Phung, Thuy L. Nelson, J. Stuart TI Long-Term Blood Vessel Removal With Combined Laser and Topical Rapamycin Antiangiogenic Therapy: Implications for Effective Port Wine Stain Treatment SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE laser dermatologic surgery; port wine stain; rapamycin; angiogenesis; laser speckle imaging; dorsal window chamber ID PULSED DYE-LASER; ENDOTHELIAL GROWTH-FACTOR; DORSAL SKIN FOLD; 577 NM TREATMENT; MICROVASCULAR RESPONSE; FLOW DYNAMICS; IN-VITRO; ANGIOGENESIS; SPECKLE; NEOVASCULARIZATION AB Background and Objectives: Complete blanching of port wine stain (PWS) birthmarks after laser therapy is rarely achieved for most patients. We postulate that the low therapeutic efficacy or treatment failure is caused by regeneration and revascularization of photocoagulated blood vessels due to angiogenesis associated with the skin's normal wound healing response. Rapamycin (RPM), an antiangiogenic agent, has been demonstrated to inhibit growth of pathological blood vessels. Our objectives were to (1) investigate whether topical RPM can inhibit reperfusion of photocoagulated blood vessels in an animal model and (2) determine the effective RPM concentration required to achieve this objective. Study Design/Materials and Methods: For both laser-only and combined laser and RPM treated animals, blood vessels in the dorsal window chambers implanted on golden Syrian banisters were photocoagulated with laser pulses. Structural and flow dynamics of blood vessels were documented with color digital photography and laser speckle imaging to evaluate photocoagulation and reperfusion. For the combined treatment group, topical RPM was applied to the epidermal side of the window daily for 14 days after laser exposure. Results: In the laser-only group, 23 out of 24 photocoagulated blood vessels reperfused within 5-14 days. In the combined treatment group with different RPM formulae and concentrations, the overall reperfusion rate of 36% was much lower as compared to the laser-only group. We also found that the reperfusion rate was not linearly proportional to the RPM concentration. Conclusions: With topical RPM application, the frequency of vessel reperfusion was considerably reduced, which implies that combined light and topical antiangiogenic therapy might be a promising approach to improve the treatment efficacy of PWS birthmarks. Lasers Surg. Med. 42:105-112, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Jia, Wangcun; Sun, Victor; Tran, Nadia; Choi, Bernard; Nelson, J. Stuart] Univ Calif Irvine, Beckman Laser Inst, Irvine, CA 92617 USA. [Choi, Bernard; Nelson, J. Stuart] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92617 USA. [Choi, Bernard] Univ Calif Irvine, Edwards Lifesci Ctr Adv Cardiovasc Technol, Irvine, CA 92617 USA. [Liu, Shaiw-wen] Conrex Pharmaceut, Newtown Sq, PA 19073 USA. [Mihm, Martin C., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatopathol, Boston, MA 02215 USA. [Phung, Thuy L.] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. RP Jia, WC (reprint author), Univ Calif Irvine, Beckman Laser Inst, 1002 Hlth Sci Rd E, Irvine, CA 92617 USA. EM wjia@uci.edu RI Jia, Wangcun/A-9935-2011 FU National Institutes of Health [AR47551, EB002495, AR056147, P41-RR001192]; American Society for Laser Medicine and Surgery; Sturge Weber Foundation; Arnold and Mabel Beckman Foundation FX Contract grant sponsor National Institutes of Health; Contract grant numbers: AR47551, EB002495, AR056147; Contract grant sponsor National Institutes of Health Laser Microbeam and Medical Program; Contract grant number P41-RR001192; Contract grant sponsor: American Society for Laser Medicine and Surgery; Contract grant sponsor: Sturge Weber Foundation; Contract grant sponsor: Arnold and Mabel Beckman Foundation. NR 42 TC 35 Z9 35 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2010 VL 42 IS 2 SI SI BP 105 EP 112 DI 10.1002/lsm.20890 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA 567LY UT WOS:000275449600003 PM 20166161 ER PT J AU Haedersdal, M Sakamoto, FH Farinelli, WA Doukas, AG Tam, J Anderson, RR AF Haedersdal, Merete Sakamoto, Fernanda H. Farinelli, William A. Doukas, Apostolos G. Tam, Josh Anderson, R. Rox TI Fractional CO2 Laser-Assisted Drug Delivery SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE fractional ablative resurfacing; photodynamic therapy; photosensitizer; topical drugs ID TOPICAL PHOTODYNAMIC THERAPY; BASAL-CELL CARCINOMA; PROTOPORPHYRIN-IX ACCUMULATION; ERBIUM-YAG LASER; 5-AMINOLEVULINIC ACID; IN-VIVO; ENDOGENOUS PROTOPORPHYRIN; PERCUTANEOUS-ABSORPTION; AMINOLEVULINIC-ACID; RESURFACING DEVICE AB Background and Objectives: Ablative fractional resurfacing (AFR) creates vertical channels that might assist the delivery of topically applied drugs into skin. The purpose of this study was to evaluate drug delivery by CO2 laser AFR using methyl 5-aminolevulinate (MAL), a porphyrin precursor, as a test drug. Materials and Methods: Two Yorkshire swine were treated with single-hole CO2 laser AFR and subsequent topical application of MAL (Metvix(R), Photocure ASA, Oslo, Not-way), placebo cream and no drug. MAL-induced porphyrin fluorescence was measured by fluorescence microscopy at skin depths down to 1,800 mu m. AFR was performed with a 10.6 mu m wavelength Prototype CO2 laser, using stacked single pulses of 3 millisecond and 91.6 mJ pet, pulse. Results: AFR created cone-shaped channels of approximately 300 mu m diameter and 1,850 mu m depth that were Surrounded by a 70 mu m thin layer of thermally coagulated dermis. There was no porphyrin fluorescence in placebo cream or untreated skin sites. AFR followed by MAL application enhanced drug delivery with significantly higher porphyrin fluorescence of hair follicles (P < 0.0011) and dermis (P < 0.0433) versus MAL alone at skin depths of 120, 500, 1,000, 1,500, and 1,800 pro. AFR before MAL application also enhanced skin surface (epidermal) porphyrin fluorescence. Radial diffusion of MAL from the laser-created channels into surrounding dermis was evidenced by uniform porphyrin fluorescence up to 1,500 mu m from the holes (1,000, 1,800 mu m depths). Skin massage after MAL application did not affect MAL-induced porphyrin fluorescence after AFR. Conclusions: Ablative fractional laser treatment facilitates delivery of topical MAL deeply into the skin. For the conditions of this study, laser channels approximately 3 mm apart followed by MAL application could produce porphyrins throughout essentially the entire skin. AFR appears to be a clinically practical means for enhancing uptake of MAL, a photodynamic therapy drug, and presumably many other topical skin medications. Lasers Surg. Med. 42:113-122, 2010. (C) 2009Wiley-Liss, Inc. C1 [Haedersdal, Merete; Sakamoto, Fernanda H.; Farinelli, William A.; Doukas, Apostolos G.; Tam, Josh; Anderson, R. Rox] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Haedersdal, Merete] Univ Copenhagen, Dept Dermatol, Bispebjerg Hosp, DK-2400 Copenhagen, Denmark. [Sakamoto, Fernanda H.] Univ Fed Sao Paulo, Dept Dermatol, Escola Paulista Med, BR-04023900 Sao Paulo, Brazil. RP Haedersdal, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, BHX 630-55 Fruit St, Boston, MA 02114 USA. EM mhaedersdal@dadlnet.dk NR 37 TC 102 Z9 105 U1 0 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2010 VL 42 IS 2 SI SI BP 113 EP 122 DI 10.1002/lsm.20860 PG 10 WC Dermatology; Surgery SC Dermatology; Surgery GA 567LY UT WOS:000275449600004 PM 20166154 ER PT J AU Yao, M Yaroslavsky, A Henry, FP Redmond, RW Kochevar, IE AF Yao, Min Yaroslavsky, Anna Henry, Frank P. Redmond, Robert W. Kochevar, Irene E. TI Phototoxicity Is Not Associated With Photochemical Tissue Bonding of Skin SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE tissue bonding; wound repair; Rose Bengal; protein crosslinks; skin incisions; wound healing; skin ID ACID-PHOTODYNAMIC THERAPY; SINGLET OXYGEN; ROSE-BENGAL; CORNEAL INCISIONS; KERATODESMOS; KINASE; GROWTH AB Background and Objective: We have developed a light-activated method called photochemical tissue bonding (PTB) for closing wounds using green light and a photosensitizing dye (Rose Bengal-RB) to initiate photochemical crosslinking of wound surface proteins. These studies were designed to determine whether RB causes phototoxicity during closure of skin incisions with PTB. Study Design/Materials and Methods: RB phototoxicity was evaluated after sealing incisions in porcine skin ex 2 vivo and rabbit skin in vivo using PTB (1 mM RB, 100 J/cm(2), 532 nm, 0.3 or 0.5 W/cm(2).) Dead cells were identified by pyknotic nuclei and eosinophilic cytoplasm on H&E-stained sections. The influence on RB phototoxicity of penetration of RB into the wound wall (by confocal microscopy), RB concentration in the tissue (by extraction), and fluence of 532 nm reaching depths in skin (calculated from skin optical properties) were investigated. Results: No significant differences were found in the percent dead cells in PTB-treated and control incisions in porcine skin at 24 hours or in rabbit skin at 2 hours and 3 and 7 days after surgery. RB was retained in a similar to 100 mu m wide band next to the Wound wall. The mean RB concentration within this band was 0.42 +/- 0.03 mM. Monte Carlo modeling of light distribution indicated that the fluence rate decreased from the subsurface peak to 0.5 W/cm(2) in the mid-dermis (similar to 350 mu m.) In vitro RB phototoxicity to dermal fibroblasts yielded an LD(50) of 0.50 +/- 0.09 J/cm(2) when the cells contained 0.46 nM RB. Conclusions: PTB does not cause phototoxicity when used to repair skin wounds even though the RB concentration and 532 nm fluence in the mid-dermis during PTB are much greater than the LD50 for RB phototoxicity in vitro. These results indicate that phototoxicity is not a concern when using PTB for tissue repair. Lasers Surg. Med. 42:123-131, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Yao, Min; Yaroslavsky, Anna; Henry, Frank P.; Redmond, Robert W.; Kochevar, Irene E.] Harvard Univ, Massachusetts Gen Hosp, Harvard MIT Hlth Sci Technol Program, Wellman Ctr Photomed,Sch Med, Boston, MA 02114 USA. RP Kochevar, IE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Harvard MIT Hlth Sci Technol Program, Wellman Ctr Photomed,Sch Med, Thier 224,50 Fruit St, Boston, MA 02114 USA. EM kochevar@helix.mgh.harvard.edu OI Henry, Francis P./0000-0003-4170-7806 FU DOD Medical Free Electron Laser Program [FA9550-04-1-0079] FX Contract grant sponsor: DOD Medical Free Electron Laser Program; Contract grant number: FA9550-04-1-0079. NR 34 TC 32 Z9 37 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2010 VL 42 IS 2 SI SI BP 123 EP 131 DI 10.1002/lsm.20869 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 567LY UT WOS:000275449600005 PM 20166159 ER PT J AU Silverman, LB Stevenson, KE O'Brien, JE Asselin, BL Barr, RD Clavell, L Cole, PD Kelly, KM Laverdiere, C Michon, B Schorin, MA Schwartz, CL O'Holleran, EW Neuberg, DS Cohen, HJ Sallan, SE AF Silverman, L. B. Stevenson, K. E. O'Brien, J. E. Asselin, B. L. Barr, R. D. Clavell, L. Cole, P. D. Kelly, K. M. Laverdiere, C. Michon, B. Schorin, M. A. Schwartz, C. L. O'Holleran, E. W. Neuberg, D. S. Cohen, H. J. Sallan, S. E. TI Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000) SO LEUKEMIA LA English DT Article DE acute lymphoblastic leukemia; long-term follow-up; asparaginase; anthracycline ID INTENSIVE ASPARAGINASE; CUMULATIVE INCIDENCE; CHILDHOOD; GENE; CHEMOTHERAPY; DEXRAZOXANE; NEOPLASMS; THERAPY; RISK; MLL AB The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20-30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985 and 2000, 1457 children aged 0-18 years were treated on four consecutive protocols: 85-01 (1985-1987), 87-01 (1987-1991), 91-01 (1991-1955) and 95-01 (1996-2000). The 10-year event-free survival (EFS) +/- s. e. by protocol was 77.9 +/- 2.8% (85-01), 74.2 +/- 2.3% (87-01), 80.8 +/- 2.1% (91-01) and 80.5 +/- 1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (P = 0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79-85% for T-cell ALL patients and 75-78% for adolescents (age 10-18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely affecting EFS or OS in high-risk (HR) patients, and frequently dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk (SR) patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities. Leukemia (2010) 24, 320-334; doi: 10.1038/leu.2009.253; published online 17 December 2009 C1 [Silverman, L. B.] Dana Farber Canc Inst, Div Hematol Oncol, Dept Pediat Oncol, Boston, MA 02115 USA. [Silverman, L. B.; Stevenson, K. E.; O'Brien, J. E.; O'Holleran, E. W.; Neuberg, D. S.; Sallan, S. E.] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Silverman, L. B.; Stevenson, K. E.; O'Brien, J. E.; O'Holleran, E. W.; Neuberg, D. S.; Sallan, S. E.] Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02115 USA. [Silverman, L. B.; Sallan, S. E.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Asselin, B. L.] Univ Rochester, Med Ctr, Div Pediat Hematol Oncol, Rochester, NY 14642 USA. [Barr, R. D.] McMaster Univ, Div Pediat Hematol Oncol, Hamilton, ON, Canada. [Clavell, L.] San Jorge Childrens Hosp, Div Pediat Hematol Oncol, San Juan, PR USA. [Cole, P. D.] Montefiore Med Ctr, Div Pediat Hematol Oncol, New York, NY USA. [Kelly, K. M.] Columbia Univ, Morgan Stanley Childrens Hosp New York Presbyteri, Med Ctr, Div Pediat Oncol, New York, NY USA. [Laverdiere, C.] Univ Montreal, Hop St Justine, Div Hematol & Oncol, Montreal, PQ H3T 1C5, Canada. [Michon, B.] CHU Quebec, Div Hematol Oncol, Quebec City, PQ, Canada. [Schorin, M. A.] Inova Fairfax Hosp, Falls Church, VA USA. [Schwartz, C. L.] Brown Univ, Div Pediat Hematol Oncol, Hasbro Childrens Hosp, Warren Alpert Med Sch, Providence, RI 02912 USA. [Cohen, H. J.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. RP Silverman, LB (reprint author), Dana Farber Canc Inst, Div Hematol Oncol, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM lewis_silverman@dfci.harvard.edu FU National Institute of Health (NCI) [5P01CA068484] FX These trials were supported in part by a grant from the National Institute of Health (NCI Grant 5P01CA068484). We thank the patients, families, physicians, nurses, clinical research coordinators and all others who participated in these trials. We acknowledge the important contributions of Jennifer Cronin, Annette Dalton, Virginia Dalton, Meghan Eaton and Richard D Gelber. NR 31 TC 115 Z9 122 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2010 VL 24 IS 2 BP 320 EP 334 DI 10.1038/leu.2009.253 PG 15 WC Oncology; Hematology SC Oncology; Hematology GA 553WO UT WOS:000274397700007 PM 20016537 ER PT J AU Chanudet, E Huang, Y Ichimura, K Dong, G Hamoudi, RA Radford, J Wotherspoon, AC Isaacson, PG Ferry, J Du, MQ AF Chanudet, E. Huang, Y. Ichimura, K. Dong, G. Hamoudi, R. A. Radford, J. Wotherspoon, A. C. Isaacson, P. G. Ferry, J. Du, M-Q TI A20 is targeted by promoter methylation, deletion and inactivating mutation in MALT lymphoma SO LEUKEMIA LA English DT Letter ID B-CELL LYMPHOMA; NF-KAPPA-B; TNFAIP3 A20 C1 [Chanudet, E.; Huang, Y.; Ichimura, K.; Dong, G.; Hamoudi, R. A.; Du, M-Q] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Radford, J.] Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England. [Radford, J.] Univ Manchester, Manchester, Lancs, England. [Wotherspoon, A. C.] Royal Marsden Hosp, Dept Histopathol, London SW3 6JJ, England. [Isaacson, P. G.] UCL, Dept Histopathol, London, England. [Ferry, J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Chanudet, E (reprint author), Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP, England. EM ec338@cam.ac.uk; mqd20@cam.ac.uk RI Radford, John/N-1331-2015; Chanudet, Estelle/N-4064-2015 OI Radford, John/0000-0001-7898-2786; NR 8 TC 60 Z9 69 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2010 VL 24 IS 2 BP 483 EP 487 DI 10.1038/leu.2009.234 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 553WO UT WOS:000274397700026 PM 19907439 ER PT J AU Butt, AA McGinnis, KA Skanderson, M Justice, AC AF Butt, Adeel A. McGinnis, Kathleen A. Skanderson, Melissa Justice, Amy C. TI Hepatitis C treatment completion rates in routine clinical care SO LIVER INTERNATIONAL LA English DT Article DE anaemia; depression; hepatitis C; HIV infection; pegylated interferon; practice variation; treatment completion ID CHRONIC KIDNEY-DISEASE; INTERFERON-ALPHA-2B PLUS RIBAVIRIN; IMMUNODEFICIENCY-VIRUS-INFECTION; UNITED-STATES VETERANS; COMBINATION THERAPY; PEGINTERFERON ALPHA-2A; EPOETIN-ALPHA; HEPATOCELLULAR-CARCINOMA; ANTIVIRAL THERAPY; HIV AB Background Treatment completion rates for hepatitis C virus (HCV) infection in clinical practice settings are unknown. Methods We assembled a national cohort of HCV-infected veterans-in-care from 1998 to 2003, using the VA National Patient Care Database for demographical/clinical information, Pharmacy Benefits Management database for pharmacy records and the Decision Support Systems database for laboratory data. We used logistic regression to determine the factors predicting treatment non-completion for HCV. Results We identified 134 934 HCV-infected veterans of whom 16 043 [11.9%; 95% confidence interval (CI) 11.7-12.1] were prescribed treatment for HCV. Among the 10 641 veterans with > 1 year of follow-up, 2396 (22.5%; 95% CI 21.7-23.3) completed a 48-week course. Non-completers were more likely to have pre-treatment anaemia, coronary artery disease, depression, substance abuse, used standard interferon, higher comorbidity count, and been treated at a low-volume treatment site (defined as sites initiating HCV treatment for < 200 individuals). In multivariable analyses, treatment completion was positively associated with pegylated interferon use [odds ratio (OR) 1.59, 95% CI 1.40-1.80] and site treatment volume (OR 1.87, 95% CI 1.56-2.24 for sites initiating treatment for > 200 individuals) and negatively associated with pre-treatment anaemia (OR 0.68, 95% CI 0.58-0.80 for haemoglobin 10-14 g/dl) and depression (OR 0.78, 95% CI 0.69-0.89). Human immunodeficiency virus coinfection and minority race were not associated with failing to complete treatment. Conclusions Among veterans-in-care with known HCV, 11.9% initiate therapy of whom 22.5% (one in 56 with known HCV infection) complete a 48-week course of treatment. Higher completion rates among higher volume treatment sites suggest that some factors associated with non-completion (pre-treatment depression and anaemia), may be modifiable with experience. C1 [Butt, Adeel A.] Univ Pittsburgh, Med Ctr, Ctr Hlth Equ Res & Promot, Sch Med,VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15213 USA. [Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Justice, Amy C.] Yale Univ, Sch Med, VA Connecticut Healthcare Syst, New Haven, CT USA. RP Butt, AA (reprint author), Univ Pittsburgh, Med Ctr, Ctr Hlth Equ Res & Promot, Sch Med,VA Pittsburgh Healthcare Syst, 3601 5th Ave,Suite 3A, Pittsburgh, PA 15213 USA. EM butta@dom.pitt.edu FU National Institutes of Health/National Institute on Drug Abuse [DA016175-01A1]; National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism [U10AA13566]; Valeant Pharmaceuticals FX This study was funded by the National Institutes of Health/National Institute on Drug Abuse (DA016175-01A1, Dr Butt). Dr Justice's time was supported by National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (U10AA13566). This material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System and the central data repositories maintained by the VA Information Resource center, including the National Patient Care Database, Decisions Support System database and the Pharmacy Benefits Management database. Disclaimer/Conflict: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. Dr Butt has received grant funding from Valeant Pharmaceuticals. NR 43 TC 32 Z9 32 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1478-3223 J9 LIVER INT JI Liver Int. PD FEB PY 2010 VL 30 IS 2 BP 240 EP 250 DI 10.1111/j.1478-3231.2009.02156.x PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 536DB UT WOS:000273021300012 PM 19889081 ER PT J AU Sun, HY Cacciarelli, TV Singh, N AF Sun, Hsin-Yun Cacciarelli, Thomas V. Singh, Nina TI Impact of Pretransplant Infections on Clinical Outcomes of Liver Transplant Recipients SO LIVER TRANSPLANTATION LA English DT Article ID SPONTANEOUS BACTERIAL PERITONITIS; HEPATITIS-C; PREEMPTIVE THERAPY; CIRRHOSIS; CYTOMEGALOVIRUS; VALGANCICLOVIR; SUSCEPTIBILITY; RECURRENCE; SEPSIS AB Whether pretransplant nonviral infections influence outcomes after transplantation in liver transplant recipients in the current era is not well defined. One hundred consecutive patients undergoing liver transplantation in 2005-2008 were studied. Demographics, posttransplant clinical events, and mortality were compared between recipients with and without infections within 12 months before transplantation. In all, 32% of the patients (32/100) developed 45 episodes of pretransplant infections, which included spontaneous bacterial peritonitis (35.6%), bloodstream infections (28.9%), cellulitis (13.3%), pneumonia (8.9%), urinary tract infections (6.7%), and other infections (6.7%). Compared with 68 recipients without pretransplant infections, those with infections had a higher Model for End-Stage Liver Disease score and a lower likelihood of transplantation from home and required longer and more frequent hospital care before and after transplantation (P < 0.05). Mortality at 90 (9.4% versus 2.9%) and 180 days (15.6% versus 10.3%) post-transplant did not differ significantly between recipients with and without pretransplant infections (P = not significant). A higher Model for End-Stage Liver Disease score (P < 0.05) and posttransplant infections (P < 0.05 and P < 0.001), but not pretransplant infections, were associated with posttransplant mortality at 90 and 180 days. In conclusion, pretransplant infections that have been adequately treated do not pose a significant risk for poor outcomes, including posttransplant mortality. Liver Transpl 16:222-228, 2010. (C) 2010 AASLD. C1 [Sun, Hsin-Yun; Cacciarelli, Thomas V.; Singh, Nina] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Sun, Hsin-Yun] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Sun, Hsin-Yun] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Cacciarelli, Thomas V.; Singh, Nina] Univ Pittsburgh, Pittsburgh, PA USA. RP Singh, N (reprint author), Vet Adm Med Ctr, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu OI SUN, HSIN-YUN/0000-0003-0074-7721 NR 22 TC 15 Z9 16 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD FEB PY 2010 VL 16 IS 2 BP 222 EP 228 DI 10.1002/lt.21982 PG 7 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 554LZ UT WOS:000274437800014 PM 20104499 ER PT J AU Bendlin, BB Carlsson, CM Gleason, CE Johnson, SC Sodhi, A Gallagher, CL Puglielli, L Engelman, CD Ries, ML Xu, G Wharton, W Asthana, S AF Bendlin, B. B. Carlsson, C. M. Gleason, C. E. Johnson, S. C. Sodhi, A. Gallagher, C. L. Puglielli, L. Engelman, C. D. Ries, M. L. Xu, G. Wharton, W. Asthana, S. TI Midlife predictors of Alzheimer's disease SO MATURITAS LA English DT Review DE Alzheimer's disease; Dementia; Midlife; Genes; Family history; Estrogen; Vascular risk; Education; MRI ID APOLIPOPROTEIN-E EPSILON-4; ESTROGEN REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; MILD COGNITIVE IMPAIRMENT; HEALTH INITIATIVE MEMORY; GENOME-WIDE ASSOCIATION; SYSTOLIC BLOOD-PRESSURE; WHITE-MATTER INTEGRITY; FEMALE 3XTG-AD MICE; WOMENS HEALTH AB Factors contributing to increased risk for Alzheimer's disease (AD) include age, sex, genes, and family history of AD. Several risk factors for AD are endogenous; however, accumulating evidence implicates modifiable risk factors in the pathogenesis of AD. Although the continued task of identifying new genes will be critical to learning more about the disease, several research findings suggest that potentially alterable environmental factors influence genetic contributions, providing targets for disease prevention and treatment. Here, we review midlife risk factors for AD, and address the potential for therapeutic intervention in midlife. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Bendlin, B. B.; Carlsson, C. M.; Gleason, C. E.; Johnson, S. C.; Sodhi, A.; Gallagher, C. L.; Puglielli, L.; Ries, M. L.; Xu, G.; Wharton, W.; Asthana, S.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Bendlin, B. B.; Carlsson, C. M.; Gleason, C. E.; Johnson, S. C.; Sodhi, A.; Gallagher, C. L.; Puglielli, L.; Ries, M. L.; Xu, G.; Wharton, W.; Asthana, S.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Engelman, C. D.] Univ Wisconsin, Dept Populat Hlth Sci, Sch Med & Publ Hlth, Madison, WI USA. RP Bendlin, BB (reprint author), Vet Adm Hosp, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. EM bbb@medicine.wisc.edu OI Bendlin, Barbara/0000-0002-0580-9875 FU University of Wisconsin, Madison FX Completion of this work was supported by the help of the Section of Geriatrics and Gerontology, Department of Medicine at the University of Wisconsin, Madison, and the Geriatric Research, Education and Clinical Center (GRECC manuscript number 2009-16), William S. Middleton Memorial Veterans Hospital. NR 132 TC 16 Z9 18 U1 4 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-5122 J9 MATURITAS JI Maturitas PD FEB PY 2010 VL 65 IS 2 SI SI BP 131 EP 137 DI 10.1016/j.maturitas.2009.12.014 PG 7 WC Geriatrics & Gerontology; Obstetrics & Gynecology SC Geriatrics & Gerontology; Obstetrics & Gynecology GA 560ZO UT WOS:000274944600009 PM 20044221 ER PT J AU Fonseca, R Richardson, P Giralt, S Lonial, S Rajkumar, SV Stewart, AK Bensinger, W Somlo, G Vescio, R Mikhael, J Reeder, C Tiedemann, R Tricot, G Rifkin, R Shaughnessy, J Munshi, N Raje, N Ghobrial, I Laubach, J Schlossman, R Treon, S Mahindra, A Avigan, D Rosenblatt, J Jagannath, S Niesvizky, R Landau, H Chen-Kiang, S Siegel, DS Zimmerman, T Mehta, J Vesole, D Rosen, S Hofmeister, C Lacy, M Dispenziere, A Borrello, I Hayman, SR Kumar, S Buadi, F Dingli, D Russell, S Alsina, M Fernandez, H Roy, V Pereira, D Stadtmauer, E Vaj, R Jakubowiak, A Lentzsch, S Song, K Bahlis, N Trudel, S Chen, C Reece, D Stewart, D Singhal, S Comenzo, R Gertz, MA Greipp, PR Durie, B Barlogie, B Anderson, K Dalton, W Coleman, M Novis, S Kyle, RA AF Fonseca, Rafael Richardson, Paul Giralt, Sergio Lonial, Sagar Rajkumar, S. Vincent Stewart, A. Keith Bensinger, William Somlo, George Vescio, Robert Mikhael, Joseph Reeder, Craig Tiedemann, Rodger Tricot, Guido Rifkin, Robert Shaughnessy, John Munshi, Nikhil Raje, Noopur Ghobrial, Irene Laubach, Jacob Schlossman, Robert Treon, Steven Mahindra, Anuj Avigan, David Rosenblatt, Jacalyn Jagannath, Sundar Niesvizky, Ruben Landau, Heather Chen-Kiang, Selina Siegel, David S. Zimmerman, Todd Mehta, Jayesh Vesole, David Rosen, Steven Hofmeister, Craig Lacy, Martha Dispenziere, Angela Borrello, Ivan Hayman, Suzanne R. Kumar, Shaji Buadi, Frances Dingli, David Russell, Stephen Alsina, Melissa Fernandez, Hugo Roy, Vivek Pereira, Denise Stadtmauer, Edward Vaj, Ravi Jakubowiak, Andrezej Lentzsch, Suzanne Song, Kevin Bahlis, Nizar Trudel, Suzanne Chen, Christine Reece, Donna Stewart, Douglas Singhal, Seema Comenzo, Raymond Gertz, Morie A. Greipp, Philip R. Durie, Brian Barlogie, Bart Anderson, Kenneth Dalton, William Coleman, Morton Novis, Susie Kyle, Robert A. TI Conflicts of Interest, Authorship, and Disclosures in Industry-Related Scientific Publications SO MAYO CLINIC PROCEEDINGS LA English DT Letter ID LENALIDOMIDE PLUS DEXAMETHASONE; REFRACTORY MULTIPLE-MYELOMA; IMPROVED SURVIVAL; MEDICAL JOURNALS; BORTEZOMIB C1 [Fonseca, Rafael; Stewart, A. Keith; Mikhael, Joseph; Reeder, Craig; Tiedemann, Rodger] Mayo Clin, Scottsdale, AZ USA. [Richardson, Paul; Munshi, Nikhil; Ghobrial, Irene; Laubach, Jacob; Schlossman, Robert; Treon, Steven; Avigan, David; Anderson, Kenneth] Dana Farber Canc Inst, Boston, MA USA. [Giralt, Sergio] MD Anderson Canc Ctr, Houston, TX USA. [Lonial, Sagar] Emory Univ, Winship Canc Ctr, Atlanta, GA USA. [Rajkumar, S. Vincent; Lacy, Martha; Dispenziere, Angela; Hayman, Suzanne R.; Kumar, Shaji; Buadi, Frances; Dingli, David; Russell, Stephen; Roy, Vivek; Gertz, Morie A.; Greipp, Philip R.; Kyle, Robert A.] Mayo Clin, Rochester, MN USA. [Bensinger, William] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Somlo, George] City Hope Natl Med Ctr, Duarte, CA USA. [Vescio, Robert; Durie, Brian] Cedars Sinai Med Ctr, Los Angeles, CA USA. [Tricot, Guido] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Rifkin, Robert] Rocky Mt Canc Ctr, Denver, CO USA. [Shaughnessy, John; Barlogie, Bart] Univ Arkansas, Little Rock, AR USA. [Raje, Noopur] Massachusetts Gen Hosp, Boston, MA USA. [Mahindra, Anuj] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA. [Rosenblatt, Jacalyn] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Jagannath, Sundar] St Vincent Comprehens Canc Ctr, New York, NY USA. [Niesvizky, Ruben; Chen-Kiang, Selina; Coleman, Morton] Cornell Univ, Weill Cornell Med Coll, New York, NY USA. [Landau, Heather; Comenzo, Raymond] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Siegel, David S.] Hackensack Univ Med Ctr, Canc Ctr, Hackensack, NJ USA. [Zimmerman, Todd] Univ Chicago, Chicago, IL USA. [Mehta, Jayesh; Rosen, Steven; Singhal, Seema] Northwestern Mem Hosp, Chicago, IL USA. [Vesole, David] Loyola Univ, Med Ctr, Maywood, IL USA. [Hofmeister, Craig] Ohio State Univ, Columbus, OH USA. [Borrello, Ivan] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Alsina, Melissa; Fernandez, Hugo; Dalton, William] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Pereira, Denise] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Stadtmauer, Edward] Univ Penn, Abramson Canc Ctr, Philadelphia, PA USA. [Vaj, Ravi] Washington Univ, St Louis, MO USA. [Jakubowiak, Andrezej] Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI USA. [Lentzsch, Suzanne] Univ Pittsburgh, Canc Inst, Pittsburgh, PA USA. [Song, Kevin] British Columbia Canc Agcy, Vancouver, BC, Canada. [Bahlis, Nizar; Stewart, Douglas] Univ Calgary, Calgary, AB, Canada. [Trudel, Suzanne; Chen, Christine; Reece, Donna] Univ Hlth Network, Princess Margaret Hosp, Toronto, ON, Canada. RP Fonseca, R (reprint author), Mayo Clin, Scottsdale, AZ USA. RI Hofmeister, Craig/E-3256-2011; Kumar, Shaji/A-9853-2008; OI Hofmeister, Craig/0000-0003-4816-1607; Kumar, Shaji/0000-0001-5392-9284; Fonseca, Rafael/0000-0002-5938-3769; Rajkumar, S. Vincent/0000-0002-5862-1833; Dispenzieri, Angela/0000-0001-8780-9512 FU NCI NIH HHS [P30 CA016672] NR 12 TC 2 Z9 2 U1 0 U2 0 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD FEB PY 2010 VL 85 IS 2 BP 197 EP 199 DI 10.4065/mcp.2009.0559 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 556QW UT WOS:000274607200017 PM 20118399 ER PT J AU Bianchi, MT AF Bianchi, Matt T. TI Promiscuous modulation of ion channels by anti-psychotic and anti-dementia medications SO MEDICAL HYPOTHESES LA English DT Article ID METHYL-D-ASPARTATE; NICOTINIC ACETYLCHOLINE-RECEPTOR; ALZHEIMERS-DISEASE; SODIUM-CHANNELS; K+ CHANNEL; DIFFERENTIAL INHIBITION; ATYPICAL ANTIPSYCHOTICS; NONCOMPETITIVE MANNER; HIPPOCAMPAL-NEURONS; POTASSIUM CHANNELS AB There is growing interest in the concept of network pharmacology, as opposed to specific pharmacological targets, as an important drug discovery paradigm. Also known as the "magic shotgun" paradigm, this strategy involves individual drugs interacting with multiple targets to achieve clinical benefit. Pharmacological promiscuity consistent with this paradigm has been suggested in vitro for antidepressants and anticonvulsants, which interact with many classes of ion channels (among other receptor targets). Although the link between certain "off-target" interactions and drug side effects is well-accepted, the potential linkage between promiscuity and clinical efficacy remains poorly understood. Here we summarize interactions of clinically useful anti-psychotic and anti-dementia medications with a diverse array of ligand- and voltage-gated ion channels. We hypothesize that promiscuous ion channel modulation may contribute to the efficacy of drugs used to treat psychosis and dementia. (C) 2009 Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Neurol, Sleep Div, Boston, MA 02114 USA. RP Bianchi, MT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Sleep Div, Wang Ambulatory Ctr 7th Floor, Boston, MA 02114 USA. EM thebianchi@gmail.com NR 80 TC 10 Z9 11 U1 1 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 J9 MED HYPOTHESES JI Med. Hypotheses PD FEB PY 2010 VL 74 IS 2 BP 297 EP 300 DI 10.1016/j.mehy.2009.09.003 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 556CH UT WOS:000274564700028 PM 19786325 ER PT J AU Malcolm, JG Michailovich, O Bouix, S Westin, CF Shenton, ME Rathi, Y AF Malcolm, James G. Michailovich, Oleg Bouix, Sylvain Westin, Carl-Fredrik Shenton, Martha E. Rathi, Yogesh TI A filtered approach to neural tractography using the Watson directional function SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Diffusion-weighted MRI; Tractography; Kalman filtering; Watson directional function ID MULTIPLE FIBER ORIENTATIONS; DIFFUSION-WEIGHTED MRI; SPHERICAL DECONVOLUTION; TENSOR MRI; RESOLUTION; TRACKING; DISTRIBUTIONS; MODEL; RECONSTRUCTION; DECOMPOSITION AB We propose a technique to simultaneously estimate the local fiber orientations and perform multi-fiber tractography. Existing techniques estimate the local fiber orientation at each voxel independently so there is no running knowledge of confidence in the measured signal or estimated fiber orientation. Further, to overcome noise, many algorithms use a filter as a post-processing step to obtain a smooth trajectory. We formulate fiber tracking as causal estimation: at each step of tracing the fiber, the current estimate of the signal is guided by the previous. To do this, we model the signal as a discrete mixture of Watson directional functions and perform tractography within a filtering framework. Starting from a seed point, each fiber is traced to its termination using an unscented Kalman filter to simultaneously fit the signal and propagate in the most consistent direction. Despite the presence of noise and uncertainty, this provides an accurate estimate of the local structure at each point along the fiber. We choose the Watson function since it provides a compact representation of the signal parameterized by the principal diffusion direction and a scaling parameter describing anisotropy, and also allows analytic reconstruction of the oriented diffusion function from those parameters. Using a mixture of two and three components (corresponding to two-fiber and three-fiber models) we demonstrate in synthetic experiments that this approach reduces signal reconstruction error and significantly improves the angular resolution at crossings and branchings. In vivo experiments examine the corpus callosum and internal capsule and confirm the ability to trace through regions known to contain such crossing and branching while providing inherent path regularization. (C) 2009 Elsevier B. V. All rights reserved. C1 [Malcolm, James G.; Bouix, Sylvain; Shenton, Martha E.; Rathi, Yogesh] Harvard Univ, Sch Med, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Boston, MA 02215 USA. [Michailovich, Oleg] Univ Waterloo, Dept Elect & Comp Engn, Waterloo, ON N2L 3G1, Canada. [Westin, Carl-Fredrik] Harvard Univ, Sch Med, Dept Radiol, Lab Math Imaging, Boston, MA 02215 USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Brockton Div, Brockton, MA USA. RP Malcolm, JG (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Boston, MA 02215 USA. EM malcolm@bwh.harvard.edu OI Bouix, Sylvain/0000-0003-1326-6054 FU Department of Veteran Affairs Merit Award; VA Schizophrenia Center; NIH [P41 RR13218, K05 MH 070047, 1P50MH080272-01, R01 MH 50740, R01 MH 082918, P50 MH080272-01, R01 MH50740-15, R03 TW008134-01]; Center for Integration of Medicine and Innovative Technology Soldier in Medicine Award FX This work was supported in part by a Department of Veteran Affairs Merit Award (Shenton, R McCarley), the VA Schizophrenia Center Grant (McCarley, Shenton) and NIH Grants: P41 RR13218 (Shenton), K05 MH 070047 (Shenton), 1P50MH080272-01 (Shenton), R01 MH 50740 (Shenton), R01 MH 082918 (Bouix), P50 MH080272-01 (McCarley), R01 MH50740-15 (Shenton), R03 TW008134-01 (Shenton), and the Center for Integration of Medicine and Innovative Technology Soldier in Medicine Award (Bouix). NR 55 TC 20 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD FEB PY 2010 VL 14 IS 1 BP 58 EP 69 DI 10.1016/j.media.2009.10.003 PG 12 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 528QB UT WOS:000272460400007 PM 19914856 ER PT J AU Hooker, RS AF Hooker, Roderick S. TI The future of the physician assistant movement SO MEDICAL JOURNAL OF AUSTRALIA LA English DT Editorial Material ID BRAIN-DRAIN C1 [Hooker, Roderick S.] Univ N Texas, Hlth Sci Ctr, Sch Publ Hlth, Ft Worth, TX USA. [Hooker, Roderick S.] US Dept Vet Affairs, Vet Hlth Adm, Dallas, TX USA. RP Hooker, RS (reprint author), Univ N Texas, Hlth Sci Ctr, Sch Publ Hlth, Ft Worth, TX USA. EM roderick.hooker@va.gov NR 6 TC 3 Z9 3 U1 0 U2 0 PU AUSTRALASIAN MED PUBL CO LTD PI PYRMONT PA LEVEL 2, 26-32 PYRMONT BRIDGE RD, PYRMONT, NSW 2009, AUSTRALIA SN 0025-729X J9 MED J AUSTRALIA JI Med. J. Aust. PD FEB 1 PY 2010 VL 192 IS 3 BP 116 EP 116 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 563RF UT WOS:000275150400001 PM 20121674 ER PT J AU Craft, D Monz, M AF Craft, David Monz, Michael TI Simultaneous navigation of multiple Pareto surfaces, with an application to multicriteria IMRT planning with multiple beam angle configurations SO MEDICAL PHYSICS LA English DT Article DE dosimetry; optimisation; radiation therapy ID FLUENCE MAP OPTIMIZATION AB Methods: The authors assume a convex optimization setting and represent the Pareto surface for each modality or given beam set by a set of discrete points on the surface. Weighted averages of these discrete points produce a continuous representation of each Pareto surface. The authors calculate a set of Pareto surfaces and use linear programming to navigate across the individual surfaces, allowing switches between surfaces. The switches are organized such that the plan profits in the requested way, while trying to keep the change in dose as small as possible. Results: The system is demonstrated on a phantom pancreas IMRT case using 100 different five beam configurations and a multicriteria formulation with six objectives. The system has intuitive behavior and is easy to control. Also, because the underlying linear programs are small, the system is fast enough to offer real-time exploration for the Pareto surfaces of the given beam configurations. Conclusions: The system presented offers a sound starting point for building clinical systems for multicriteria exploration of different modalities and offers a controllable way to explore hundreds of beam angle configurations in IMRT planning, allowing the users to focus their attention on the dose distribution and treatment planning objectives instead of spending excessive time on the technicalities of delivery. C1 [Craft, David] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Monz, Michael] Fraunhofer Inst Ind Math, Dept Optimizat, D-67663 Kaiserslautern, Germany. RP Craft, D (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM dcraft@partners.org FU NCI [1 R01 CA103904-01 Al] FX This work was sponsored by NCI Grant No. 1 R01 CA103904-01 Al: Multicriteria IMRT Optimization and by RaySearch Laboratories. NR 13 TC 15 Z9 15 U1 0 U2 2 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD FEB PY 2010 VL 37 IS 2 BP 736 EP 741 DI 10.1118/1.3292636 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 549SW UT WOS:000274075600035 PM 20229883 ER PT J AU McHenry, CR Phitayakorn, R AF McHenry, C. R. Phitayakorn, R. TI Difficult problems in thyroid cancer surgery SO MINERVA CHIRURGICA LA English DT Review DE Thyroid neoplasms; Lymph node excision; Tracheal diseases; Esophageal diseases ID RECURRENT-LARYNGEAL NERVE; POSTOPERATIVE THYROGLOBULIN LEVELS; SUFFICIENT SURGICAL-TREATMENT; UNILATERAL TOTAL LOBECTOMY; HURTHLE CELL-CARCINOMA; PAPILLARY CARCINOMA; TRACHEAL RESECTION; UNITED-STATES; PREOPERATIVE ULTRASONOGRAPHY; ESOPHAGEAL INVOLVEMENT AB vThe incidence of thyroid cancer has increased dramatically, yet the mortality has remained unchanged. There remain many challenges and "difficult problems" in diagnosing and treating patients with differentiated thyroid cancer (DTC). A significant percentage of patients with DTC will present with a thyroid nodule and an indeterminate fine needle aspiration biopsy underscoring the importance of proper evaluation and management. It is important when considering the extent of thyroidectomy and the management of lymph node metastases to balance the outcome of treatment-in terms of recurrence and mortality with the morbidity of the procedure. Total thyroidectomy and lymphadenectomy for macroscopic lymph node metastases appear to be the optimal therapy for most patients with DTC. Preservation of function is a priority in managing patients with DTC invading the recurrent laryngeal nerve, trachea, esophagus, or the larynx. C1 [McHenry, C. R.] Case Western Reserve Univ, Dept Surg, Metrohlth Med Ctr, Sch Med, Cleveland, OH 44109 USA. [Phitayakorn, R.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp,Div Gastrointestinal & End, Boston, MA 02115 USA. RP McHenry, CR (reprint author), Case Western Reserve Univ, Dept Surg, Metrohlth Med Ctr, Sch Med, 2500 Metrohlth Dr, Cleveland, OH 44109 USA. EM cmchenry@metrohealth.org OI Phitayakorn, Roy/0000-0002-8327-1484 NR 74 TC 1 Z9 1 U1 0 U2 1 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0026-4733 J9 MINERVA CHIR JI Minerva Chir. PD FEB PY 2010 VL 65 IS 1 BP 83 EP 93 PG 11 WC Surgery SC Surgery GA 586FH UT WOS:000276887900010 PM 20212420 ER PT J AU Antonescu, CR Zhang, L Chang, NE Pawel, BR Travis, W Rosenberg, AE Nielsen, GP Dal Cin, P Fletcher, CD AF Antonescu, C. R. Zhang, L. Chang, N. E. Pawel, B. R. Travis, W. Rosenberg, A. E. Nielsen, G. P. Dal Cin, P. Fletcher, C. D. TI Novel EWSR1-POU5F1 Fusion in Soft Tissue Myoepithelial Tumors. A Molecular Analysis of 29 Cases, Including Soft Tissue, Bone and Visceral Locations Showing Common Involvement of EWSR1 Gene Rearrangement SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RI Pawel, Bruce/G-5466-2011 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 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 49 BP 14A EP 15A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582500050 ER PT J AU Bridge, JA Streblow, R Frayer, RW Dal Cin, P Rosenberg, A Meloni-Ehrig, A Sumegi, J AF Bridge, J. A. Streblow, R. Frayer, R. W. Dal Cin, P. Rosenberg, A. Meloni-Ehrig, A. Sumegi, J. TI Recurrent (2;2) and (2;8) Translocations in Rhabdomyosarcoma without the Canonical PAX-FOXO1 Fuse PAX3 to Members of the Nuclear Receptor Transcriptional Coactivator (NCOA) Family SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Univ Nebraska, Med Ctr, Omaha, NE USA. Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Quest Diagnost Nichols Inst, Chantilly, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 55 BP 16A EP 16A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500056 ER PT J AU Demicco, EG Rosenberg, AE Antonescu, CR Kobler, JB Nielsen, GP AF Demicco, E. G. Rosenberg, A. E. Antonescu, C. R. Kobler, J. B. Nielsen, G. P. TI Benign Notochordal Cell Proliferations in the Ferret: An Animal with a High Incidence of Chordoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 69 BP 19A EP 19A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500070 ER PT J AU Lee, AF Hayes, MM Rosenberg, AE Nielsen, TO Lee, CH AF Lee, A. F. Hayes, M. M. Rosenberg, A. E. Nielsen, T. O. Lee, C. H. TI FLI-1 Distinguishes Ewing Sarcoma from Small Cell Osteosarcoma and Mesenchymal Chondrosarcoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Vancouver Gen Hosp, Vancouver, BC, Canada. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 87 BP 22A EP 22A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500088 ER PT J AU Lee, CH Liebsch, NJ Nielsen, GP Ganguly, A Rosenberg, AE AF Lee, C. H. Liebsch, N. J. Nielsen, G. P. Ganguly, A. Rosenberg, A. E. TI Morphologic and Immunohistochemical Characterization of a Series of Clinically Atypical Skull Base Chordomas in the Paediatric Population SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Vancouver Gen Hosp, Vancouver, BC, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 89 BP 23A EP 23A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500090 ER PT J AU Romeo, S Duim, RAJ Bridge, JA Mertens, F De Jong, D Dal Cin, P Wijers-Koster, PM Debiec-Rychter, M Sciot, R Rosenberg, A Szuhai, K Hogendoorn, PCW AF Romeo, S. Duim, R. A. J. Bridge, J. A. Mertens, F. De Jong, D. Dal Cin, P. Wijers-Koster, P. M. Debiec-Rychter, M. Sciot, R. Rosenberg, A. Szuhai, K. Hogendoorn, P. C. W. TI Heterogeneous and Complex Rearragements of the Long Arm of Chromosome 6 in Chondromyxoid Fibroma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Treviso Re Hosp, Treviso, Italy. Leiden Univ, Med Ctr, Leiden, Netherlands. Univ Nebraska Med Ctr, Omaha, NE USA. Univ Lund Hosp, S-22185 Lund, Sweden. Brigham & Womens Hosp, Boston, MA 02115 USA. Catholic Univ Louvain, B-3000 Louvain, Belgium. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Szuhai, Karoly/A-1100-2008 OI Szuhai, Karoly/0000-0002-1228-4245 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 107 BP 27A EP 27A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500108 ER PT J AU Imielinski, M Cha, S Richardson, EA Thakur, D Rejtar, T Wu, SL Karger, B Sgroi, D AF Imielinski, M. Cha, S. Richardson, E. A. Thakur, D. Rejtar, T. Wu, S-L Karger, B. Sgroi, D. TI Combined Proteomic-Transcriptomic Profiling of Laser Capture Microdissected Normal and Breast Cancer Epithelium Reveals Systematic Biochemical Network Alterations SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Northeastern Univ, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 225 BP 52A EP 53A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582500225 ER PT J AU Johnson, MM Dialani, V Johnson, NB AF Johnson, M. M. Dialani, V. Johnson, N. B. TI Histologic Characteristics of Benign Breast Lesions Identified for Biopsy by Magnetic Resonance Imaging SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 231 BP 54A EP 54A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500231 ER PT J AU Kaplan, J Schnitt, S Collins, L Wang, Y Garber, J Montgomery, K West, R Tung, N AF Kaplan, J. Schnitt, S. Collins, L. Wang, Y. Garber, J. Montgomery, K. West, R. Tung, N. TI Histologic and Immunophenotypic Comparison of Estrogen Receptor (ER)-Positive Breast Cancers in BRCA1 Mutation Carriers and Sporadic ER-Positive Breast Cancers: A Case-Control Study SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Stanford Univ, Palo Alto, CA 94304 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 235 BP 55A EP 55A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500235 ER PT J AU Marotti, JD Collins, LC Gelber, S Ruddy, K Kereakoglow, S Brachtel, EF Winer, E Partridge, A AF Marotti, J. D. Collins, L. C. Gelber, S. Ruddy, K. Kereakoglow, S. Brachtel, E. F. Winer, E. Partridge, A. TI Pathologic Features and Distribution of Molecular Phenotype among Young Women with Breast Cancer: Results from the Young Women's Breast Cancer Study SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 266 BP 62A EP 62A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500266 ER PT J AU Stone, JR Khosroshahi, A Deshpande, V Stone, JH AF Stone, J. R. Khosroshahi, A. Deshpande, V. Stone, J. H. TI Thoracic Lymphoplasmacytic Aortitis Is Often Associated with IgG4-Related Systemic Disease SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 370 BP 84A EP 84A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500370 ER PT J AU Wang, H Smith, RN Stone, JR AF Wang, H. Smith, R. N. Stone, J. R. TI Ascending Giant Cell Aortitis without Systemic Symptoms Is Associated with an Increased Frequency of Subsequent Distal Aortic Events SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 375 BP 85A EP 85A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500375 ER PT J AU Chebib, I Yeager, K Mino-Kenudsen, M Brugge, W Pitman, MB AF Chebib, I. Yeager, K. Mino-Kenudsen, M. Brugge, W. Pitman, M. B. TI The Role of Cytopathology in the Diagnosis and Management of Pancreatic Cysts Greater Than 3 cm SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 [Chebib, I.; Yeager, K.; Mino-Kenudsen, M.; Brugge, W.; Pitman, M. B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 394 BP 90A EP 90A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500394 ER PT J AU Moatamed, NA Apple, SK Moatamed, F AF Moatamed, N. A. Apple, S. K. Moatamed, F. TI Inclusion of the Uniform Tetraploid Cells Reduces the Specificity of the Urine FISH Assay SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. VA Greater Healthcare Syst, Los Angeles, CA 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 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 447 BP 102A EP 102A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500447 ER PT J AU Baran, JL Laga, AC Duncan, LM Murphy, GF AF Baran, J. L. Laga, A. C. Duncan, L. M. Murphy, G. F. TI The Embryonic Stem Cell Transcription Factor SOX2 Is Expressed by Spitz Nevi SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 489 BP 111A EP 111A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500489 ER PT J AU Baran, JL Scott, K Muzikansky, A Chin, L Duncan, LM AF Baran, J. L. Scott, K. Muzikansky, A. Chin, L. Duncan, L. M. TI MITF Expression in Cutaneous Melanoma and Spitz Nevi: A Genomic and Immunohistochemical Study SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 490 BP 111A EP 111A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500490 ER PT J AU Sepehr, A Chao, E Mihm, MC Tsao, H AF Sepehr, A. Chao, E. Mihm, M. C., Jr. Tsao, H. TI Comparative Analysis of Spitz Tumors: A Clinicopathologic Follow-Up of 163 Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 536 BP 121A EP 121A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500536 ER PT J AU Ryan, R Brodsky, V Louissaint, A Gilbertson, J Yagi, Y AF Ryan, R. Brodsky, V. Louissaint, A. Gilbertson, J. Yagi, Y. TI Usage and Participation in a Resident-Built Virtual Slide-Based Atlas of Anatomic Pathology SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Weill Cornell Med Coll, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 552 BP 125A EP 125A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500552 ER PT J AU Kolman, OK Sadow, PM Hunt, JL AF Kolman, O. K. Sadow, P. M. Hunt, J. L. TI Sampling, Assessment, and Reporting of Thyroid Follicular Lesions: Survey of 165 Pathologists SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 567 BP 128A EP 129A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582500567 ER PT J AU Agoston, AT Lauwers, GY Odze, RD AF Agoston, A. T. Lauwers, G. Y. Odze, R. D. TI Evidence That Dysplasia Begins in the Bases of the Pits in the Pathogenesis of Gastric Cancer SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 593 BP 134A EP 134A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500593 ER PT J AU Coco, D Goldblum, J Hornick, J Lauwers, GY Montgomery, E Srivastava, A Wang, H Odze, RD AF Coco, D. Goldblum, J. Hornick, J. Lauwers, G. Y. Montgomery, E. Srivastava, A. Wang, H. Odze, R. D. TI Interobserver Variability in the Diagnosis of Crypt Dysplasia in Barrett's Esophagus SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Cleveland Clin, Cleveland, OH 44106 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Dartmouth Med Ctr, Lebanon, NH USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 621 BP 140A EP 140A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500621 ER PT J AU Courville, EL Srivastava, A Hong, TS Yilmaz, OH Calvo, LN Zaki, BI Mino-Kenudson, M AF Courville, E. L. Srivastava, A. Hong, T. S. Yilmaz, O. H. Calvo, L. N. Zaki, B. I. Mino-Kenudson, M. TI Lack of ERCC1 and Olfactomedin 4 (Olfm4) Protein Expression Predicts Neoadjuvant Therapy Sensitivity in GE Junction Adenocarcinoma (GEJAd) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 625 BP 141A EP 141A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500625 ER PT J AU Demicco, EG Farris, AB Iafrate, AJ Gaissert, HA Fukuoka, J Cohen, C Zukerberg, LR Lauwers, GY Mino-Kenudson, M AF Demicco, E. G. Farris, A. B. Iafrate, A. J. Gaissert, H. A. Fukuoka, J. Cohen, C. Zukerberg, L. R. Lauwers, G. Y. Mino-Kenudson, M. TI Microsatellite Unstable Barrett's Esophagus-Associated Adenocarcinomas Are Rare, but Clinicopathologically Similar to the Colonic Counterpart SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Univ, Atlanta, GA 30322 USA. Toyama Med Univ, Toyama, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 630 BP 142A EP 143A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582500630 ER PT J AU Demicco, EG Farris, AB Agbor-Etang, B Fukuoka, J Daives, D Snimizu, M Gaissert, HA Mino-Kenudson, M AF Demicco, E. G. Farris, A. B. Agbor-Etang, B. Fukuoka, J. Daives, D. Snimizu, M. Gaissert, H. A. Mino-Kenudson, M. TI Validation of a Topographic-Anatomic Subclassification for Adenocarcinoma of the GE Junction (GEJ) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Univ, Atlanta, GA 30322 USA. Toyama Univ Hosp, Toyama, Japan. Saitama Med Univ, Saitama, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 631 BP 143A EP 143A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500631 ER PT J AU Golden, KL Baba, Y Fuchs, CS Ogino, S AF Golden, K. L. Baba, Y. Fuchs, C. S. Ogino, S. TI Loss of CDH1 Expression in Colorectal Cancer Is Independently Associated with Microsatellite Instability and Female Gender SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 645 BP 146A EP 146A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582500645 ER PT J AU Kolman, OK Brown, I Moran, CJ Russell, GJ Mino-Kenudson, M AF Kolman, O. K. Brown, I. Moran, C. J. Russell, G. J. Mino-Kenudson, M. TI Neutrophilic Infiltration in Gluten Sensitive Enteropathy (GSE): A Series of 100 Pediatric Patients SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Sullivan Nicolaides Pathol, Taringa, Australia. 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 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 671 BP 152A EP 152A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501007 ER PT J AU Lennerz, JK Srivastava, A Batten, J Chen, JH Iafrate, AJ Lauwers, G AF Lennerz, J. K. Srivastava, A. Batten, J. Chen, J. H. Iafrate, A. J. Lauwers, G. TI Molecular Profile of Crohn's Colitis-Associated Colorectal Adenocarcinoma Is More Similar to the 'Sporadic' Rather Than Ulcerative Colitis-Associated Profile SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Indiana Univ, Indianapolis, IN 46204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 678 BP 153A EP 153A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501014 ER PT J AU Ogino, S Nosho, K Glickman, JN Mino-Kenudson, M Fuchs, CS AF Ogino, S. Nosho, K. Glickman, J. N. Mino-Kenudson, M. Fuchs, C. S. TI Lymphoid Reaction to Colorectal Cancer Predicts Patient Survival Independent of Lymph Node Count and MSI, and Explains the Association between CIMP and Good Prognosis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 701 BP 158A EP 159A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582501037 ER PT J AU Ogino, S Nosho, K Tanaka, N Hornick, JL Fuchs, CS AF Ogino, S. Nosho, K. Tanaka, N. Hornick, J. L. Fuchs, C. S. TI Can We Predict Lymph Node Count in Colorectal Cancer Resection Specimen Using Clinical, Pathologic and Molecular Variables? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 703 BP 159A EP 160A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582501039 ER PT J AU Ogino, S Nosho, K Mino-Kenudson, M Meyerhardt, JA Fuchs, CS AF Ogino, S. Nosho, K. Mino-Kenudson, M. Meyerhardt, J. A. Fuchs, C. S. TI Negative Lymph Node Count in Colorectal Cancer Resection Predicts Patient Survival, Independent of Positive Node Count, Tumoral Molecular Alterations and Lymphocytic Reaction SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 702 BP 159A EP 159A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501038 ER PT J AU Park, DY Kang, HJ Shin, DH Choi, KU Lee, CH Huh, GY Sol, MY Lauwers, GY AF Park, D. Y. Kang, H. J. Shin, D. H. Choi, K. U. Lee, C. H. Huh, G. Y. Sol, M. Y. Lauwers, G. Y. TI Gastric Foveolar Hyperplasia, Foveolar Dysplasia and Pit Dysplasia in 414 Gastric Cancers-Prevalence and Clinicopathological Significance SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Pusan Natl Univ Hosp, Pusan, South Korea. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 708 BP 160A EP 161A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582501044 ER PT J AU Shima, K Nosho, K Chen, L Fuchs, CS Ogino, S AF Shima, K. Nosho, K. Chen, L. Fuchs, C. S. Ogino, S. TI Loss of PPARG Expression Is Common in CpG Island Methylator Phenotype-Low (CIMP-Low) Colorectal Cancer SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 738 BP 167A EP 168A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582501074 ER PT J AU Yilmaz, OH Bhan, AK Lauwers, GY Deshpande, V AF Yilmaz, O. H. Bhan, A. K. Lauwers, G. Y. Deshpande, V. TI Olfactomedin-4, a Novel Marker of Intestinal Stem Cell Identity, Is Upregulated in Long-Standing Ulcerative Colitis and Accompanying Low Grade Dysplasia SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Yilmaz, O. H.; Bhan, A. K.; Lauwers, G. Y.; Deshpande, V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 763 BP 173A EP 173A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501099 ER PT J AU Sangoi, AR Beck, AH Amin, MB Cheng, L Epstein, JI Hansel, DE Iczkowski, KA Ro, JY Lopez-Beltran, A Oliva, E Paner, GP Reuter, VE Shah, RB Shen, SS Tamboli, P McKenney, JK AF Sangoi, A. R. Beck, A. H. Amin, M. B. Cheng, L. Epstein, J. I. Hansel, D. E. Iczkowski, K. A. Ro, J. Y. Lopez-Beltran, A. Oliva, E. Paner, G. P. Reuter, V. E. Shah, R. B. Shen, S. S. Tamboli, P. McKenney, J. K. TI Interobserver Reproducibility (IOR) in the Diagnosis of Invasive Micropapillary Carcinoma (MPC) of the Genitourinary Tract among Expert Urologic Pathologists SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Cedars Sinai, Los Angeles, CA USA. U Indiana, Indianapolis, IN USA. Johns Hopkins, Baltimore, MD USA. Cleveland Clin, Cleveland, OH 44106 USA. U Colorado, Aurora, CO USA. Methodist, Houston, TX USA. Univ Cordoba, Fac Med, Anat Pathol Unit, E-14071 Cordoba, Spain. Massachusetts Gen Hosp, Boston, MA 02114 USA. Northwestern, Chicago, IL USA. Mem Sloan Kettering, New York, NY USA. U Michigan, Ann Arbor, MI USA. UT MD Anderson, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 965 BP 216A EP 216A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501300 ER PT J AU Chiang, S Fazlollahi, L Nguyen, A Roberts, DJ Iafrate, AJ AF Chiang, S. Fazlollahi, L. Nguyen, A. Roberts, D. J. Iafrate, A. J. TI In Situ Genetic Analysis of Hydatidiform Moles by Polymorphic Deletion Probe Fluorescence In Situ Hybridization SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Chiang, S.; Fazlollahi, L.; Nguyen, A.; Roberts, D. J.; Iafrate, A. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1061 BP 237A EP 237A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501396 ER PT J AU Han, G Soslow, RA Reuter, VE Oliva, E Gilks, CB Asad, H Tickoo, SK AF Han, G. Soslow, R. A. Reuter, V. E. Oliva, E. Gilks, C. B. Asad, H. Tickoo, S. K. TI Hypoxia-Inducible Factor (HIF) and Mammalian Target of Rapamycin (mTOR) Pathway Markers in Ovarian Clear Cell Carcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Vancouver Gen Hosp, Vancouver, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1098 BP 246A EP 246A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501433 ER PT J AU Kindelberger, DW Matulonis, U AF Kindelberger, D. W. Matulonis, U. TI The Utility of Circulating Tumor Cells in Monitoring Patients with Recurrent Ovarian Cancer SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1117 BP 250A EP 250A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501451 ER PT J AU Knoepp, SM Kuebler, DL Wilbur, DC AF Knoepp, S. M. Kuebler, D. L. Wilbur, D. C. TI Correlation of the Hybrid Capture II High-Risk HPV DNA Test Chemiluminescense Intensity from Cervical Samples with Follow-Up Histologic Results: A Cytologic/Histologic Review of 367 Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Univ Michigan, Ann Arbor, MI 48109 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1118 BP 250A EP 250A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501452 ER PT J AU Laury, AR Hornick, JL Corson, JM Krane, JF Drapkin, R Hirsch, MS AF Laury, A. R. Hornick, J. L. Corson, J. M. Krane, J. F. Drapkin, R. Hirsch, M. S. TI PAX8 Distinguishes Serous Ovarian Neoplasms from Malignant Mesothelioma with High Sensitivity and Specificity SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1125 BP 251A EP 252A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582501459 ER PT J AU Mutter, GL Monte, NM Webster, KA Neuberg, D Dressler, GR AF Mutter, G. L. Monte, N. M. Webster, K. A. Neuberg, D. Dressler, G. R. TI Interaction of PAX2 and PTEN Drives Emergence of Endometrial Precancers from a Preclinical Latent Phase SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1146 BP 256A EP 256A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501480 ER PT J AU Schulte, S Roh, M Folkins, AK Jarboe, EA Garber, J Hecht, J Crum, CP AF Schulte, S. Roh, M. Folkins, A. K. Jarboe, E. A. Garber, J. Hecht, J. Crum, C. P. TI BRCA 1 or 2-Associated (BRCA plus ) Pelvic Serous Carcinomas Arise from Both the Ovaries and Fallopian Tubes: The Contrast between Symptomatic and Asymptomatic Women SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Univ Penn, Philadelphia, PA 19104 USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. Univ Utah, Med Ctr, Salt Lake City, UT USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1171 BP 262A EP 262A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501505 ER PT J AU Van De Vijver, KK Castilla, MA Romero, L Biscuola, M Moreno-Bueno, G Palacios, J Oliva, E AF Van De Vijver, K. K. Castilla, M. A. Romero, L. Biscuola, M. Moreno-Bueno, G. Palacios, J. Oliva, E. TI Study of Epithelial-Mesenchymal Transition in 70 Endometrial Carcinosarcomas (ECS) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Maastricht Univ Med Ctr, Maastricht, Netherlands. Hosp Univ Virgen del Rocio, Seville, Spain. Massachusetts Gen Hosp, Boston, MA 02114 USA. CSIC, Inst Invest Biomed, Madrid, Spain. RI Castilla, M Angeles/C-9454-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1199 BP 267A EP 267A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501533 ER PT J AU Xian, W Mehra, KK Vathipadiekal, V Tay, SW Birrer, M Crum, CP AF Xian, W. Mehra, K. K. Vathipadiekal, V. Tay, S. W. Birrer, M. Crum, C. P. TI Ovarian Cancer Risk Assessment Via Expression Profiling of the Distal Fallopian Tube Epithelium SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Inst Mol Biol, Singapore, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1207 BP 269A EP 269A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501541 ER PT J AU Xian, W Mehra, KK Miron, A Oliva, E Garber, J Roh, M Quade, BJ Crum, CP AF Xian, W. Mehra, K. K. Miron, A. Oliva, E. Garber, J. Roh, M. Quade, B. J. Crum, C. P. TI The Li Fraumeni Syndrome: A New Paradigm for p53 Signature Initiation in the Distal Fallopian Tube and In Vitro Modeling SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Inst Mol Biol, Singapore, Singapore. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1206 BP 269A EP 269A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501540 ER PT J AU Hafezi, S Seethalu, RR Stelow, EB Mills, S Perez-Ordonez, B Leong, I Hunt, JL Weinreb, I AF Hafezi, S. Seethalu, R. R. Stelow, E. B. Mills, S. Perez-Ordonez, B. Leong, I. Hunt, J. L. Weinreb, I. TI Ewing Family of Tumors of the Sinonasal Tract SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Univ Hlth Network, Toronto, ON, Canada. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1229 BP 274A EP 274A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501563 ER PT J AU Adam, P Vela-Chavez, T Cremer, M Bink, K Ferry, JA Fend, F Jaffe, E Quintanilla-Martinez, L AF Adam, P. Vela-Chavez, T. Cremer, M. Bink, K. Ferry, J. A. Fend, F. Jaffe, E. Quintanilla-Martinez, L. TI Cyclin D1 Positive Diffuse Large B-Cell Lymphomas Feature a Post-Germinal Center - Immunophenotype and Lack Alterations in the CCND1 Gene Locus SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Univ Tubingen, Tubingen, Germany. Tech Univ Munich, Munich, Germany. Massachusetts Gen Hosp, Boston, MA 02114 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1267 BP 282A EP 282A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582501601 ER PT J AU Gibson, SE Swerdlow, SH Ferry, JA Surti, U Harris, NL Hasserjian, RP AF Gibson, S. E. Swerdlow, S. H. Ferry, J. A. Surti, U. Harris, N. L. Hasserjian, R. P. TI Reassessment of Small Lymphocytic Lymphoma (SLL) in the Era of Monoclonal B Lymphocytosis (MBL) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1328 BP 296A EP 297A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582502009 ER PT J AU Klepeis, VE Deshpande, V Sohani, AR Ferry, JA AF Klepeis, V. E. Deshpande, V. Sohani, A. R. Ferry, J. A. TI Sclerosing Inflammatory Pseudotumor of the Orbit: An IgG4-Related Disease SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Klepeis, V. E.; Deshpande, V.; Sohani, A. R.; Ferry, J. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 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 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1371 BP 307A EP 307A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502052 ER PT J AU Nardi, V Abramson, JS Hasserjian, RP AF Nardi, V. Abramson, J. S. Hasserjian, R. P. TI Morphologic Dysplasia in Staging Marrow from High-Grade Non-Hodgkin's Lymphoma Patients: A Paraneoplastic Phenomenon Associated with Adverse Clinical Outcome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Nardi, V.; Abramson, J. S.; Hasserjian, R. P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1403 BP 314A EP 314A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502084 ER PT J AU Ahmad, BR Viswanathan, SR Daley, GQ Frazier, AL Perez-Atayde, AR AF Ahmad, B. R. Viswanathan, S. R. Daley, G. Q. Frazier, A. L. Perez-Atayde, A. R. TI Lin28 a Novel, Lineage-Specific, Marker of Germ Cell Neoplasia SO MODERN PATHOLOGY LA English DT Meeting Abstract CT Spring Meeting of the Society-for-Pediatric-Patholoy CY MAR 20-21, 2010 CL Washington, DC SP Soc Pediat Pathol C1 Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 IS 2 MA 20 BP 315 EP 315 PG 1 WC Pathology SC Pathology GA 551TL UT WOS:000274233100036 ER PT J AU Rodig, SJ Kutok, JL Paterson, JC Zhang, W Shipp, MA Grogan, T Pileri, SA Montes-Moreno, S Johnson, NA Ben-Neriah, S Farinha, P Piris, MA Gascoyne, R Marafioti, T AF Rodig, S. J. Kutok, J. L. Paterson, J. C. Zhang, W. Shipp, M. A. Grogan, T. Pileri, S. A. Montes-Moreno, S. Johnson, N. A. Ben-Neriah, S. Farinha, P. Piris, M. A. Gascoyne, R. Marafioti, T. TI VpreB3, a Pre-BCR Associated Protein, Is Expressed by a Subset of Mature, Germinal Center B Cells and a Biomarker of Burkitt Lymphoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Oxford, Oxford, England. Ventana Med Syst, Tucson, AZ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Arizona, Tucson, AZ USA. Univ Bologna, Sch Med, Bologna, Italy. Spanish Natl Canc Ctr CNIO, Madrid, Spain. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1424 BP 318A EP 319A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582502105 ER PT J AU Ryan, RJH Zukerberg, L Sloan, JM Collins, B Ferry, J AF Ryan, R. J. H. Zukerberg, L. Sloan, J. M. Collins, B. Ferry, J. TI MALT Lymphoma with Associated Amyloid Deposition - A Clinico-Pathological Study of 18 Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1430 BP 320A EP 320A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502111 ER PT J AU Wang, SA Abruzzo, LV Hasserjian, RP Medeiros, LJ Miranda, RN AF Wang, S. A. Abruzzo, L. V. Hasserjian, R. P. Medeiros, L. J. Miranda, R. N. TI Myelodysplastic Syndromes with Interstitial Deletions of 11q Lack Cryptic 11q23 Translocations and Exhibit Characteristic Clinicopathologic Features SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acad Pathol C1 UT MD Anderson, Houston, TX USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1460 BP 327A EP 327A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502141 ER PT J AU Louissaint, A Ferry, JA Harris, NL Zukerberg, LR AF Louissaint, A. Ferry, J. A. Harris, N. L. Zukerberg, L. R. TI Morphology and Immunophenotype of Infectious Mononucleosis Presenting in Axillary and Inguinal Lymph Nodes and Other Unusual Locations SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Louissaint, A.; Ferry, J. A.; Harris, N. L.; Zukerberg, L. R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1491 BP 334A EP 334A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502172 ER PT J AU Farris, AB Taheri, D Fazlollahi, L Iafrate, AJ Smith, RN Collins, AB Tolkoff-Rubin, N Spitzer, TR Kawai, T Cosimi, AB Sachs, DH Colvin, RB AF Farris, A. B. Taheri, D. Fazlollahi, L. Iafrate, A. J. Smith, R. N. Collins, A. B. Tolkoff-Rubin, N. Spitzer, T. R. Kawai, T. Cosimi, A. B. Sachs, D. H. Colvin, R. B. TI Distinctive Renal Biopsy Pathology in the Engraftment Syndrome: A Response to Combined Kidney and Bone Marrow Transplantation SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory U, Atlanta, GA USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1512 BP 339A EP 339A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502193 ER PT J AU Farris, AB Coban, I Klimstra, DS Kim, G Deshpande, V Ohike, N Adsay, N AF Farris, A. B. Coban, I. Klimstra, D. S. Kim, G. Deshpande, V. Ohike, N. Adsay, N. TI Necrotizing Arteritis Presenting as a Pancreatic Mass: A New Addition to the Immune-Related Tumoral Pancreatitides SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Emory U, Atlanta, GA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. UCSF, San Francisco, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1576 BP 354A EP 355A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582502257 ER PT J AU Gupta, RK Genevay, M Johnson, NB Lauwers, GY Deshpande, V AF Gupta, R. K. Genevay, M. Johnson, N. B. Lauwers, G. Y. Deshpande, V. TI Is Autoimmune Pancreatitis Associated with an Increased Risk of Malignancy? A Retrospective and Comparative Study SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Geneva, Geneva, Switzerland. Beth Israel Deaconess Med Ctr, Boston, MA USA. NR 0 TC 1 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1584 BP 356A EP 357A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582502265 ER PT J AU Lennerz, JK Chapman, WC Brunt, EM AF Lennerz, J. K. Chapman, W. C. Brunt, E. M. TI Epithelial-Mesenchymal Transition (EMT) of K19 Structures within the Stromal Compartment of HCV Cirrhosis Parallels Hepatocarcinogenesis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Washington Univ, St Louis, MO 63130 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1604 BP 361A EP 361A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502285 ER PT J AU Lisovsky, M Dresser, K Woda, B Mino-Kenudson, M AF Lisovsky, M. Dresser, K. Woda, B. Mino-Kenudson, M. TI Differentiation of Pancreatic Intraepithelial Neoplasia-3 (PanIN-3) and Ductal Adenocarcinoma of the Pancreas from Lower Grade PanINs Utilizing Immunohistochemistry for Cell Polarity Protein Lethal Giant Larva 2 (IgI2) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. UMassMem Med Ctr, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1615 BP 363A EP 363A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502296 ER PT J AU Nagata, K Lauwers, GY Murata, S Shimizu, M AF Nagata, K. Lauwers, G. Y. Murata, S. Shimizu, M. TI Gallbladder Intramural Papillary Mucinous Neoplasm: A New Entity Similar to IPMN of the Pancreas SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Saitama Med Univ, Saitama Int Med Ctr, Hidaka, Saitama, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1628 BP 366A EP 366A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502309 ER PT J AU Shen, J Konstantinidis, I Ferrone, CR Deshpande, V AF Shen, J. Konstantinidis, I. Ferrone, C. R. Deshpande, V. TI Intrapancreatic Cholangiocarcinomas: A Clinicopathological and Immunohistochemical Analysis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Shen, J.; Konstantinidis, I.; Ferrone, C. R.; Deshpande, V.] 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 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1651 BP 371A EP 371A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502332 ER PT J AU Xiao, HD Yamaguchi, H Dias-Santagata, D Kuboki, Y Akhavanfard, S Hatori, T Yamamoto, M Shiratori, K Kobayashi, M Shimizu, M Mino-Kenudson, M Furukawa, T AF Xiao, H. D. Yamaguchi, H. Dias-Santagata, D. Kuboki, Y. Akhavanfard, S. Hatori, T. Yamamoto, M. Shiratori, K. Kobayashi, M. Shimizu, M. Mino-Kenudson, M. Furukawa, T. TI Molecular Characteristics and Biological Behavior of Intraductal Papillary-Mucinous Neoplasm, Oncocytic Type (IPMN-O) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Saitama Med Univ, Saitama, Japan. Int Res & Educ Inst Integrated Med Sci, Tokyo, Japan. Tokyo Womens Med Univ, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1667 BP 374A EP 375A PG 2 WC Pathology SC Pathology GA 556HX UT WOS:000274582502348 ER PT J AU Laury, AR Hornick, JL Piao, H Perets, R Barletta, J Chirieac, LR Krane, JF Lis, R Loda, M Drapkin, R Hirsch, MS AF Laury, A. R. Hornick, J. L. Piao, H. Perets, R. Barletta, J. Chirieac, L. R. Krane, J. F. Lis, R. Loda, M. Drapkin, R. Hirsch, M. S. TI PAX8 Is Highly Sensitive and Specific for Mullerian, Renal and Thyroid Neoplasms: A Study of 1500 Epithelial Tumors SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1730 BP 388A EP 388A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502411 ER PT J AU Cheng, L Janne, PA Jackman, DM Johnson, BE Joshi, VA Lindeman, NI AF Cheng, L. Janne, P. A. Jackman, D. M. Johnson, B. E. Joshi, V. A. Lindeman, N. I. TI Mutational Analysis of EGFR, KRAS, BRAF, PIK3CA, and ERBB2 in Non-Small-Cell Lung Carcinomas (NSCLC) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Mol Med Lab, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1783 BP 399A EP 399A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502464 ER PT J AU Klepeis, VE Mark, EG Dias-Santagata, D Iafrate, AJ Mino-Kenudson, M AF Klepeis, V. E. Mark, E. G. Dias-Santagata, D. Iafrate, A. J. Mino-Kenudson, M. TI Genotype-Phenotype Correlation in Lung Adenocarcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1812 BP 406A EP 406A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502493 ER PT J AU Hunt, JL Smith, MT Black-Schaffer, WS AF Hunt, J. L. Smith, M. T. Black-Schaffer, W. S. TI Joint Commission Standards for Ongoing and Focused Performance Evaluation in Anatomic Pathology: Current Trends in Practice SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1870 BP 418A EP 418A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502551 ER PT J AU Morgan, EA Oh, KY Waghorne, CG Neuberg, D Stevenson, K Kutok, JL AF Morgan, E. A. Oh, K. Y. Waghorne, C. G. Neuberg, D. Stevenson, K. Kutok, J. L. TI Flow Cytometry Underestimates the Bone Marrow CD34-Positive Blast Population Compared to Immunohistochemical and Morphologic Assessments SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1874 BP 419A EP 419A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502555 ER PT J AU Ryan, RJH Snuderl, M Black-Schaffer, WS Hunt, J AF Ryan, R. J. H. Snuderl, M. Black-Schaffer, W. S. Hunt, J. TI Improvements in Training and Credentialing of Residents for Independent Frozen Section Sign-Out Responsibility SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 2010 CL Washington, DC SP US & Canadian Acac Pathol C1 [Ryan, R. J. H.; Snuderl, M.; Black-Schaffer, W. S.; Hunt, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2010 VL 23 SU 1 MA 1880 BP 421A EP 421A PG 1 WC Pathology SC Pathology GA 556HX UT WOS:000274582502561 ER PT J AU Park, ES Rabinovsky, R Carey, M Hennessy, BT Agarwal, R Liu, WB Ju, ZL Deng, WL Lu, YL Woo, HG Kim, SB Cheong, JH Garraway, LA Weinstein, JN Mills, GB Lee, JS Davies, MA AF Park, Eun Sung Rabinovsky, Rosalia Carey, Mark Hennessy, Bryan T. Agarwal, Roshan Liu, Wenbin Ju, Zhenlin Deng, Wanleng Lu, Yiling Woo, Hyun Goo Kim, Sang-Bae Cheong, Jae-Ho Garraway, Levi A. Weinstein, John N. Mills, Gordon B. Lee, Ju-Seog Davies, Michael A. TI Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID GENE-EXPRESSION PATTERNS; CHEMOSENSITIVITY PREDICTION; MOLECULAR PHARMACOLOGY; TUMOR PROGRESSION; PANEL; PROFILES; SENSITIVITY; MICROARRAY; DATABASE; OVARIAN AB Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA ( siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer. Mol Cancer Ther; 9(2); 257-67. (C) 2010 AACR. C1 [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Unit 0904, Houston, TX 77030 USA. [Park, Eun Sung; Carey, Mark; Hennessy, Bryan T.; Agarwal, Roshan; Lu, Yiling; Kim, Sang-Bae; Cheong, Jae-Ho; Weinstein, John N.; Mills, Gordon B.; Lee, Ju-Seog; Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Hennessy, Bryan T.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Med Oncol, Houston, TX 77030 USA. [Liu, Wenbin; Ju, Zhenlin; Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Rabinovsky, Rosalia; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Woo, Hyun Goo] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Davies, MA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Unit 0904, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM mdavies@mdanderson.org FU M.D. Anderson Cancer Center (MDACC); National Cancer Institute (NCI) [CA-16672] FX M.D. Anderson Cancer Center (MDACC) Melanoma Spore Development Grant (M. A. Davies). The M.D. Anderson Reverse Phase Protein Array Core Facility is supported by a National Cancer Institute (NCI) Cancer Center Support Grant (CA-16672). NR 33 TC 54 Z9 55 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2010 VL 9 IS 2 BP 257 EP 267 DI 10.1158/1535-7163.MCT-09-0743 PG 11 WC Oncology SC Oncology GA 607GN UT WOS:000278487200001 PM 20124458 ER PT J AU Biswas, S Heetveld, S Wolf, P Cao, Y Norton, S Haggarty, S Cotman, S AF Biswas, Sunita Heetveld, Sasja Wolf, Pavlina Cao, Yi Norton, Stephanie Haggarty, Stephen Cotman, Susan TI A chemical genetic approach to identifying therapeutictargets for NCL SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 6th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 10-12, 2010 CL Miami, FL SP Lysosomal Dis Network C1 [Biswas, Sunita; Heetveld, Sasja; Wolf, Pavlina; Cao, Yi; Cotman, Susan] Harvard Univ, Sch Med, Boston, MA USA. [Biswas, Sunita; Heetveld, Sasja; Norton, Stephanie; Haggarty, Stephen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wolf, Pavlina] Broad Inst MIT & Harvard, Cambridge, MA 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2010 VL 99 IS 2 MA 16 BP S11 EP S11 DI 10.1016/j.ymgme.2009.10.033 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 548XV UT WOS:000274004300029 ER PT J AU Cotman, S Cao, Y Biswas, S Wolf, P Massey, A Cuervo, AM MacDonald, M Lee, JM AF Cotman, Susan Cao, Yi Biswas, Sunita Wolf, Pavlina Massey, Ashish Cuervo, Ana Maria MacDonald, Marcy Lee, Jong-Min TI Distinct features of disease phenotypes in two genetic models of NCL SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 6th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 10-12, 2010 CL Miami, FL SP Lysosomal Dis Network C1 [Cotman, Susan; Cao, Yi; Biswas, Sunita; Wolf, Pavlina; MacDonald, Marcy; Lee, Jong-Min] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Massey, Ashish; Cuervo, Ana Maria] Albert Einstein Coll Med, Bronx, NY 10467 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2010 VL 99 IS 2 MA 32 BP S14 EP S15 DI 10.1016/j.ymgme.2009.10.049 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 548XV UT WOS:000274004300045 ER PT J AU Curcio-Morelli, C Charles, FA Micsenyi, MC Cao, Y Venugopal, B Browning, MF Dobrenis, K Cotman, SL Walkley, SU Slaugenhaupt, SA AF Curcio-Morelli, Cyntia Charles, Florie A. Micsenyi, Matthew C. Cao, Yi Venugopal, Bhuvarahamurthy Browning, Marsha F. Dobrenis, Kostantin Cotman, Susan L. Walkley, Steven U. Slaugenhaupt, Susan A. TI Macroautophagy is defective in mucolipin 1-deficient mouse neurons SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 6th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 10-12, 2010 CL Miami, FL SP Lysosomal Dis Network C1 [Curcio-Morelli, Cyntia; Charles, Florie A.; Cao, Yi; Venugopal, Bhuvarahamurthy; Browning, Marsha F.; Cotman, Susan L.; Slaugenhaupt, Susan A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Micsenyi, Matthew C.; Dobrenis, Kostantin; Walkley, Steven U.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10467 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2010 VL 99 IS 2 MA 34 BP S15 EP S15 DI 10.1016/j.ymgme.2009.10.051 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 548XV UT WOS:000274004300047 ER PT J AU Sleat, D Ding, L Wang, SD Zhao, CF Wang, YH Xin, W Zheng, HY Moore, D Sims, K Lobel, P AF Sleat, David Ding, Lin Wang, Shudan Zhao, Caifeng Wang, Yanhong Xin, Winnie Zheng, Haiyan Moore, Dirk Sims, Katherine Lobel, Peter TI Comparative proteomics and lysosomal disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 6th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 10-12, 2010 CL Miami, FL SP Lysosomal Dis Network C1 [Sleat, David; Ding, Lin; Zhao, Caifeng; Wang, Yanhong; Zheng, Haiyan] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Sleat, David; Lobel, Peter] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. [Sleat, David; Wang, Shudan] McGill Univ, Montreal, PQ, Canada. [Sleat, David; Xin, Winnie; Sims, Katherine] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sleat, David; Moore, Dirk] Univ Med & Dent New Jersey, Sch Publ Hlth, Dept Biostat, Piscataway, NJ 08854 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2010 VL 99 IS 2 MA 127 BP S34 EP S34 DI 10.1016/j.ymgme.2009.10.144 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 548XV UT WOS:000274004300140 ER PT J AU Encinales, L Zuniga, J Granados-Montiel, J Yunis, M Granados, J Almeciga, I Clavijo, O Awad, C Collazos, V Vargas-Rojas, MI Banales-Mendez, JL Vazquez-Castaneda, L Stern, JN Romero, V Frindkis-Hareli, M Terreros, D Fernandez-Vina, M Yunis, EJ AF Encinales, Liliana Zuniga, Joaquin Granados-Montiel, Julio Yunis, Maria Granados, Julio Almeciga, Ingrid Clavijo, Olga Awad, Carlos Collazos, Vilma Ines Vargas-Rojas, Maria Luis Banales-Mendez, Jose Vazquez-Castaneda, Lilia Stern, Joel N. Romero, Viviana Frindkis-Hareli, Masha Terreros, Daniel Fernandez-Vina, Marcelo Yunis, Edmond J. TI Humoral immunity in tuberculin skin test anergy and its role in high-risk persons exposed to active tuberculosis SO MOLECULAR IMMUNOLOGY LA English DT Article DE Humoral immunity; Tuberculosis; Immunoglobulins; Anergy; Cell-mediated immunity ID T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; LATENT TUBERCULOSIS; MOLECULAR MIMICRY; INFECTION; CYTOKINES; ANTIGENS; SUBSETS; PROTEIN AB The most common test to identify latent tuberculosis is the tuberculin skin test that detects T cell responses of delayed type hypersensitivity type IV Since it produces false negative reactions in active tuberculosis or in high-risk persons exposed to tuberculosis patients as shown in this report, we studied antibody profiles to explain the anergy Of Such responses in high-risk individuals without active infection Our results showed that humoral immunity against tuberculin, regardless of the result of the tuberculin skin test is important for protection from active tuberculosis and that the presence of high antibody titers is a more reliable indicator of infection latency suggesting that latency can be based on the levels of antibodies together with in vitro proliferation of peripheral blood mononuclear cells in the presence of the purified protein derivative Importantly, anti-tuberculin IgG antibody levels mediate the anergy described herein, which Could also prevent reactivation of disease in high-risk individuals with high antibody titers. Such anti-tuberculin IgG antibodies were also found associated with blocking and/or stimulation of in vitro cultures of PBMC with tuberculin In this regard. future studies need to establish if immune responses to Mycobacterium tuberculosis can generate a broad spectrum of reactions either toward Th1 responses favoring stimulation by cytokines or by antibodies and those toward diminished responses by Th2 cytokines or blocking by antibodies; possibly involving mechanisms of antibody dependent protection from Mtb by different subclasses of IgG Published by Elsevier Ltd. C1 [Encinales, Liliana; Granados-Montiel, Julio; Almeciga, Ingrid; Clavijo, Olga; Stern, Joel N.; Romero, Viviana; Frindkis-Hareli, Masha; Yunis, Edmond J.] Dana Farber Canc Inst, Dept Canc Immunol, Boston, MA 02115 USA. [Encinales, Liliana; Granados-Montiel, Julio; Almeciga, Ingrid; Clavijo, Olga; Stern, Joel N.; Romero, Viviana; Frindkis-Hareli, Masha; Yunis, Edmond J.] Dana Farber Canc Inst, AIDS, Boston, MA 02115 USA. [Zuniga, Joaquin; Ines Vargas-Rojas, Maria; Luis Banales-Mendez, Jose; Vazquez-Castaneda, Lilia] Inst Nacl Enfermedades Respiratorias, Lab Immunobiol & Genet, Mexico City, DF, Mexico. [Luis Banales-Mendez, Jose] Inst Nacl Cardiol Ignacio Chavez, Mol Biol Lab, Mexico City, DF, Mexico. [Granados, Julio] Inst Nacl Ciencias Med & Nutr Mexico City, Dept Immunol & Rheumatol, Mexico City, DF, Mexico. [Terreros, Daniel] Paul L Foster SOM, Texas Tech Hlth Sci Ctr, Dept Biomed Sci, El Paso, TX 79905 USA. [Fernandez-Vina, Marcelo] Univ Texas MD Anderson Canc Ctr, Dept Lab Med, Houston, TX 77030 USA. [Fernandez-Vina, Marcelo] Univ Texas Houston, Sch Med, Div Immunol & Organ Transplantat, Houston, TX 77030 USA. [Awad, Carlos] Hosp Santa Clara, Bogota, Colombia. [Yunis, Maria] MyDesign, Arlington, MA USA. RP Yunis, EJ (reprint author), Dana Farber Canc Inst, Dept Canc Immunol, 44 Binney St, Boston, MA 02115 USA. OI Stern, Joel N.H./0000-0002-1259-2256 FU NIH [AI49213, HL29583, HL59838]; department of Cancer Immunology and AIDS, Dana Farber Cancer Institute FX This work was Supported by NIH grants AI49213, HL29583 and HL59838, and funds from the department of Cancer Immunology and AIDS, Dana Farber Cancer Institute. NR 31 TC 11 Z9 13 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD FEB PY 2010 VL 47 IS 5 BP 1066 EP 1073 DI 10.1016/j.molimm.2009.11.005 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 560ZT UT WOS:000274945100014 PM 20004475 ER PT J AU Cowart, LA Shotwell, M Worley, ML Richards, AJ Montefusco, DJ Hannun, YA Lu, XH AF Cowart, L. Ashley Shotwell, Matthew Worley, Mitchell L. Richards, Adam J. Montefusco, David J. Hannun, Yusuf A. Lu, Xinghua TI Revealing a signaling role of phytosphingosine-1-phosphate in yeast SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE information integration; lipidomics; signal transduction; sphingolipids; transcriptomics ID HEAT-STRESS RESPONSE; TRANSCRIPTIONAL REGULATORY NETWORKS; SACCHAROMYCES-CEREVISIAE; COMPONENT ANALYSIS; GENE-EXPRESSION; SPHINGOID BASE; SPHINGOLIPIDS; SPHINGOSINE-1-PHOSPHATE; BIOSYNTHESIS; METABOLOMICS AB Sphingolipids including sphingosine-1-phosphate and ceramide participate innumerous cell programs through signaling mechanisms. This class of lipids has important functions in stress responses; however, determining which sphingolipid mediates specific events has remained encumbered by the numerous metabolic interconnections of sphingolipids,such that modulating a specific lipid of interest through manipulating metabolic enzymes causes 'ripple effects', which change levels of many other lipids. Here, we develop a method of integrative analysis for genomic, transcriptomic, and lipidomic data to address this previously intractable problem. This method revealed a specific signaling role for phytosphingosine-1-phosphate, a lipid with no previously defined specific function in yeast, in regulating genes required for mitochondrial respiration through the HAP complex transcription factor. This approach could be applied to extract meaningful biological information from a similar experimental design that produces multiple sets of high-throughput data. Molecular Systems Biology 6: 349; published online 16 February 2010; doi:10.1038/msb.2010.3 C1 [Cowart, L. Ashley; Worley, Mitchell L.; Richards, Adam J.; Montefusco, David J.; Hannun, Yusuf A.; Lu, Xinghua] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Shotwell, Matthew] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Cowart, L. Ashley] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Lu, XH (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, 174 Ashley Ave, Charleston, SC 29425 USA. EM hannun@musc.edu; lux@musc.edu FU Department of Veterans' Affairs Merit award [5R01LM009153, 3T15LM07438, 5T32GM074934]; [P20 RR017677-]; [1R01LM10144]; [5R01GM63265] FX We acknowledge the following grant supports: P20 RR017677-07 (to LAC and XL). 1R01LM10144 to XL, 5R01GM63265 to YAH, the Department of Veterans' Affairs Merit award to LAC, 5R01LM009153, 3T15LM07438 to XL and AJR, and 5T32GM074934 to MS. We thank Alan Wilder and Jason Gandy for technical assistance. We also acknowledge the MUSC Lipidomics Core Facility of the COBRE in Lipidomics and Pathobiology for sample analysis, the MUSC Proteogenomics Core Facility for microarray assays, the MUSC department of Art Services for assistance with figure preparation, and Dr Hiroko Hama for critical reading of the paper. NR 39 TC 27 Z9 27 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD FEB PY 2010 VL 6 AR 349 DI 10.1038/msb.2010.3 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564AU UT WOS:000275183700002 PM 20160710 ER PT J AU Hardcastle, J Kurozumi, K Dmitrieva, N Sayers, MP Ahmad, S Waterman, P Weissleder, R Chiocca, EA Kaur, B AF Hardcastle, Jayson Kurozumi, Kazuhiko Dmitrieva, Nina Sayers, Martin P. Ahmad, Sarwat Waterman, Peter Weissleder, Ralph Chiocca, E. Antonio Kaur, Balveen TI Enhanced Antitumor Efficacy of Vasculostatin (Vstat120) Expressing Oncolytic HSV-1 SO MOLECULAR THERAPY LA English DT Article ID HERPES-SIMPLEX-VIRUS; BRAIN ANGIOGENESIS INHIBITOR-1; GROWTH-FACTOR; TUMOR-GROWTH; IN-VIVO; GENE-EXPRESSION; CANCER; GLIOMA; MUTANT; G207 AB Oncolytic viral (OV) therapy is a promising therapeutic modality for brain tumors. Vasculostatin (Vstat120) is the cleaved and secreted extracellular fragment of brain-specific angiogenesis inhibitor 1 (BAI1), a brain-specific receptor. To date, the therapeutic efficacy of Vstat120 delivery into established tumors has not been investigated. Here we tested the therapeutic efficacy of combining Vstat120 gene delivery in conjunction with OV therapy. We constructed RAMBO (Rapid Antiangiogenesis Mediated By Oncolytic virus), which expresses Vstat120 under the control of the herpes simplex virus (HSV) IE4/5 promoter. Secreted Vstat120 was detected as soon as 4 hours postinfection in vitro and was retained for up to 13 days after OV therapy in subcutaneous tumors. RAMBO-produced Vstat120 efficiently inhibited endothelial cell migration and tube formation in vitro (P = 0.0005 and P = 0.0184, respectively) and inhibited angiogenesis (P = 0.007) in vivo. There was a significant suppression of intracranial and subcutaneous glioma growth in mice treated with RAMBO compared to the control virus, HSVQ (P = 0.0021 and P < 0.05, respectively). Statistically significant reduction in tumor vascular volume fraction (VVF) and microvessel density (MVD) was observed in tumors treated with RAMBO. This is the first study to report the antitumor effects of Vstat120 delivery into established tumors and supports the further development of RAMBO as a possible cancer therapy. C1 [Kaur, Balveen] Ohio State Univ, Dardinger Lab Neurooncol & Neurosci, Dept Neurol Surg, James Comprehens Canc Ctr, Columbus, OH 43210 USA. [Hardcastle, Jayson] Ohio State Univ, Med Ctr, Integrated Biomed Sci Grad Program, Columbus, OH 43210 USA. [Ahmad, Sarwat] Ohio State Univ, Med Ctr, Coll Med, Columbus, OH 43210 USA. [Waterman, Peter; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. [Waterman, Peter; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA USA. RP Kaur, B (reprint author), Ohio State Univ, Dardinger Lab Neurooncol & Neurosci, Dept Neurol Surg, James Comprehens Canc Ctr, 385-D OSUCCC,410 W 12th Ave, Columbus, OH 43210 USA. EM Balveen.Kaur@osumc.edu RI kaur, Balveen/E-3355-2011 FU National Institutes of Health [1K01NS059575, R01NS064607, R21NS056203, P01 CA069246, R24 CA92782]; American Association for Neurological Surgeons/Congress of Neurological Surgeons, Section on Tumors/BrainLAB International Research Fellowship; American Brain Tumor Association; Alex Lemonade Stand Foundation FX This work was supported by funding from the National Institutes of Health grant (1K01NS059575, R01NS064607, and R21NS056203 to B.K.; P01 CA069246 to E. A. C. and R. W.; and R24 CA92782 to R.W.); American Association for Neurological Surgeons/Congress of Neurological Surgeons, Section on Tumors/BrainLAB International Research Fellowship (to K.K.); American Brain Tumor Association medical student summer fellowship (to S.A.); and the Alex Lemonade Stand Foundation young investigator award (to B.K.). NR 50 TC 42 Z9 45 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD FEB PY 2010 VL 18 IS 2 BP 285 EP 294 DI 10.1038/mt.2009.232 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 554PQ UT WOS:000274447300008 PM 19844198 ER PT J AU Kim, SS Peer, D Kumar, P Subramanya, S Wu, HQ Asthana, D Habiro, K Yang, YG Manjunath, N Shimaoka, M Shankar, P AF Kim, Sang-Soo Peer, Dan Kumar, Priti Subramanya, Sandesh Wu, Huaquan Asthana, Deshratan Habiro, Katsuyoshi Yang, Yong-Guang Manjunath, N. Shimaoka, Motomu Shankar, Premlata TI RNAi-mediated CCR5 Silencing by LFA-1-targeted Nanoparticles Prevents HIV Infection in BLT Mice SO MOLECULAR THERAPY LA English DT Article ID SMALL INTERFERING RNA; T-CELLS; ENTRY INHIBITORS; IMMUNE-SYSTEM; TARGET-CELLS; MOUSE MODEL; DELIVERY; SIRNA; LIPOSOMES; LFA-1 AB RNA interference (RNAi)-mediated knockdown of gene expression offers a novel treatment strategy for human immunodeficiency virus (HIV) infection. However, the major hurdle for clinical use is a practical strategy for small interfering RNA (siRNA) delivery to the multiple immune cell types important in viral pathogenesis. We have developed a novel immunoliposome method targeting the lymphocyte function-associated antigen-1 (LFA-1) integrin expressed on all leukocytes and evaluated it for systemic delivery of siRNA in a humanized mouse model. We show that in vivo administration of the LFA-1 integrin-targeted and stabilized nanoparticles (LFA-1 I-tsNPs) results in selective uptake of siRNA by T cells and macrophages, the prime targets of HIV. Further, in vivo administration of anti-CCR5 siRNA/LFA-1 I-tsNPs resulted in leukocyte-specific gene silencing that was sustained for 10 days. Finally, humanized mice challenged with HIV after anti-CCR5 siRNA treatment showed enhanced resistance to infection as assessed by the reduction in plasma viral load and disease-associated CD4 T-cell loss. This study demonstrates the potential in vivo applicability of LFA-1-directed siRNA delivery as anti-HIV prophylaxis. C1 [Kim, Sang-Soo; Subramanya, Sandesh; Wu, Huaquan; Manjunath, N.; Shankar, Premlata] Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, Dept Biomed Sci,Ctr Excellence Infect Dis, El Paso, TX 79905 USA. [Kim, Sang-Soo; Peer, Dan; Subramanya, Sandesh; Wu, Huaquan; Manjunath, N.; Shimaoka, Motomu; Shankar, Premlata] Immune Dis Inst, Boston, MA USA. [Peer, Dan; Shimaoka, Motomu] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Peer, Dan; Shimaoka, Motomu] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Peer, Dan] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, Lab Nanomed, IL-69978 Tel Aviv, Israel. [Kumar, Priti] Yale Sch Med, Dept Internal Med, Infect Dis Sect, New Haven, CT USA. [Asthana, Deshratan] Univ Miami, Miller Sch Med, Lab Clin & Biol Studies, Miami, FL 33136 USA. [Habiro, Katsuyoshi; Yang, Yong-Guang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. RP Shankar, P (reprint author), Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, Dept Biomed Sci,Ctr Excellence Infect Dis, 5001 El Paso Dr, El Paso, TX 79905 USA. EM shimaoka@idi.harvard.edu; premlata.shankar@ttuhsc.edu RI Peer, Dan/A-1785-2011; Kumar, Priti/C-5699-2009 OI Peer, Dan/0000-0001-8238-0673; FU NIH (National Institutes of Health) [AI071882, AI063421]; Leukemia & Lymphoma Society; KRF (Korea Research Foundation); MOEHRD (Ministry of Education and Human Resource Development) [KRF-2006-352-D00070]; CFAR (Center for AIDS Research) [P30 A060354] FX This work was supported by grants from NIH (National Institutes of Health), AI071882 (P.S.) and AI063421 (M.S.); the Leukemia & Lymphoma Society (M.S.); the KRF (Korea Research Foundation) and MOEHRD (Ministry of Education and Human Resource Development), KRF-2006-352-D00070 (S.-S.K.); and the CFAR (Center for AIDS Research) fellowship P30 A060354 (P.K.). We thank Erica Nakajima from the Yale School of Medicine for technical assistance and critical reading of the manuscript. NR 31 TC 102 Z9 112 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD FEB PY 2010 VL 18 IS 2 BP 370 EP 376 DI 10.1038/mt.2009.271 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 554PQ UT WOS:000274447300017 PM 19997090 ER PT J AU Liu, XH Lee, DJ Skittone, LK Natsuhara, K Kim, HT AF Liu, Xuhui Lee, David J. Skittone, Laura K. Natsuhara, Kyle Kim, Hubert T. TI ROLE OF GELATINASES IN DISUSE-INDUCED SKELETAL MUSCLE ATROPHY SO MUSCLE & NERVE LA English DT Article DE gelatinases; muscular atrophy; extracellular matrix; disuse; basement membrane ID MATRIX METALLOPROTEINASES; IV COLLAGENASE; HINDLIMB IMMOBILIZATION; HUMAN-FIBROBLASTS; EXPRESSION; RATS; INHIBITOR; SECRETION; RECOVERY AB Gelatinases are a subgroup of the family of matrix metalloproteinases, which contains two members-gelatinase A and B. These enzymes play an important role in basement membrane homeostasis. Previous studies have associated basement membrane degradation with skeletal muscle atrophy. However, the specific contribution of gelatinases to the pathobiology of muscle atrophy remains unknown. In this study we examined the specific roles of gelatinase A and B in disuse-induced skeletal muscle atrophy using knockout mice. Although both gelatinase A and B are highly upregulated in disused muscle, only gelatinase A null mice had significantly reduced muscle atrophy as compared to wildtype littermates. Type IV collagen and laminin, two major components of basement membrane, were relatively well-preserved in disused muscle in gelatinase A null mice, but not in gelatinase B null mice. These findings suggest that gelatinase A, and not gelatinase B, plays a critical role in disuse-induced skeletal muscle atrophy. Muscle Nerve 41: 174-178, 2010 C1 [Liu, Xuhui; Skittone, Laura K.; Natsuhara, Kyle; Kim, Hubert T.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA 94121 USA. [Liu, Xuhui; Lee, David J.; Kim, Hubert T.] Univ Calif San Francisco, Dept Orthoped Surg, San Francisco, CA 94143 USA. RP Kim, HT (reprint author), San Francisco VA Med Ctr, Dept Vet Affairs, 4150 Clement St 112, San Francisco, CA 94121 USA. EM Kimh@orthosurg.ucsf.edu FU Orthopedic Research & Education Foundation; Illinois Bone and Joint Institute FX Supported by the Orthopedic Research & Education Foundation and the Illinois Bone and Joint Institute. We thank Dr. Rajabrata Sarkar for gifts of MMP-2 and MMP-9 knockout, mice. We think Dr. Mostafa Gabr for technique help in histology. NR 26 TC 5 Z9 5 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD FEB PY 2010 VL 41 IS 2 BP 174 EP 178 DI 10.1002/mus.21463 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 550LZ UT WOS:000274130700003 PM 19790245 ER PT J AU Kim, J Orkin, SH AF Kim, Jonghwan Orkin, Stuart H. TI Systematic tracking of cell fate changes SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID EMBRYONIC STEM-CELLS; NANOG; PLURIPOTENCY C1 [Kim, Jonghwan; Orkin, Stuart H.] Childrens Hosp, Boston, MA 02115 USA. [Kim, Jonghwan; Orkin, Stuart H.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kim, J (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu NR 9 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD FEB PY 2010 VL 28 IS 2 BP 146 EP 147 DI 10.1038/nbt0210-146 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 552TT UT WOS:000274317200022 PM 20139953 ER PT J AU Mootha, VK Hirschhorn, JN AF Mootha, Vamsi K. Hirschhorn, Joel N. TI Inborn variation in metabolism SO NATURE GENETICS LA English DT Editorial Material ID VARIANTS; ASSOCIATION; DISEASE AB Advances in analytical biochemistry have recently made it possible to obtain global snapshots of metabolism. A new study couples such technology with genome-wide genetic analysis to explore inherited variation in human metabolism. C1 [Mootha, Vamsi K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Mootha, Vamsi K.; Hirschhorn, Joel N.] Broad Inst Metab Initiat, Cambridge, MA USA. [Hirschhorn, Joel N.] Harvard Univ, Childrens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Mootha, VK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. EM vamsi@hms.harvard.edu; joeth@broadinstitute.org FU NIDDK NIH HHS [R01 DK081457, R01 DK081457-02] NR 15 TC 10 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2010 VL 42 IS 2 BP 97 EP 98 DI 10.1038/ng0210-97 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 549WG UT WOS:000274084400002 PM 20104246 ER PT J AU Dupuis, J Langenberg, C Prokopenko, I Saxena, R Soranzo, N Jackson, AU Wheeler, E Glazer, NL Bouatia-Naji, N Gloyn, AL Lindgren, CM Magi, R Morris, AP Randall, J Johnson, T Elliott, P Rybin, D Thorleifsson, G Steinthorsdottir, V Henneman, P Grallert, H Dehghan, A Hottenga, JJ Franklin, CS Navarro, P Song, K Goel, A Perry, JRB Egan, JM Lajunen, T Grarup, N Sparso, T Doney, A Voight, BF Stringham, HM Li, M Kanoni, S Shrader, P Cavalcanti-Proenca, C Kumari, M Qi, L Timpson, NJ Gieger, C Zabena, C Rocheleau, G Ingelsson, E An, P O'Connell, J Luan, J Elliott, A McCarroll, SA Payne, F Roccasecca, RM Pattou, F Sethupathy, P Ardlie, K Ariyurek, Y Balkau, B Barter, P Beilby, JP Ben-Shlomo, Y Benediktsson, R Bennett, AJ Bergmann, S Bochud, M Boerwinkle, E Bonnefond, A Bonnycastle, LL Borch-Johnsen, K Bottcher, Y Brunner, E Bumpstead, SJ Charpentier, G Chen, YDI Chines, P Clarke, R Coin, LJM Cooper, MN Cornelis, M Crawford, G Crisponi, L Day, INM de Geus, EJC Delplanque, J Dina, C Erdos, MR Fedson, AC Fischer-Rosinsky, A Forouhi, NG Fox, CS Frants, R Franzosi, MG Galan, P Goodarzi, MO Graessler, J Groves, CJ Grundy, S Gwilliam, R Gyllensten, U Hadjadj, S Hallmans, G Hammond, N Han, XJ Hartikainen, AL Hassanali, N Hayward, C Heath, SC Hercberg, S Herder, C Hicks, AA Hillman, DR Hingorani, AD Hofman, A Hui, J Hung, J Isomaa, B Johnson, PRV Jorgensen, T Jula, A Kaakinen, M Kaprio, J Kesaniemi, YA Kivimaki, M Knight, B Koskinen, S Kovacs, P Kyvik, KO Lathrop, GM Lawlor, DA Le Bacquer, O Lecoeur, C Li, Y Lyssenko, V Mahley, R Mangino, M Manning, AK Martinez-Larrad, MT McAteer, JB McCulloch, LJ McPherson, R Meisinger, C Melzer, D Meyre, D Mitchell, BD Morken, MA Mukherjee, S Naitza, S Narisu, N Neville, MJ Oostra, BA Orru, M Pakyz, R Palmer, CNA Paolisso, G Pattaro, C Pearson, D Peden, JF Pedersen, NL Perola, M Pfeiffer, AFH Pichler, I Polasek, O Posthuma, D Potter, SC Pouta, A Province, MA Psaty, BM Rathmann, W Rayner, NW Rice, K Ripatti, S Rivadeneira, F Roden, M Rolandsson, O Sandbaek, A Sandhu, M Sanna, S Sayer, AA Scheet, P Scott, LJ Seedorf, U Sharp, SJ Shields, B Sigurosson, G Sijbrands, EJG Silveira, A Simpson, L Singleton, A Smith, NL Sovio, U Swift, A Syddall, H Syvanen, AC Tanaka, T Thorand, B Tichet, J Tonjes, A Tuomi, T Uitterlinden, AG van Dijk, KW van Hoek, M Varma, D Visvikis-Siest, S Vitart, V Vogelzangs, N Waeber, G Wagner, PJ Walley, A Walters, GB Ward, KL Watkins, H Weedon, MN Wild, SH Willemsen, G Witteman, JCM Yarnell, JWG Zeggini, E Zelenika, D Zethelius, B Zhai, GJ Zhao, JH Zillikens, MC Borecki, IB Loos, RJF Meneton, P Magnusson, PKE Nathan, DM Williams, GH Hattersley, AT Silander, K Salomaa, V Smith, GD Bornstein, SR Schwarz, P Spranger, J Karpe, F Shuldiner, AR Cooper, C Dedoussis, GV Serrano-Rios, M Morris, AD Lind, L Palmer, LJ Hu, FB Franks, PW Ebrahim, S Marmot, M Kao, WHL Pankow, JS Sampson, MJ Kuusisto, J Laakso, M Hansen, T Pedersen, O Pramstaller, PP Wichmann, HE Illig, T Rudan, I Wright, AF Stumvoll, M Campbell, H Wilson, JF Bergman, RN Buchanan, TA Collins, FS Mohlke, KL Tuomilehto, J Valle, TT Altshuler, D Rotter, JI Siscovick, DS Penninx, BWJH Boomsma, DI Deloukas, P Spector, TD Frayling, TM Ferrucci, L Kong, A Thorsteinsdottir, U Stefansson, K van Duijn, CM Aulchenko, YS Cao, A Scuteri, A Schlessinger, D Uda, M Ruokonen, A Jarvelin, MR Waterworth, DM Vollenweider, P Peltonen, L Mooser, V Abecasis, GR Wareham, NJ Sladek, R Froguel, P Watanabe, RM Meigs, JB Groop, L Boehnke, M McCarthy, MI Florez, JC Barroso, I AF Dupuis, Josee Langenberg, Claudia Prokopenko, Inga Saxena, Richa Soranzo, Nicole Jackson, Anne U. Wheeler, Eleanor Glazer, Nicole L. Bouatia-Naji, Nabila Gloyn, Anna L. Lindgren, Cecilia M. Magi, Reedik Morris, Andrew P. Randall, Joshua Johnson, Toby Elliott, Paul Rybin, Denis Thorleifsson, Gudmar Steinthorsdottir, Valgerdur Henneman, Peter Grallert, Harald Dehghan, Abbas Hottenga, Jouke Jan Franklin, Christopher S. Navarro, Pau Song, Kijoung Goel, Anuj Perry, John R. B. Egan, Josephine M. Lajunen, Taina Grarup, Niels Sparso, Thomas Doney, Alex Voight, Benjamin F. Stringham, Heather M. Li, Man Kanoni, Stavroula Shrader, Peter Cavalcanti-Proenca, Christine Kumari, Meena Qi, Lu Timpson, Nicholas J. Gieger, Christian Zabena, Carina Rocheleau, Ghislain Ingelsson, Erik An, Ping O'Connell, Jeffrey Luan, Jian'an Elliott, Amanda McCarroll, Steven A. Payne, Felicity Roccasecca, Rosa Maria Pattou, Francois Sethupathy, Praveen Ardlie, Kristin Ariyurek, Yavuz Balkau, Beverley Barter, Philip Beilby, John P. Ben-Shlomo, Yoav Benediktsson, Rafn Bennett, Amanda J. Bergmann, Sven Bochud, Murielle Boerwinkle, Eric Bonnefond, Amelie Bonnycastle, Lori L. Borch-Johnsen, Knut Boettcher, Yvonne Brunner, Eric Bumpstead, Suzannah J. Charpentier, Guillaume Chen, Yii-Der Ida Chines, Peter Clarke, Robert Coin, Lachlan J. M. Cooper, Matthew N. Cornelis, Marilyn Crawford, Gabe Crisponi, Laura Day, Ian N. M. de Geus, Eco J. C. Delplanque, Jerome Dina, Christian Erdos, Michael R. Fedson, Annette C. Fischer-Rosinsky, Antje Forouhi, Nita G. Fox, Caroline S. Frants, Rune Franzosi, Maria Grazia Galan, Pilar Goodarzi, Mark O. Graessler, Juergen Groves, Christopher J. Grundy, Scott Gwilliam, Rhian Gyllensten, Ulf Hadjadj, Samy Hallmans, Goeran Hammond, Naomi Han, Xijing Hartikainen, Anna-Liisa Hassanali, Neelam Hayward, Caroline Heath, Simon C. Hercberg, Serge Herder, Christian Hicks, Andrew A. Hillman, David R. Hingorani, Aroon D. Hofman, Albert Hui, Jennie Hung, Joe Isomaa, Bo Johnson, Paul R. V. Jorgensen, Torben Jula, Antti Kaakinen, Marika Kaprio, Jaakko Kesaniemi, Y. Antero Kivimaki, Mika Knight, Beatrice Koskinen, Seppo Kovacs, Peter Kyvik, Kirsten Ohm Lathrop, G. Mark Lawlor, Debbie A. Le Bacquer, Olivier Lecoeur, Cecile Li, Yun Lyssenko, Valeriya Mahley, Robert Mangino, Massimo Manning, Alisa K. Teresa Martinez-Larrad, Maria McAteer, Jarred B. McCulloch, Laura J. McPherson, Ruth Meisinger, Christa Melzer, David Meyre, David Mitchell, Braxton D. Morken, Mario A. Mukherjee, Sutapa Naitza, Silvia Narisu, Narisu Neville, Matthew J. Oostra, Ben A. Orru, Marco Pakyz, Ruth Palmer, Colin N. A. Paolisso, Giuseppe Pattaro, Cristian Pearson, Daniel Peden, John F. Pedersen, Nancy L. Perola, Markus Pfeiffer, Andreas F. H. Pichler, Irene Polasek, Ozren Posthuma, Danielle Potter, Simon C. Pouta, Anneli Province, Michael A. Psaty, Bruce M. Rathmann, Wolfgang Rayner, Nigel W. Rice, Kenneth Ripatti, Samuli Rivadeneira, Fernando Roden, Michael Rolandsson, Olov Sandbaek, Annelli Sandhu, Manjinder Sanna, Serena Sayer, Avan Aihie Scheet, Paul Scott, Laura J. Seedorf, Udo Sharp, Stephen J. Shields, Beverley Sigurosson, Gunnar Sijbrands, Eric J. G. Silveira, Angela Simpson, Laila Singleton, Andrew Smith, Nicholas L. Sovio, Ulla Swift, Amy Syddall, Holly Syvanen, Ann-Christine Tanaka, Toshiko Thorand, Barbara Tichet, Jean Tonjes, Anke Tuomi, Tiinamaija Uitterlinden, Andre G. van Dijk, Ko Willems van Hoek, Mandy Varma, Dhiraj Visvikis-Siest, Sophie Vitart, Veronique Vogelzangs, Nicole Waeber, Gerard Wagner, Peter J. Walley, Andrew Walters, G. Bragi Ward, Kim L. Watkins, Hugh Weedon, Michael N. Wild, Sarah H. Willemsen, Gonneke Witteman, Jaqueline C. M. Yarnell, John W. G. Zeggini, Eleftheria Zelenika, Diana Zethelius, Bjorn Zhai, Guangju Zhao, Jing Hua Zillikens, M. Carola Borecki, Ingrid B. Loos, Ruth J. F. Meneton, Pierre Magnusson, Patrik K. E. Nathan, David M. Williams, Gordon H. Hattersley, Andrew T. Silander, Kaisa Salomaa, Veikko Smith, George Davey Bornstein, Stefan R. Schwarz, Peter Spranger, Joachim Karpe, Fredrik Shuldiner, Alan R. Cooper, Cyrus Dedoussis, George V. Serrano-Rios, Manuel Morris, Andrew D. Lind, Lars Palmer, Lyle J. Hu, Frank B. Franks, Paul W. Ebrahim, Shah Marmot, Michael Kao, W. H. Linda Pankow, James S. Sampson, Michael J. Kuusisto, Johanna Laakso, Markku Hansen, Torben Pedersen, Oluf Pramstaller, Peter Paul Wichmann, H. Erich Illig, Thomas Rudan, Igor Wright, Alan F. Stumvoll, Michael Campbell, Harry Wilson, James F. Bergman, Richard N. Buchanan, Thomas A. Collins, Francis S. Mohlke, Karen L. Tuomilehto, Jaakko Valle, Timo T. Altshuler, David Rotter, Jerome I. Siscovick, David S. Penninx, Brenda W. J. H. Boomsma, Dorret I. Deloukas, Panos Spector, Timothy D. Frayling, Timothy M. Ferrucci, Luigi Kong, Augustine Thorsteinsdottir, Unnur Stefansson, Kari van Duijn, Cornelia M. Aulchenko, Yurii S. Cao, Antonio Scuteri, Angelo Schlessinger, David Uda, Manuela Ruokonen, Aimo Jarvelin, Marjo-Riitta Waterworth, Dawn M. Vollenweider, Peter Peltonen, Leena Mooser, Vincent Abecasis, Goncalo R. Wareham, Nicholas J. Sladek, Robert Froguel, Philippe Watanabe, Richard M. Meigs, James B. Groop, Leif Boehnke, Michael McCarthy, Mark I. Florez, Jose C. Barroso, Ines CA DIAGRAM Consortium GIANT Consortium Global BPgen Consortium Anders Hamsten Procardis Consortiu MAGIC Investigators TI New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BETA-CELL DYSFUNCTION; PLASMA-GLUCOSE; INSULIN-SECRETION; TRIGLYCERIDE LEVELS; ESSENTIAL COMPONENTS; MODEL ASSESSMENT; COMMON VARIANTS; CIRCADIAN CLOCK; DISEASE RISK AB Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. C1 [Jackson, Anne U.; Stringham, Heather M.; Han, Xijing; Li, Yun; Lyssenko, Valeriya; Scott, Laura J.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Dupuis, Josee; Manning, Alisa K.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Langenberg, Claudia; Luan, Jian'an; Forouhi, Nita G.; Sandhu, Manjinder; Sharp, Stephen J.; Zhao, Jing Hua; Loos, Ruth J. F.; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge, England. [Prokopenko, Inga; Gloyn, Anna L.; Lindgren, Cecilia M.; Magi, Reedik; Bennett, Amanda J.; Groves, Christopher J.; Hassanali, Neelam; Johnson, Paul R. V.; McCulloch, Laura J.; Neville, Matthew J.; Rayner, Nigel W.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Prokopenko, Inga; Lindgren, Cecilia M.; Magi, Reedik; Morris, Andrew P.; Randall, Joshua; Goel, Anuj; Peden, John F.; Rayner, Nigel W.; Watkins, Hugh; Zeggini, Eleftheria; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Saxena, Richa; Voight, Benjamin F.; Elliott, Amanda; McCarroll, Steven A.; Crawford, Gabe; McAteer, Jarred B.; Altshuler, David; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Saxena, Richa; Voight, Benjamin F.; Elliott, Amanda; McCarroll, Steven A.; Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Soranzo, Nicole; Bumpstead, Suzannah J.; Gwilliam, Rhian; Hammond, Naomi; Potter, Simon C.; Varma, Dhiraj; Zeggini, Eleftheria; Deloukas, Panos; Spector, Timothy D.; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge, England. [Soranzo, Nicole; Mangino, Massimo; Zhai, Guangju; Spector, Timothy D.] Kings Coll London, Twin Res & Genet Epidemiol Dept, London WC2R 2LS, England. [Wheeler, Eleanor; Payne, Felicity; Roccasecca, Rosa Maria; Barroso, Ines] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge, England. [Glazer, Nicole L.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Glazer, Nicole L.; Psaty, Bruce M.; Ferrucci, Luigi] Univ Washington, Dept Med, Seattle, WA USA. [Bouatia-Naji, Nabila; Cavalcanti-Proenca, Christine; Bonnefond, Amelie; Delplanque, Jerome; Dina, Christian; Le Bacquer, Olivier; Lecoeur, Cecile; Meyre, David; Froguel, Philippe] Univ Lille 2, Inst Pasteur, CNRS, Unite Mixte Rech 8090, Lille, France. 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[Kaprio, Jaakko; Perola, Markus; Ripatti, Samuli; Wagner, Peter J.; Silander, Kaisa; Peltonen, Leena] Univ Helsinki, Inst tute Mol Med Finland FIMM, Helsinki, Finland. [Kesaniemi, Y. Antero] Univ Oulu, Dept Internal Med, SF-90220 Oulu, Finland. [Koskinen, Seppo] Natl Inst Hlth & Welf, Unit Living Condit Hlth & Wellbeing, Helsinki, Finland. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. [Kyvik, Kirsten Ohm] Univ So Denmark, Inst Publ Hlth, Danish Twin Registry, Odense, Denmark. [Lyssenko, Valeriya; Groop, Leif] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Mahley, Robert] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94143 USA. [McAteer, Jarred B.; Nathan, David M.; Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [McAteer, Jarred B.; Nathan, David M.; Williams, Gordon H.; Altshuler, David; Meigs, James B.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada. [Neville, Matthew J.; Karpe, Fredrik; McCarthy, Mark I.] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England. [Oostra, Ben A.] Erasmus Med Coll, Dept Clin Genet, Rotterdam, Netherlands. [Palmer, Colin N. A.; Morris, Andrew D.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland. [Paolisso, Giuseppe] Univ Naples 2, Dept Geriatr Med & Metab Dis, Naples, Italy. [Perola, Markus; Ripatti, Samuli; Wagner, Peter J.; Silander, Kaisa; Peltonen, Leena] Natl Inst Hlth & Welf, Unit Publ Hlth Genom, Helsinki, Finland. [Perola, Markus; Peltonen, Leena] Univ Helsinki, Dept Med Genet, Helsinki, Finland. 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[Rolandsson, Olov] Umea Univ, Sect Family Med, Dept Publ Hlth & Clin Med, Umea, Sweden. [Sandbaek, Annelli] Univ Aarhus, Dept Gen Practice, Sch Publ Hlth, Aarhus, Denmark. [Sandhu, Manjinder] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. [Sayer, Avan Aihie; Syddall, Holly; Cooper, Cyrus] Univ Southampton, Southampton Gen Hosp, MRC, Epidemiol Resource Ctr, Southampton, Hants, England. [Scheet, Paul] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. [Silveira, Angela; Anders Hamsten Procardis Consortiu] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, Stockholm, Sweden. [Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA. [Syvanen, Ann-Christine; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Tanaka, Toshiko] MedStar Res Inst, Baltimore, MD USA. [Tichet, Jean] Inst Interreg Sante IRSA, La Riche, France. [Tonjes, Anke] Univ Leipzig, Coordinat Ctr Clin Trials, Leipzig, Germany. [Tuomi, Tiinamaija] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland. [van Dijk, Ko Willems] Leiden Univ, Med Ctr, Dept Internal Med, Leiden, Netherlands. [Visvikis-Siest, Sophie] Nancy Univ Henri Poincare, Res Unit, Nancy, France. [Vogelzangs, Nicole; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Walley, Andrew; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [Yarnell, John W. G.] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Zethelius, Bjorn] Med Prod Agcy, Uppsala, Sweden. [Salomaa, Veikko] Natl Inst Hlth & Welf, Unit Chron Dis Epidemiol & Prevent, Helsinki, Finland. [Hu, Frank B.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Franks, Paul W.] Umea Univ Hosp, Med Sect, Dept Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. [Ebrahim, Shah] London Sch Hyg & Trop Med, London WC1, England. [Kao, W. H. Linda] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Kao, W. H. Linda] Johns Hopkins Univ, Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Sampson, Michael J.] Norfolk & Norwich Univ Hosp Natl Hlth Serv Trust, Dept Endocrinol & Diabet, Norwich, Norfolk, England. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Hansen, Torben] Univ So Denmark, Fac Hlth Sci, Odense, Denmark. [Pramstaller, Peter Paul] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter Paul] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Wichmann, H. Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Rudan, Igor] Univ Split, Sch Med, Split, Croatia. [Rudan, Igor] Gen Info Ltd, Zagreb, Croatia. [Bergman, Richard N.; Buchanan, Thomas A.; Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Buchanan, Thomas A.] Univ So Calif, Keck Sch Med, Div Endocrinol, Dept Med, Los Angeles, CA 90033 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Tuomilehto, Jaakko; Valle, Timo T.] Natl Inst Hlth & Welf, Unit Diabet Prevent, Helsinki, Finland. [Siscovick, David S.] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Scuteri, Angelo] Univ Iceland, Fac Med, Reykjavik, Iceland. [Ruokonen, Aimo] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Dept Clin Sci Clin Chem, Oulu, Finland. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC, Hlth Protect Agcy Ctr Environm & Hlth, London, England. RP Boehnke, M (reprint author), Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. EM boehnke@umich.edu; mark.mccarthy@drl.ox.ac.uk; jcflorez@partners.org; ib1@sanger.ac.uk RI Elliott, Amanda/G-5120-2012; Kaprio, Jaakko/A-1820-2008; Rudan, Igor/I-1467-2012; Heath, Simon/J-4138-2012; Rice, Kenneth/A-4150-2013; Deloukas, Panos/B-2922-2013; Lajunen, Taina/J-7337-2013; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; van Hoek, Mandy/B-9325-2014; Meisinger, Christine/B-5358-2014; Visvikis-Siest, Sophie/H-2324-2014; Walley, Andrew/D-2573-2009; Grarup, Niels/K-2807-2015; Kyvik, Kirsten /K-5680-2016; Study, GoDARTS/K-9448-2016; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; BOUATIA-NAJI, NABILA/D-5863-2013; Coin, Lachlan/A-9001-2014; Schwarz, Peter/B-5127-2013; Davey Smith, George/A-7407-2013; Magnusson, Patrik/C-4458-2017; Naitza, Silvia/D-5620-2017; Hicks, Andrew/E-9518-2017; Pramstaller, Peter/C-2357-2008; Thorand, Barbara/B-5349-2014; Cooper, Matthew/J-4420-2014; Palmer, Lyle/K-3196-2014; Dina, Christian/D-3535-2015; SIMPSON, LAILA/O-7281-2014; Boehm, Bernhard/F-8750-2015; Grallert, Harald/B-3424-2013; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; de Geus, Eco/M-9318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Willems van Dijk, Ko/A-1798-2008; Abecasis, Goncalo/B-7840-2010; Bochud, Murielle/A-3981-2010; Polasek, Ozren/B-6002-2011; Altshuler, David/A-4476-2009; Meyre, David/D-7315-2011; Singleton, Andrew/C-3010-2009; Voight, Benjamin/F-1775-2011; Brunner, Eric/H-2114-2011; Aihie Sayer, Avan/A-4359-2012; Palmer, Colin/C-7053-2008; Kivimaki, Mika/B-3607-2012; Spector, Tim/F-6533-2012 OI Lawlor, Debbie A/0000-0002-6793-2262; Payne, Felicity/0000-0003-4228-581X; Pankow, James/0000-0001-7076-483X; Bergmann, Sven/0000-0002-6785-9034; Dehghan, Abbas/0000-0001-6403-016X; Rudan, Igor/0000-0001-6993-6884; Rice, Kenneth/0000-0001-5779-4495; Deloukas, Panos/0000-0001-9251-070X; Aulchenko, Yurii/0000-0002-7899-1575; Visvikis-Siest, Sophie/0000-0001-8104-8425; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Monsalve, Beatriz Elena/0000-0002-5994-866X; Johnson, Toby/0000-0002-5998-3270; Aihie Sayer, Avan/0000-0003-1283-6457; Abecasis, Goncalo/0000-0003-1509-1825; Zeggini, Eleftheria/0000-0003-4238-659X; Tuomi, Tiinamaija/0000-0002-8306-6202; Karpe, Fredrik/0000-0002-2751-1770; Jorgensen, Torben/0000-0001-9453-2830; Watkins, Hugh/0000-0002-5287-9016; Sladek, Robert/0000-0002-2730-1204; Marmot, Michael/0000-0002-2431-6419; Mitchell, Braxton/0000-0003-4920-4744; Kaprio, Jaakko/0000-0002-3716-2455; Timpson, Nicholas/0000-0002-7141-9189; Dupuis, Josee/0000-0003-2871-3603; Gieger, Christian/0000-0001-6986-9554; Kumari, Meena/0000-0001-9716-1035; Melzer, David/0000-0002-0170-3838; Forouhi, Nita/0000-0002-5041-248X; Seedorf, Udo/0000-0003-4652-5358; Magi, Reedik/0000-0002-2964-6011; Soranzo, Nicole/0000-0003-1095-3852; Bouatia-Naji, Nabila/0000-0001-5424-2134; Meisinger, Christa/0000-0002-9026-6544; Kaakinen, Marika/0000-0002-9228-0462; Walley, Andrew/0000-0001-7707-7549; Pichler, Irene/0000-0001-8251-0757; Sijbrands, Eric/0000-0001-8857-7389; Paolisso, Giuseppe/0000-0002-2137-455X; Rybin, Denis/0000-0002-3657-4829; Grarup, Niels/0000-0001-5526-1070; Kyvik, Kirsten /0000-0003-2981-0245; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Coin, Lachlan/0000-0002-4300-455X; Schwarz, Peter/0000-0001-6317-7880; Davey Smith, George/0000-0002-1407-8314; Hicks, Andrew/0000-0001-6320-0411; Thorand, Barbara/0000-0002-8416-6440; Cooper, Matthew/0000-0003-1139-3682; Palmer, Lyle/0000-0002-1628-3055; Dina, Christian/0000-0002-7722-7348; SIMPSON, LAILA/0000-0001-7189-4791; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; de Geus, Eco/0000-0001-6022-2666; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Willems van Dijk, Ko/0000-0002-2172-7394; Bochud, Murielle/0000-0002-5727-0218; Polasek, Ozren/0000-0002-5765-1862; Altshuler, David/0000-0002-7250-4107; Palmer, Colin/0000-0002-6415-6560; FU British Heart Foundation [RG/07/008/23674]; Chief Scientist Office [CZB/4/710]; Medical Research Council [G0100222, G0600331, G0600705, G0601261, G0700222, G0700222(81696), G0701863, G0801056, G0902037, G19/35, G8802774, MC_U106179471, MC_U106188470, MC_U127561128, MC_U127592696, MC_U137686857, MC_UP_A620_1014, MC_UP_A620_1015]; NIDDK NIH HHS [K24 DK080140, P30 DK040561, P30 DK040561-14, R01 DK029867, R01 DK072193, R01 DK078616, R01 DK078616-01A1]; The Dunhill Medical Trust [R69/0208]; Wellcome Trust [064890, 077011, 077016, 081682, 088885, 089061, 090532, 091746] NR 74 TC 927 Z9 946 U1 21 U2 155 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2010 VL 42 IS 2 BP 105 EP U32 DI 10.1038/ng.520 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 549WG UT WOS:000274084400005 PM 20081858 ER PT J AU Saxena, R Hivert, MF Langenberg, C Tanaka, T Pankow, JS Vollenweider, P Lyssenko, V Bouatia-Naji, N Dupuis, J Jackson, AU Kao, WHL Li, M Glazer, NL Manning, AK Luan, J Stringham, HM Prokopenko, I Johnson, T Grarup, N Boesgaard, TW Lecoeur, C Shrader, P O'Connell, J Ingelsson, E Couper, DJ Rice, K Song, KJ Andreasen, CH Dina, C Kottgen, A Le Bacquer, O Pattou, F Taneera, J Steinthorsdottir, V Rybin, D Ardlie, K Sampson, M Qi, L van Hoek, M Weedon, MN Aulchenko, YS Voight, BF Grallert, H Balkau, B Bergman, RN Bielinski, SJ Bonnefond, A Bonnycastle, LL Borch-Johnsen, K Boettcher, Y Brunner, E Buchanan, TA Bumpstead, SJ Cavalcanti-Proenca, C Charpentier, G Chen, YDI Chines, PS Collins, FS Cornelis, M Crawford, GJ Delplanque, J Doney, A Egan, JM Erdos, MR Firmann, M Forouhi, NG Fox, CS Goodarzi, MO Graessler, J Hingorani, A Isomaa, B Jorgensen, T Kivimaki, M Kovacs, P Krohn, K Kumari, M Lauritzen, T Levy-Marchal, C Mayor, V McAteer, JB Meyre, D Mitchell, BD Mohlke, KL Morken, MA Narisu, N Palmer, CNA Pakyz, R Pascoe, L Payne, F Pearson, D Rathmann, W Sandbaek, A Sayer, AA Scott, LJ Sharp, SJ Sijbrands, E Singleton, A Siscovick, DS Smith, NL Sparso, T Swift, AJ Syddall, H Thorleifsson, G Tonjes, A Tuomi, T Tuomilehto, J Valle, TT Waeber, G Walley, A Waterworth, DM Zeggini, E Zhao, JH Illig, T Wichmann, HE Wilson, JF van Duijn, C Hu, FB Morris, AD Frayling, TM Hattersley, AT Thorsteinsdottir, U Stefansson, K Nilsson, P Syvanen, AC Shuldiner, AR Walker, M Bornstein, SR Schwarz, P Williams, GH Nathan, DM Kuusisto, J Laakso, M Cooper, C Marmot, M Ferrucci, L Mooser, V Stumvoll, M Loos, RJF Altshuler, D Psaty, BM Rotter, JI Boerwinkle, E Hansen, T Pedersen, O Florez, JC McCarthy, MI Boehnke, M Barroso, I Sladek, R Froguel, P Meigs, JB Groop, L Wareham, NJ Watanabe, RM AF Saxena, Richa Hivert, Marie-France Langenberg, Claudia Tanaka, Toshiko Pankow, James S. Vollenweider, Peter Lyssenko, Valeriya Bouatia-Naji, Nabila Dupuis, Josee Jackson, Anne U. Kao, W. H. Linda Li, Man Glazer, Nicole L. Manning, Alisa K. Luan, Jian'an Stringham, Heather M. Prokopenko, Inga Johnson, Toby Grarup, Niels Boesgaard, Trine W. Lecoeur, Cecile Shrader, Peter O'Connell, Jeffrey Ingelsson, Erik Couper, David J. Rice, Kenneth Song, Kijoung Andreasen, Camilla H. Dina, Christian Koettgen, Anna Le Bacquer, Olivier Pattou, Francois Taneera, Jalal Steinthorsdottir, Valgerdur Rybin, Denis Ardlie, Kristin Sampson, Michael Qi, Lu van Hoek, Mandy Weedon, Michael N. Aulchenko, Yurii S. Voight, Benjamin F. Grallert, Harald Balkau, Beverley Bergman, Richard N. Bielinski, Suzette J. Bonnefond, Amelie Bonnycastle, Lori L. Borch-Johnsen, Knut Boettcher, Yvonne Brunner, Eric Buchanan, Thomas A. Bumpstead, Suzannah J. Cavalcanti-Proenca, Christine Charpentier, Guillaume Chen, Yii-Der Ida Chines, Peter S. Collins, Francis S. Cornelis, Marilyn Crawford, Gabriel J. Delplanque, Jerome Doney, Alex Egan, Josephine M. Erdos, Michael R. Firmann, Mathieu Forouhi, Nita G. Fox, Caroline S. Goodarzi, Mark O. Graessler, Juergen Hingorani, Aroon Isomaa, Bo Jorgensen, Torben Kivimaki, Mika Kovacs, Peter Krohn, Knut Kumari, Meena Lauritzen, Torsten Levy-Marchal, Claire Mayor, Vladimir McAteer, Jarred B. Meyre, David Mitchell, Braxton D. Mohlke, Karen L. Morken, Mario A. Narisu, Narisu Palmer, Colin N. A. Pakyz, Ruth Pascoe, Laura Payne, Felicity Pearson, Daniel Rathmann, Wolfgang Sandbaek, Annelli Sayer, Avan Aihie Scott, Laura J. Sharp, Stephen J. Sijbrands, Eric Singleton, Andrew Siscovick, David S. Smith, Nicholas L. Sparso, Thomas Swift, Amy J. Syddall, Holly Thorleifsson, Gudmar Toenjes, Anke Tuomi, Tiinamaija Tuomilehto, Jaakko Valle, Timo T. Waeber, Gerard Walley, Andrew Waterworth, Dawn M. Zeggini, Eleftheria Zhao, Jing Hua Illig, Thomas Wichmann, H. Erich Wilson, James F. van Duijn, Cornelia Hu, Frank B. Morris, Andrew D. Frayling, Timothy M. Hattersley, Andrew T. Thorsteinsdottir, Unnur Stefansson, Kari Nilsson, Peter Syvanen, Ann-Christine Shuldiner, Alan R. Walker, Mark Bornstein, Stefan R. Schwarz, Peter Williams, Gordon H. Nathan, David M. Kuusisto, Johanna Laakso, Markku Cooper, Cyrus Marmot, Michael Ferrucci, Luigi Mooser, Vincent Stumvoll, Michael Loos, Ruth J. F. Altshuler, David Psaty, Bruce M. Rotter, Jerome I. Boerwinkle, Eric Hansen, Torben Pedersen, Oluf Florez, Jose C. McCarthy, Mark I. Boehnke, Michael Barroso, Ines Sladek, Robert Froguel, Philippe Meigs, James B. Groop, Leif Wareham, Nicholas J. Watanabe, Richard M. CA GIANT Consortium MAGIC Investigators TI Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge SO NATURE GENETICS LA English DT Article ID FASTING PLASMA-GLUCOSE; GASTRIC-INHIBITORY POLYPEPTIDE; GLUCAGON-LIKE PEPTIDE-1; BETA-CELL FUNCTION; ASSOCIATION; RISK; RECEPTOR; SENSITIVITY; EXPRESSION; VARIANTS AB Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2- h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)). C1 [Bergman, Richard N.; Buchanan, Thomas A.; Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. 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[Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Ingelsson, Erik] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Couper, David J.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Song, Kijoung; Waterworth, Dawn M.; Mooser, Vincent] GlaxoSmithKline Inc, Drug Discovery, Genet, King Of Prussia, PA USA. [Pattou, Francois] Univ Lille Nord France, INSERM, Lille, France. [Pattou, Francois] Ctr Hosp Reg & Univ Lille, F-59037 Lille, France. [Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Rybin, Denis] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Sampson, Michael] Norfolk & Norwich Univ Hosp Natl Hlth Serv Trust, Dept Endocrinol & Diabet, Norwich, Norfolk, England. [Qi, Lu; Cornelis, Marilyn; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, Lu; Cornelis, Marilyn; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [van Hoek, Mandy; Sijbrands, Eric; van Duijn, Cornelia] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Weedon, Michael N.] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Aulchenko, Yurii S.] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Grallert, Harald; Illig, Thomas; Wichmann, H. Erich] Helmholtz Zentrum Muenchen, Inst Epidemiol, Neuherberg, Germany. [Balkau, Beverley] INSERM, Villejuif, France. [Balkau, Beverley] Univ Paris 11, Orsay, France. [Bielinski, Suzette J.] Mayo Clin, Coll Med, Rochester, MN USA. [Bonnycastle, Lori L.; Chines, Peter S.; Collins, Francis S.; Erdos, Michael R.; Morken, Mario A.; Narisu, Narisu; Pearson, Daniel; Swift, Amy J.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Borch-Johnsen, Knut] Steno Diabet Ctr, Copenhagen, Denmark. [Borch-Johnsen, Knut] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark. [Boettcher, Yvonne; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, Leipzig, Germany. [Brunner, Eric; Hingorani, Aroon; Kivimaki, Mika; Kumari, Meena; Marmot, Michael] UCL, Dept Epidemiol & Publ Hlth, London, England. [Buchanan, Thomas A.] Univ So Calif, Keck Sch Med, Div Endocrinol, Dept Med, Los Angeles, CA 90033 USA. [Bumpstead, Suzannah J.; Payne, Felicity; Zeggini, Eleftheria; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge, England. [Charpentier, Guillaume] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Essonnes, France. [Chen, Yii-Der Ida; Goodarzi, Mark O.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Doney, Alex] Univ Dundee, Ninewells Hosp & Med Sch, Dept Med & Therapeut, Dundee DD1 9SY, Scotland. [Egan, Josephine M.] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Fox, Caroline S.; Williams, Gordon H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Graessler, Juergen; Bornstein, Stefan R.; Schwarz, Peter] Univ Dresden, Div Prevent & Care Diabet, Dept Med 3, Dresden, Germany. [Isomaa, Bo; Tuomi, Tiinamaija] Folkhalsan Res Ctr, Helsinki, Finland. [Isomaa, Bo] Malmska Municipal Hlth Care Ctr & Hosp, Pietarsaari, Finland. [Jorgensen, Torben] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Kovacs, Peter; Krohn, Knut] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. [Lauritzen, Torsten; Sandbaek, Annelli] Univ Aarhus, Dept Gen Practice, Aarhus, Denmark. [Levy-Marchal, Claire] Robert Debre Hosp, INSERM, Paris, France. [Levy-Marchal, Claire] Paris Diderot Univ, Paris, France. [McAteer, Jarred B.; Nathan, David M.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Palmer, Colin N. A.; Morris, Andrew D.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland. [Pascoe, Laura; Walker, Mark] Fac Med Sci, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Rathmann, Wolfgang] German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany. [Sayer, Avan Aihie; Syddall, Holly; Cooper, Cyrus] Univ Southampton, Southampton Gen Hosp, MRC, Epidemiol Resource Ctr, Southampton, Hants, England. [Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Siscovick, David S.; Smith, Nicholas L.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Off Res & Dev, Dept Vet Affairs, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Toenjes, Anke] Univ Leipzig, Coordinat Ctr Clin Trials, Leipzig, Germany. [Tuomi, Tiinamaija; Tuomilehto, Jaakko] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland. [Tuomilehto, Jaakko] Natl Publ Hlth Inst, Diabet Unit, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Valle, Timo T.] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. [Walley, Andrew; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [Wichmann, H. Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Hu, Frank B.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Frayling, Timothy M.; Hattersley, Andrew T.] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Nilsson, Peter] Lund Univ, Malmo Univ Hosp, Dept Clin Sci, Malmo, Sweden. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Hansen, Torben] Univ So Denmark, Fac Hlth Sci, Odense, Denmark. [Pedersen, Oluf] Univ Copenhagen, Fac Hlth Sci, Inst Biomed, DK-1168 Copenhagen, Denmark. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res Biomed Res Ctr, Oxford OX3 7LJ, England. [Sladek, Robert] McGill Univ, Fac Med, Dept Human Genet, Montreal, PQ, Canada. [Sladek, Robert] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Watanabe, RM (reprint author), Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. EM jmeigs@partners.org; Leif.Groop@med.lu.se; nick.wareham@mrc-epid.cam.ac.uk; rwatanab@usc.edu RI van Hoek, Mandy/B-9325-2014; Dina, Christian/D-3535-2015; Grallert, Harald/B-3424-2013; Wilson, James F/A-5704-2009; Prokopenko, Inga/H-3241-2014; Bielinski, Suzette/A-2238-2009; Grarup, Niels/K-2807-2015; Study, GoDARTS/K-9448-2016; BOUATIA-NAJI, NABILA/D-5863-2013; Schwarz, Peter/B-5127-2013; Walley, Andrew/D-2573-2009; Singleton, Andrew/C-3010-2009; Voight, Benjamin/F-1775-2011; Brunner, Eric/H-2114-2011; Aihie Sayer, Avan/A-4359-2012; Kivimaki, Mika/B-3607-2012; Kottgen, Anna/D-2920-2012; Rice, Kenneth/A-4150-2013; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Palmer, Colin/C-7053-2008; Altshuler, David/A-4476-2009; Meyre, David/D-7315-2011; OI Dina, Christian/0000-0002-7722-7348; Wilson, James F/0000-0001-5751-9178; Prokopenko, Inga/0000-0003-1624-7457; Bielinski, Suzette/0000-0002-2905-5430; Grarup, Niels/0000-0001-5526-1070; Schwarz, Peter/0000-0001-6317-7880; Bouatia-Naji, Nabila/0000-0001-5424-2134; Walley, Andrew/0000-0001-7707-7549; Sijbrands, Eric/0000-0001-8857-7389; Rice, Kenneth/0000-0001-5779-4495; Aulchenko, Yurii/0000-0002-7899-1575; Palmer, Colin/0000-0002-6415-6560; Altshuler, David/0000-0002-7250-4107; Forouhi, Nita/0000-0002-5041-248X; Tuomi, Tiinamaija/0000-0002-8306-6202; Jorgensen, Torben/0000-0001-9453-2830; Sladek, Robert/0000-0002-2730-1204; Marmot, Michael/0000-0002-2431-6419; Mitchell, Braxton/0000-0003-4920-4744; Pankow, James/0000-0001-7076-483X; Taneera, Jalal/0000-0002-3341-1063; Rybin, Denis/0000-0002-3657-4829; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; Aihie Sayer, Avan/0000-0003-1283-6457; Zeggini, Eleftheria/0000-0003-4238-659X; Dupuis, Josee/0000-0003-2871-3603; Kumari, Meena/0000-0001-9716-1035 FU British Heart Foundation [RG/07/008/23674]; Chief Scientist Office [CZB/4/710]; Intramural NIH HHS [Z01 HG000024-14]; Medical Research Council [G0100222, G0600331, G0701863, G0902037, G19/35, G8802774, MC_U106179471, MC_U106188470, MC_UP_A620_1014, MC_UP_A620_1015]; NCI NIH HHS [P01 CA087969, P01 CA087969-12]; NCRR NIH HHS [M01 RR000052, M01 RR000052-46, M01 RR001066-26, M01 RR016500, M01 RR016500-08]; NHGRI NIH HHS [U01 HG004399, U01 HG004399-02, U01 HG004402, U01 HG004402-02]; NHLBI NIH HHS [N01 HC055022, N01 HC015103, N01 HC025195, N01 HC035129, N01 HC045133, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055222, N01 HC075150, N01 HC085079, N01 HC085080, N01 HC085081, N01 HC085082, N01 HC085083, N01 HC085084, N01 HC085085, N01 HC085086, N02 HL64278, R01 HL036310, R01 HL036310-21, R01 HL059367, R01 HL059367-10, R01 HL086694, R01 HL086694-03, R01 HL087641, R01 HL087641-03, R01 HL087652, R01 HL087652-03, U01 HL072515, U01 HL072515-06, U01 HL080295, U01 HL080295-04]; NIA NIH HHS [R01 AG013196, R01 AG013196-16]; NIDA NIH HHS [U54 DA021519, U54 DA021519-04]; NIDDK NIH HHS [K23 DK065978, K23 DK065978-05, K24 DK080140, K24 DK080140-04, P30 DK072488, P30 DK072488-06, P30 DK079637, P60 DK079637, P60 DK079637-04, R01 DK029867, R01 DK054261, R01 DK054261-09, R01 DK058845, R01 DK058845-11, R01 DK062370, R01 DK062370-05, R01 DK069922, R01 DK069922-03, R01 DK072193, R01 DK072193-04, R01 DK078616, R01 DK078616-03, R01 DK091718]; Wellcome Trust [077016, 088885] NR 35 TC 300 Z9 307 U1 2 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2010 VL 42 IS 2 BP 142 EP U75 DI 10.1038/ng.521 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 549WG UT WOS:000274084400011 PM 20081857 ER PT J AU Pfeufer, A van Noord, C Marciante, KD Arking, DE Larson, MG Smith, AV Tarasov, KV Muller, M Sotoodehnia, N Sinner, MF Verwoert, GC Li, M Kao, WHL Kottgen, A Coresh, J Bis, JC Psaty, BM Rice, K Rotter, JI Rivadeneira, F Hofman, A Kors, JA Stricker, BHC Uitterlinden, AG van Duijn, CM Beckmann, BM Sauter, W Gieger, C Lubitz, SA Newton-Cheh, C Wang, TJ Magnani, JW Schnabel, RB Chung, MK Barnard, J Smith, JD Van Wagoner, DR Vasan, RS Aspelund, T Eiriksdottir, G Harris, TB Launer, LJ Najjar, SS Lakatta, E Schlessinger, D Uda, M Abecasis, GR Muller-Myhsok, B Ehret, GB Boerwinkle, E Chakravarti, A Soliman, EZ Lunetta, KL Perz, S Wichmann, HE Meitinger, T Levy, D Gudnason, V Ellinor, PT Sanna, S Kaab, S Witteman, JCM Alonso, A Benjamin, EJ Heckbert, SR AF Pfeufer, Arne van Noord, Charlotte Marciante, Kristin D. Arking, Dan E. Larson, Martin G. Smith, Albert Vernon Tarasov, Kirill V. Mueller, Martina Sotoodehnia, Nona Sinner, Moritz F. Verwoert, Germaine C. Li, Man Kao, W. H. Linda Koettgen, Anna Coresh, Josef Bis, Joshua C. Psaty, Bruce M. Rice, Kenneth Rotter, Jerome I. Rivadeneira, Fernando Hofman, Albert Kors, Jan A. Stricker, Bruno H. C. Uitterlinden, Andre G. van Duijn, Cornelia M. Beckmann, Britt M. Sauter, Wiebke Gieger, Christian Lubitz, Steven A. Newton-Cheh, Christopher Wang, Thomas J. Magnani, Jared W. Schnabel, Renate B. Chung, Mina K. Barnard, John Smith, Jonathan D. Van Wagoner, David R. Vasan, Ramachandran S. Aspelund, Thor Eiriksdottir, Gudny Harris, Tamara B. Launer, Lenore J. Najjar, Samer S. Lakatta, Edward Schlessinger, David Uda, Manuela Abecasis, Goncalo R. Mueller-Myhsok, Bertram Ehret, Georg B. Boerwinkle, Eric Chakravarti, Aravinda Soliman, Elsayed Z. Lunetta, Kathryn L. Perz, Siegfried Wichmann, H-Erich Meitinger, Thomas Levy, Daniel Gudnason, Vilmundur Ellinor, Patrick T. Sanna, Serena Kaeaeb, Stefan Witteman, Jacqueline C. M. Alonso, Alvaro Benjamin, Emelia J. Heckbert, Susan R. TI Genome-wide association study of PR interval SO NATURE GENETICS LA English DT Article ID ATRIAL-FIBRILLATION; COMMON VARIANTS; SODIUM-CHANNEL; HEART-RATE; ATHEROSCLEROSIS RISK; NATIONAL HEART; SYSTEM; DESIGN; INDIVIDUALS; VARIABILITY AB The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-nalysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX25 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation. C1 [Pfeufer, Arne; Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-80804 Munich, Germany. [Pfeufer, Arne; Meitinger, Thomas] German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [van Noord, Charlotte; Verwoert, Germaine C.; Rivadeneira, Fernando; Hofman, Albert; Stricker, Bruno H. C.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Noord, Charlotte] Dutch Med Evaluat Board, The Hague, Netherlands. [van Noord, Charlotte; Witteman, Jacqueline C. M.] Netherlands Consortium Healthy Aging Leiden, Leiden, Netherlands. [Sotoodehnia, Nona] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. [Arking, Dan E.; Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Wang, Thomas J.; Schnabel, Renate B.; Vasan, Ramachandran S.; Levy, Daniel; Benjamin, Emelia J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Smith, Albert Vernon; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Heart Prevent Clin & Res Inst, Iceland Heart Assoc, Kopavogur, Iceland. [Tarasov, Kirill V.; Najjar, Samer S.; Lakatta, Edward] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Tarasov, Kirill V.; Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Mueller, Martina; Sauter, Wiebke; Gieger, Christian; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Mueller, Martina; Sinner, Moritz F.; Beckmann, Britt M.; Kaeaeb, Stefan] Univ Munich, Klinikum Grosshadern, Dept Med 1, D-80804 Munich, Germany. [Verwoert, Germaine C.; Rivadeneira, Fernando; Stricker, Bruno H. C.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Li, Man; Kao, W. H. Linda; Koettgen, Anna; Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Res Inst, Seattle, WA USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Dept Common Dis Genet Program, Inst Med Genet, W Hollywood, CA USA. [Kors, Jan A.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Stricker, Bruno H. C.] Inspectorate Hlth Care, The Hague, Netherlands. [Lubitz, Steven A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Lubitz, Steven A.; Newton-Cheh, Christopher; Wang, Thomas J.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Ellinor, Patrick T.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Wang, Thomas J.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Med Clin Cardiol 2, Mainz, Germany. [Chung, Mina K.; Barnard, John; Smith, Jonathan D.; Van Wagoner, David R.] Cleveland Clin, Heart & Vasc Res Inst, Cleveland, OH 44106 USA. [Chung, Mina K.; Barnard, John; Smith, Jonathan D.; Van Wagoner, David R.] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Heart Prevent Clin & Res Inst, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Uda, Manuela; Sanna, Serena] CNR, Ist Neurogenet Neurofarmacol, Cagliari, Italy. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Chakravarti, Aravinda] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Soliman, Elsayed Z.] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE,Med Ctr, Winston Salem, NC 27109 USA. [Perz, Siegfried] Helmholtz Ctr, Inst Biol & Med Imaging, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, Munich, Germany. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Cardiol & Prevent Med Div,Evans Dept Med, Boston, MA 02118 USA. RP Pfeufer, A (reprint author), Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-80804 Munich, Germany. EM arne.pfeufer@web.de; heckbert@u.washington.edu RI Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; EHRET, Georg/A-9532-2009; Van Wagoner, David/C-6783-2008; Abecasis, Goncalo/B-7840-2010; Alonso, Alvaro/A-4917-2010; Soliman, Elsayed/D-8124-2011; Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Kottgen, Anna/D-2920-2012; Kaab, Stefan/H-3915-2012; Muller-Myhsok, Bertram/A-3289-2013; Rice, Kenneth/A-4150-2013; Pfeufer, Arne/B-6634-2013; Schnabel, Renate/F-6527-2014; OI Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Lunetta, Kathryn/0000-0002-9268-810X; Larson, Martin/0000-0002-9631-1254; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Ramachandran, Vasan/0000-0001-7357-5970; EHRET, Georg/0000-0002-5730-0675; Van Wagoner, David/0000-0001-8250-9828; Alonso, Alvaro/0000-0002-2225-8323; Soliman, Elsayed/0000-0001-5632-8150; Aspelund, Thor/0000-0002-7998-5433; Rice, Kenneth/0000-0001-5779-4495; Benjamin, Emelia/0000-0003-4076-2336; Gieger, Christian/0000-0001-6986-9554 FU US National Institutes of Health [N01-AG-12100]; US National Institute on Aging (NIA); Hjartavernd (Icelandic Heart Association); Althingi (Icelandic parliament); US National Heart, Lung, and Blood Institute (NHLBI); US National Eye Institute; US National Institute on Deafness and Other Communication Disorders; NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55022, R01-HL-087641, R01-HL-59367, R01-HL-086694, R01-HL-054512, R01-HL090620, P50-HL077107, N01-HC85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01-HL-080295, R01-HL-087652]; US National Human Genome Research Institute (NHGRI) [U01-HG004402]; NIH [HHSN268200625226C, UL1-RR025005, N01-HC-25195, HL-076784, AG-028321, N01-HC25195, HL-080025, 6R01-NS-17950]; Donald W. Reynolds Cardiovascular Clinical Research Center; Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic; US National Center for Research Resources [M01-RR-00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; US National Institute of Neurological Disorders and Stroke; Cedars-Sinai Board of Governors; Boston University School of Medicine and Boston Medical Center (LINGA-II); Robert Dawson Evans Endowment; Doris Duke Charitable Foundation; Deutsche Forschungsgemeinschaft [SCHN 1149/1-1]; Pfizer; Bundesministerium fur Bildung und Forschung Nationales Genomforschungsnetz; Leducq Foundation [07-03 Ludvig 03]; Ludwig-Maximilians University (LMU) [FuFoLe 557/569]; Helmholtz Zentrum Munchen fur Gesundheit und Umwelt; The Netherlands Organisation for Scientific Research [175.010.2005.011, 911.03.012, 050-060-810]; European Commission; Erasmus Medical Center, Erasmus University Rotterdam; NIA [NO1-AG-1-2109, 263-MA-410953]; [01-GS-0499]; [01-GR-0103]; [01-GR-0803]; [AFNET 01-GI-0204 01-GS-0838] FX We gratefully acknowledge all of the participants in the studies. AGES: US National Institutes of Health (NIH) N01-AG-12100, US National Institute on Aging (NIA) and NIH Intramural Research Programs, Hjartavernd (Icelandic Heart Association), Althingi (Icelandic parliament), US National Heart, Lung, and Blood Institute (NHLBI), US National Eye Institute and US National Institute on Deafness and Other Communication Disorders. ARIC: NHLBI N01-HC-55015, N01-HC-55016, N01-HC-55018 through N01-HC-55022, R01-HL-087641, R01-HL-59367, R01-HL-086694 and R01-HL-054512; US National Human Genome Research Institute (NHGRI) U01-HG004402; NIH HHSN268200625226C; and the Donald W. Reynolds Cardiovascular Clinical Research Center. Infrastructure was supported by NIH UL1-RR025005. CCAF: NHLBI R01-HL090620 and P50-HL077107, and intramural funding from the Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic. CHS: NHLBI N01-HC85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01-HL-080295, R01-HL-087652 and R01-HL088456; US National Center for Research Resources M01-RR-00425; National Institute of Diabetes and Digestive and Kidney Diseases DK063491; US National Institute of Neurological Disorders and Stroke; and the Cedars-Sinai Board of Governors. FHS: NIH N01-HC-25195, HL-076784, AG-028321, N01-HC25195, HL-080025 and 6R01-NS-17950; NHLBI N01-HC-25195; Boston University School of Medicine and Boston Medical Center (LINGA-II); the Robert Dawson Evans Endowment; the Doris Duke Charitable Foundation; the SHARe project; Deutsche Forschungsgemeinschaft fellowship SCHN 1149/1-1; Affymetrix contract for genotyping services (N02-HL-6-4278); and Pfizer. KORA/AFNET: We thank B. Putz, M. Putz and G. Fischer for their contributions to genotyping and imputation. Bundesministerium fur Bildung und Forschung Nationales Genomforschungsnetz; 01-GS-0499, 01-GR-0103, 01-GR-0803, AFNET 01-GI-0204 01-GS-0838, the Leducq Foundation 07-03 Ludvig 03, Ludwig-Maximilians University (LMU) FuFoLe 557/569, the LMU Excellence Initiative, MC Health as part of LMUinnovativ, the Helmholtz Zentrum Munchen fur Gesundheit und Umwelt and the state of Bavaria. Rotterdam Study: We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the database, K. Estrada for his help with the analyses and M. Struchalin for contributions to genotype imputation. Nederlandse Organisatie voor Wetenschappelijk Onderzoek (The Netherlands Organisation for Scientific Research) 175.010.2005.011, 911.03.012 and 050-060-810, the Research Institute of Diseases in the Elderly, Netherlands Genome Initiative, Stichting Zorgonderzoek Nederland-Medische Wetenschappen (The Netherlands Organisation for Health Research and Development), Netherlands Hartstichting, Netherlands Ministry of Education Culture and Science, Netherlands Ministry of Health Welfare and Sports; the European Commission; Erasmus Medical Center, Erasmus University Rotterdam and the municipality of Rotterdam. SardiNIA: We thank A. Scuteri and M. Orr for longstanding, continual support of the project and for phenotype characterization. NIA NO1-AG-1-2109, 263-MA-410953, NIH and NIA Intramural Research Programs, NHGRI and NHLBI. Role of the sponsors: None of the funding organizations had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript. More detailed acknowledgments can be found in the Supplementary Note. NR 51 TC 204 Z9 206 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2010 VL 42 IS 2 BP 153 EP U89 DI 10.1038/ng.517 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 549WG UT WOS:000274084400013 PM 20062060 ER PT J AU Deng, HX Klein, CJ Yan, JH Shi, Y Wu, YH Fecto, F Yau, HJ Yang, Y Zhai, H Siddique, N Hedley-Whyte, ET DeLong, R Martina, M Dyck, PJ Siddique, T AF Deng, Han-Xiang Klein, Christopher J. Yan, Jianhua Shi, Yong Wu, Yanhong Fecto, Faisal Yau, Hau-Jie Yang, Yi Zhai, Hong Siddique, Nailah Hedley-Whyte, E. Tessa DeLong, Robert Martina, Marco Dyck, Peter J. Siddique, Teepu TI Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4 SO NATURE GENETICS LA English DT Article ID MARIE-TOOTH-DISEASE; ANKYRIN REPEAT DOMAIN; HEREDITARY MOTOR; CATION CHANNEL; NEUROPATHY; MUTATIONS; VARIANTS; GENE; MICE AB Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC, also known as HMSN2C or Charcot-Marie-Tooth disease type 2C (CMT2C)) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. We originally described a large New England family of French-Canadian origin with SPSMA and an American family of English and Scottish descent with CMT2C(1,2). We mapped SPSMA and CMT2C risk loci to 12q24.1-q24.31 with an overlapping region between the two diseases(3,4). Further analysis reduced the CMT2C risk locus to a 4-Mb region(5). Here we report that SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4). Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins. Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy for these disorders. C1 [Deng, Han-Xiang; Yan, Jianhua; Shi, Yong; Fecto, Faisal; Yang, Yi; Zhai, Hong; Siddique, Nailah; Siddique, Teepu] Northwestern Univ, Feinberg Sch Med, Davee Dept Neurol & Clin Neurosci, Div Neuromuscular Med, Chicago, IL 60611 USA. [Klein, Christopher J.; Dyck, Peter J.] Mayo Clin Fdn, Dept Neurol, Div Peripheral Nerve Dis, Rochester, MN USA. [Wu, Yanhong] Mayo Clin Fdn, Dept Lab Med & Pathol, Rochester, MN USA. [Fecto, Faisal; Siddique, Teepu] Northwestern Univ, Interdept Neurosci Program, Feinberg Sch Med, Chicago, IL 60611 USA. [Yau, Hau-Jie; Martina, Marco] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Hedley-Whyte, E. Tessa] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [DeLong, Robert] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA. RP Deng, HX (reprint author), Northwestern Univ, Feinberg Sch Med, Davee Dept Neurol & Clin Neurosci, Div Neuromuscular Med, Chicago, IL 60611 USA. EM h-deng@northwestern.edu; t-siddique@northwestern.edu OI YAU, HAU-JIE/0000-0001-7454-7971 FU National Institute of Neurological Disorders and Stroke [NS050641]; Les Turner ALS Foundation; Vena E. Schaff ALS Research Fund; Harold Post Research Professorship; Herbert and Florence C. Wenske Foundation; David C. Asselin MD Memorial Fund; Help America Foundation; Les Turner ALS Foundation/Herbert C. Wenske Foundation; Epilepsy Foundation FX The authors acknowledge the support from the National Institute of Neurological Disorders and Stroke (NS050641), the Les Turner ALS Foundation, the Vena E. Schaff ALS Research Fund, the Harold Post Research Professorship, the Herbert and Florence C. Wenske Foundation, the David C. Asselin MD Memorial Fund, the Help America Foundation, the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship and the Epilepsy Foundation. We thank R.J. Miller and A. Belmadani for help with the calcium imaging studies and J. Caliendo for proofreading this manuscript. NR 31 TC 123 Z9 125 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2010 VL 42 IS 2 BP 165 EP U102 DI 10.1038/ng.509 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 549WG UT WOS:000274084400015 PM 20037587 ER PT J AU Stewart, CR Stuart, LM Wilkinson, K van Gils, JM Deng, JS Halle, A Rayner, KJ Boyer, L Zhong, RQ Frazier, WA Lacy-Hulbert, A El Khoury, J Golenbock, DT Moore, KJ AF Stewart, Cameron R. Stuart, Lynda M. Wilkinson, Kim van Gils, Janine M. Deng, Jiusheng Halle, Annett Rayner, Katey J. Boyer, Laurent Zhong, Ruiqin Frazier, William A. Lacy-Hulbert, Adam El Khoury, Joseph Golenbock, Douglas T. Moore, Kathryn J. TI CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer SO NATURE IMMUNOLOGY LA English DT Article ID ALZHEIMERS-DISEASE; SCAVENGER RECEPTORS; ASP299GLY POLYMORPHISM; SIGNALING CASCADE; APOLIPOPROTEIN-E; IMMUNE-RESPONSE; INNATE IMMUNITY; LIPID UPTAKE; ATHEROSCLEROSIS; TOLL-LIKE-RECEPTOR-4 AB In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-beta triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-beta stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events. C1 [Stuart, Lynda M.; Boyer, Laurent; Lacy-Hulbert, Adam] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp,Lab Dev Immunol, Boston, MA 02115 USA. [Halle, Annett; Golenbock, Douglas T.] Univ Massachusetts, Sch Med, Dept Immunol & Infect Dis, Worcester, MA USA. [Zhong, Ruiqin; Frazier, William A.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [El Khoury, Joseph] Harvard Univ, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Sch Med, Charlestown, MA USA. [Stewart, Cameron R.; Wilkinson, Kim; van Gils, Janine M.; Deng, Jiusheng; Rayner, Katey J.; Moore, Kathryn J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Lipid Metab Unit, Boston, MA USA. RP Moore, KJ (reprint author), NYU, Sch Med, Dept Med, Leon H Charney Div Cardiol, New York, NY 10003 USA. EM kathryn.moore@nyumc.org RI Stewart, Cameron/E-6823-2011; Rayner, Katey/K-8914-2012; Boyer, laurent/F-8921-2015; OI Boyer, laurent/0000-0002-1375-1706; Lacy-Hulbert, Adam/0000-0003-2162-0156; Moore, kathryn/0000-0003-2505-2547 FU US National Institutes of Health [R01AG20255, R01NS059005, R01 AG032349]; Ellison Medical Foundation; American Health Assistance Foundation [A2008-130]; Wellcome Trust [068089/Z/02/Z] FX We thank S. Akira (Osaka University) and K. Miyake (Japan Science and Technology Agency) for knockout mice. Supported by the US National Institutes of Health (R01AG20255 to K. J. M.; R01NS059005 to J. E. K.; R01 AG032349 to K. J. M. and J. E. K.), the Ellison Medical Foundation (K. J. M.), the American Health Assistance Foundation (A2008-130 to K. J. M.) and the Wellcome Trust (068089/Z/02/Z to L. M. S.). NR 42 TC 494 Z9 512 U1 4 U2 56 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2010 VL 11 IS 2 BP 155 EP U75 DI 10.1038/ni.1836 PG 8 WC Immunology SC Immunology GA 545KF UT WOS:000273730200013 PM 20037584 ER PT J AU Hettmer, S Wagers, AJ AF Hettmer, Simone Wagers, Amy J. TI Muscling in Uncovering the origins of rhabdomyosarcoma SO NATURE MEDICINE LA English DT Editorial Material ID ALVEOLAR RHABDOMYOSARCOMA; STEM-CELLS; MOUSE; GENE C1 [Hettmer, Simone; Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Hettmer, Simone; Wagers, Amy J.] Joslin Diabet Ctr, Cambridge, MA USA. [Hettmer, Simone] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hettmer, Simone] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. RP Hettmer, S (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM amy.wagers@joslin.harvard.edu FU Howard Hughes Medical Institute NR 14 TC 48 Z9 49 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2010 VL 16 IS 2 BP 171 EP 173 DI 10.1038/nm0210-171 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 552MZ UT WOS:000274297000037 PM 20134473 ER PT J AU Li, Y Zou, LH Li, QY Haibe-Kains, B Tian, RY Li, Y Desmedt, C Sotiriou, C Szallasi, Z Iglehart, JD Richardson, AL Wang, ZC AF Li, Yang Zou, Lihua Li, Qiyuan Haibe-Kains, Benjamin Tian, Ruiyang Li, Yan Desmedt, Christine Sotiriou, Christos Szallasi, Zoltan Iglehart, J. Dirk Richardson, Andrea L. Wang, Zhigang Charles TI Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer SO NATURE MEDICINE LA English DT Article ID GENE-EXPRESSION PROFILES; MULTIDRUG-RESISTANCE; HISTOLOGIC GRADE; SURVIVAL; SIGNATURE; TUMORS; ABERRATIONS; 14-3-3-ZETA; METASTASIS; PREDICTION AB Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates(1). However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes(2). By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy. C1 [Li, Yang; Zou, Lihua; Tian, Ruiyang; Li, Yan; Iglehart, J. Dirk; Richardson, Andrea L.; Wang, Zhigang Charles] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Li, Yang; Iglehart, J. Dirk; Wang, Zhigang Charles] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Zou, Lihua] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Li, Qiyuan; Szallasi, Zoltan] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Haibe-Kains, Benjamin; Desmedt, Christine; Sotiriou, Christos] Inst Jules Bordet, Dept Med Oncol, B-1000 Brussels, Belgium. [Haibe-Kains, Benjamin] Univ Libre Bruxelles, Machine Learning Grp, Brussels, Belgium. [Szallasi, Zoltan] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Childrens Hosp Informat Program, Boston, MA USA. [Richardson, Andrea L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Richardson, AL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM arichardson@partners.org; zhigang_wang@dfci.harvard.edu RI Zou, Lihua/E-6748-2010; Haibe-Kains, Benjamin/D-3702-2011; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Szallasi, Zoltan/0000-0001-5395-7509; Desmedt, Christine/0000-0002-5223-5579 FU NCI NIH HHS [BC053041, CA89393, P50 CA089393, P50 CA089393-01, P50 CA089393-10] NR 36 TC 148 Z9 149 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2010 VL 16 IS 2 BP 214 EP U121 DI 10.1038/nm.2090 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 552MZ UT WOS:000274297000043 PM 20098429 ER PT J AU Houghton, AM Rzymkiewicz, DM Ji, HB Gregory, AD Egea, EE Metz, HE Stolz, DB Land, SR Marconcini, LA Kliment, CR Jenkins, KM Beaulieu, KA Mouded, M Frank, SJ Wong, KK Shapiro, SD AF Houghton, A. McGarry Rzymkiewicz, Danuta M. Ji, Hongbin Gregory, Alyssa D. Egea, Eduardo E. Metz, Heather E. Stolz, Donna B. Land, Stephanie R. Marconcini, Luiz A. Kliment, Corrine R. Jenkins, Kimberly M. Beaulieu, Keith A. Mouded, Majd Frank, Stuart J. Wong, Kwok K. Shapiro, Steven D. TI Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth SO NATURE MEDICINE LA English DT Article ID INSULIN-RECEPTOR SUBSTRATE-1; LEUKOCYTE ELASTASE; G972R VARIANT; K-RAS; CANCER; INTERLEUKIN-8; ASSOCIATION; EXPRESSION; PHOSPHORYLATION; INFLAMMATION AB Lung cancer is the leading cause of cancer death worldwide(1). Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness(2,3). To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma(4) to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling. C1 [Houghton, A. McGarry; Gregory, Alyssa D.; Egea, Eduardo E.; Metz, Heather E.; Kliment, Corrine R.; Jenkins, Kimberly M.; Beaulieu, Keith A.; Mouded, Majd; Shapiro, Steven D.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA. [Houghton, A. McGarry; Gregory, Alyssa D.; Egea, Eduardo E.; Metz, Heather E.; Jenkins, Kimberly M.; Beaulieu, Keith A.; Mouded, Majd; Shapiro, Steven D.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Houghton, A. McGarry; Stolz, Donna B.; Land, Stephanie R.; Shapiro, Steven D.] Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA USA. [Rzymkiewicz, Danuta M.; Marconcini, Luiz A.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Ji, Hongbin] Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China. [Ji, Hongbin] Chinese Acad Sci, Shanghai, Peoples R China. [Stolz, Donna B.] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA USA. [Land, Stephanie R.] Univ Pittsburgh, Sch Med, Dept Biostat, Pittsburgh, PA USA. [Frank, Stuart J.] Univ Alabama, Div Endocrinol Diabet & Metab, Birmingham, AL USA. [Wong, Kwok K.] Dana Farber Canc Inst, Dept Med, Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA. [Wong, Kwok K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wong, Kwok K.] Harvard Univ, Sch Med, Boston, MA USA. RP Houghton, AM (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA. EM houghtonm@dom.pitt.edu FU US National Institutes of Health National Heart, Lung, and Blood Institute [K08HL085286, RO1HL054853, RO1DK058259] FX This work was supported by grants K08HL085286 and RO1HL054853 from the US National Institutes of Health National Heart, Lung, and Blood Institute ( A. M. H. and S. D. S.) and by grant RO1DK058259 from the US National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (S.J.F.). ONO Pharmaceutical provided the ONO-5046. LSL-K-ras mice were provided by T. Jacks ( Massachusetts Institute of Technology). AdenoCre was obtained from the University of Iowa Gene Transfer Vector Core. We would like to recognize members of the Shapiro lab for their assistance and comments regarding the preparation of this manuscript. NR 32 TC 160 Z9 169 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2010 VL 16 IS 2 BP 219 EP U127 DI 10.1038/nm.2084 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 552MZ UT WOS:000274297000044 PM 20081861 ER PT J AU Joung, JK Voytas, DF Cathomen, T AF Joung, J. Keith Voytas, Daniel F. Cathomen, Toni TI Genome editing with modularly assembled zinc-finger nucleases reply SO NATURE METHODS LA English DT Letter C1 [Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA 02129 USA. [Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Voytas, Daniel F.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA. [Voytas, Daniel F.] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN USA. [Cathomen, Toni] Hannover Med Sch, Dept Expt Hematol, D-3000 Hannover, Germany. RP Joung, JK (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA 02129 USA. EM jjoung@partners.org; voytas@umn.edu; cathomen.toni@mh-hannover.de NR 7 TC 16 Z9 16 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD FEB PY 2010 VL 7 IS 2 BP 91 EP 92 DI 10.1038/nmeth0210-91b PG 3 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 549WW UT WOS:000274086200004 ER PT J AU Neal, JW Sequist, LV AF Neal, Joel W. Sequist, Lecia V. TI TARGETED THERAPIES Optimal first-line therapy for NSCLC with EGFR mutations SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; GEFITINIB; ERLOTINIB C1 [Neal, Joel W.; Sequist, Lecia V.] Massachusetts Gen Hosp, Ctr Canc, Ctr Thorac Canc, Boston, MA 02114 USA. [Neal, Joel W.; Sequist, Lecia V.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Sequist, LV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Thorac Canc, 32 Fruit St,Suite 7B, Boston, MA 02114 USA. EM lvsequist@partners.org NR 10 TC 5 Z9 5 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD FEB PY 2010 VL 7 IS 2 BP 70 EP 71 DI 10.1038/nrclinonc.2009.191 PG 2 WC Oncology SC Oncology GA 549VO UT WOS:000274082600002 PM 20118973 ER PT J AU Lantermann, AB Straub, T Stralfors, A Yuan, GC Ekwall, K Korber, P AF Lantermann, Alexandra B. Straub, Tobias Stralfors, Annelie Yuan, Guo-Cheng Ekwall, Karl Korber, Philipp TI Schizosaccharomyces pombe genome-wide nucleosome mapping reveals positioning mechanisms distinct from those of Saccharomyces cerevisiae SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID DIFFERENTIAL COFACTOR REQUIREMENTS; TRANSCRIPTION FACTOR-BINDING; HISTONE-DNA INTERACTIONS; FISSION YEAST DNA; CHROMATIN STRUCTURE; HIGH-RESOLUTION; IN-VIVO; ORGANIZATION; PROMOTERS; GENES AB Positioned nucleosomes limit the access of proteins to DNA and implement regulatory features encoded in eukaryotic genomes. Here we have generated the first genome-wide nucleosome positioning map for Schizosaccharomyces pombe and annotated transcription start and termination sites genome wide. Using this resource, we found surprising differences from the previously published nucleosome organization of the distantly related yeast Saccharomyces cerevisiae. DNA sequence guides nucleosome positioning differently: for example, poly(dA-dT) elements are not enriched in S. pombe nucleosome-depleted regions. Regular nucleosomal arrays emanate more asymmetrically-mainly codirectionally with transcription-from promoter nucleosome-depleted regions, but promoters harboring the histone variant H2A.Z also show regular arrays upstream of these regions. Regular nucleosome phasing in S. pombe has a very short repeat length of 154 base pairs and requires a remodeler, Mit1, that is conserved in humans but is not found in S. cerevisiae. Nucleosome positioning mechanisms are evidently not universal but evolutionarily plastic. C1 [Stralfors, Annelie; Ekwall, Karl] Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci NOVUM, Huddinge, Sweden. [Lantermann, Alexandra B.; Straub, Tobias; Korber, Philipp] Univ Munich, Adolf Butenandt Inst, Munich, Germany. [Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Ekwall, K (reprint author), Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci NOVUM, Huddinge, Sweden. EM karl.ekwall@ki.se; pkorber@lmu.de RI Straub, Tobias/B-2023-2009 OI Straub, Tobias/0000-0002-0547-0453 FU German Research Community; European Union; Swedish Cancer Society; Swedish Research Council; Claudia Adams Barr Program FX We thank H. Bhuiyan and J. Walfridsson for generating the S. pombe expression data during their work in the group of K. Ekwall, R. R. Barrales (group of J. J. Ibeas, Universidad Pablo de Olavide, Sevilla, Spain) for bringing the first S. pombe strains into the Korber group, F. Thoma (ETH Zurich, Switzerland) for advice on chromatin analysis in S. pombe, F. Fagerstrom-Billai at the BEA microarray facility at Novum, Karolinska Institutet, for assistance, and F. Muller-Planitz (Adolf-Butenandt-Institut, Univ. Munich) for help with MATLAB. We are grateful for the communication of replication origin coordinates by C. Heichinger (Univ. Zurich) and of TSS coordinates by W. Lee (Stanford Univ.) and N. Dutrow (Univ. Utah). We thank H. Madhani and co-workers (Univ. California San Francisco) for sharing data before publication and for comments on the manuscript. This work was funded by the German Research Community (Transregio 5; P. K. and co-workers), the 6th Framework Programme of the European Union (NET programme; P. K. and K. E. and co-workers), the Swedish Cancer Society and Swedish Research Council (K. E. laboratory) and the Claudia Adams Barr Program (G.-C. Y.). NR 56 TC 133 Z9 134 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD FEB PY 2010 VL 17 IS 2 BP 251 EP U15 DI 10.1038/nsmb.1741 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 551RZ UT WOS:000274228400021 PM 20118936 ER PT J AU Clauss, A Ng, V Liu, J Piao, HY Russo, M Vena, N Sheng, Q Hirsch, MS Bonome, T Matulonis, U Ligon, AH Birrer, MJ Drapkin, R AF Clauss, Adam Ng, Vivian Liu, Joyce Piao, Huiying Russo, Moises Vena, Natalie Sheng, Qing Hirsch, Michelle S. Bonome, Tomas Matulonis, Ursula Ligon, Azra H. Birrer, Michael J. Drapkin, Ronny TI Overexpression of Elafin in Ovarian Carcinoma Is Driven by Genomic Gains and Activation of the Nuclear Factor kappa B Pathway and Is Associated with Poor Overall Survival SO NEOPLASIA LA English DT Article ID LEUKOCYTE PROTEASE INHIBITOR; ELASTASE-SPECIFIC INHIBITOR; MAMMARY EPITHELIAL-CELLS; IMMUNOHISTOCHEMICAL EXPRESSION; DIFFERENTIAL EXPRESSION; PROTEINASE-INHIBITORS; CANCER CELLS; GENES; IDENTIFICATION; SKALP/ELAFIN AB Ovarian cancer is a leading cause of cancer mortality in women. The aim of this study was to elucidate whether whey acidic protein (WAP) genes on chromosome 20q13.12, a region frequently amplified in this cancer, are expressed in serous carcinoma, the most common form of the disease. Herein, we report that a trio of WAP genes (HE4, SLPI, and Elafin) is overexpressed and secreted by serous ovarian carcinomas. To our knowledge, this is the first report linking Elafin to ovarian cancer. Fluorescence in situ hybridization analysis of primary tumors demonstrates genomic gains of the Elafin locus in a majority of cases. In addition, a combination of peptidomimetics, RNA interference, and chromatin immunoprecipitation experiments shows that Elafin expression can be transcriptionally upregulated by inflammatory cytokines through activation of the nuclear factor kappa B pathway. Importantly, using a clinically annotated tissue microarray composed of late-stage, high-grade serous ovarian carcinomas, we show that Elafin expression correlates with poor overall survival. These results, combined with our observation that Elafin is secreted by ovarian tumors and is minimally expressed in normal tissues, suggest that Elafin may serve as a determinant of poor survival in this disease. C1 [Clauss, Adam; Ng, Vivian; Liu, Joyce; Piao, Huiying; Russo, Moises; Matulonis, Ursula; Drapkin, Ronny] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Clauss, Adam; Liu, Joyce; Russo, Moises; Sheng, Qing; Hirsch, Michelle S.; Matulonis, Ursula; Ligon, Azra H.; Birrer, Michael J.; Drapkin, Ronny] Harvard Univ, Sch Med, Boston, MA USA. [Vena, Natalie; Ligon, Azra H.; Drapkin, Ronny] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Sheng, Qing] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Hirsch, Michelle S.; Ligon, Azra H.; Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bonome, Tomas] NIH, Mol Mech Sect, Bethesda, MD 20892 USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Drapkin, R (reprint author), Dana Farber Canc Inst, Dept Med Oncol, JF215D,44 Binney St, Boston, MA 02115 USA. EM ronny_drapkin@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU National Cancer Institute (NCI) [P50-CA105009, K08 CA108748, K12 CA87723]; Robert and Deborah First Fund; Randi and Joel Cutler Ovarian Cancer Research Fund; Fannie E. Ripple Foundation; Phi Beta Psi Sorority Charitable Trust; Ovarian Cancer Research Fund; Madeline Franchi Ovarian Cancer Foundation; Harvard Medical School Center of Excellence in Women's Health FX This work was supported by National Cancer Institute (NCI) P50-CA105009 SPORE in Ovarian Cancer (Career Development Award, to R.D.), NCI K08 CA108748 (R.D.), NCI K12 CA87723 (J.L.), The Robert and Deborah First Fund (R.D.), The Randi and Joel Cutler Ovarian Cancer Research Fund ( R. D.), The Fannie E. Ripple Foundation (R.D. and U.M.), Phi Beta Psi Sorority Charitable Trust (R.D.), Ovarian Cancer Research Fund (A.C. and R. D.), The Madeline Franchi Ovarian Cancer Foundation (A.C.), and the Harvard Medical School Center of Excellence in Women's Health Award (M.S.H. and U.M.). NR 47 TC 35 Z9 38 U1 0 U2 1 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD FEB PY 2010 VL 12 IS 2 BP 161 EP U88 DI 10.1593/neo.91542 PG 14 WC Oncology SC Oncology GA 554AX UT WOS:000274409000006 PM 20126474 ER PT J AU Odden, MC Tager, IB Gansevoort, RT Bakker, SJL Katz, R Fried, LF Newman, AB Canada, RB Harris, T Sarnak, MJ Siscovick, D Shlipak, MG AF Odden, Michelle C. Tager, Ira B. Gansevoort, Ron T. Bakker, Stephan J. L. Katz, Ronit Fried, Linda F. Newman, Anne B. Canada, Robert B. Harris, Tamara Sarnak, Mark J. Siscovick, David Shlipak, Michael G. TI Age and cystatin C in healthy adults: a collaborative study SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE ageing; chronic kidney disease; cystatin C; epidemiology ID URINARY ALBUMIN EXCRETION; SERUM CREATININE; RENAL-FUNCTION; PULMONARY-FUNCTION; KIDNEY-FUNCTION; UNITED-STATES; DISEASE; DYSFUNCTION; POPULATION; DECLINE AB Methods. The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. Results. Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those < 40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction). Conclusions. There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons. C1 [Odden, Michelle C.; Tager, Ira B.] Univ Calif Berkeley, Sch Publ Hlth, Dept Epidemiol, Berkeley, CA 94720 USA. [Odden, Michelle C.] Univ Calif San Francisco, Dept Gen Internal Med, San Francisco, CA 94143 USA. [Gansevoort, Ron T.; Bakker, Stephan J. L.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, Groningen, Netherlands. [Katz, Ronit] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Fried, Linda F.] Vet Affairs Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Sch Med, Dept Epidemiol, Pittsburgh, PA USA. [Canada, Robert B.] Univ Tennessee, Ctr Hlth Sci, Dept Med, Memphis, TN 38163 USA. [Canada, Robert B.] Univ Tennessee, Ctr Hlth Sci, Dept Nephrol, Memphis, TN 38163 USA. [Harris, Tamara] NIA, Lab Epidemiol, Demog Biometry Program, NIH, Bethesda, MD 20892 USA. [Sarnak, Mark J.] Tufts Med Ctr, Dept Med, Div Nephrol, Boston, MA USA. [Siscovick, David] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA USA. RP Odden, MC (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Dept Epidemiol, Berkeley, CA 94720 USA. EM michelle.odden@ucsf.edu RI Newman, Anne/C-6408-2013; Bakker, Stephan/J-4023-2015 OI Newman, Anne/0000-0002-0106-1150; Bakker, Stephan/0000-0003-3356-6791 FU National Heart, Lung and Blood Institute [N01HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01-HL-63963-01A1, N01-HC-95159, N01-HC-95165, N01-HC-95169]; National Institute on Aging [N01-AG-6-2101, N01AG-6-2103, N01-AG-6-2106, R01AG027002]; NIH, National Institute on Aging; Dutch Kidney Foundation, Bussum, The Netherlands [E013]; National Institute of Diabetes and Digestive, and Kidney Diseases [T32DK07791, DK52866]; institutional Health Resources & Services Administration National Research Service Award [T32HP19025]; American Federation for Aging Research; Robert Wood Johnson Foundation; American Heart Association FX CHS was supported by contract numbers N01HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant number U01 HL080295 from the National Heart, Lung and Blood Institute, 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. Health ABC was supported through the National Institute on Aging contracts N01-AG-6-2101, N01AG-6-2103 and N01-AG-6-2106 and in part by the Intramural Research Program of the NIH, National Institute on Aging. MESA was supported by grant R01-HL-63963-01A1 and by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung and Blood Institute. PREVEND is supported by grant E013 of the Dutch Kidney Foundation, Bussum, The Netherlands, and grants T32DK07791 and DK52866 from the National Institute of Diabetes and Digestive, and Kidney Diseases. This project was also supported by grant R01AG027002 from the National Institutes on Aging. Dr Odden is supported by an institutional Health Resources & Services Administration National Research Service Award (T32HP19025). Dr Shlipak was supported by the American Federation for Aging Research and National Institute on Aging (Paul Beeson Scholars Program), by the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program), and the American Heart Association. NR 34 TC 28 Z9 29 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD FEB PY 2010 VL 25 IS 2 BP 463 EP 469 DI 10.1093/ndt/gfp474 PG 7 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 547LY UT WOS:000273891600024 PM 19749145 ER PT J AU Salat, DH Tuch, DS van der Kouwe, AJW Greve, DN Pappu, V Lee, SY Hevelone, ND Zaleta, AK Growdon, JH Corkin, S Fischl, B Rosas, HD AF Salat, D. H. Tuch, D. S. van der Kouwe, A. J. W. Greve, D. N. Pappu, V. Lee, S. Y. Hevelone, N. D. Zaleta, A. K. Growdon, J. H. Corkin, S. Fischl, B. Rosas, H. D. TI White matter pathology isolates the hippocampal formation in Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer; Aging; Diffusion tensor imaging; Fractional anisotropy; Diffusivity; MRI; White matter; Dementia; Hippocampus; Entorhinal; Memory; Axial diffusivity; Radial diffusivity; Tractography; Volume; Hyperintensities; T2; Myelin; Axon ID MILD COGNITIVE IMPAIRMENT; DIFFUSION-TENSOR MRI; MEMORY IMPAIRMENT; TEMPORAL-LOBE; SPIN-ECHO; IN-VIVO; DEMENTIA; BRAIN; AGE; CORTEX AB Prior work has demonstrated that the memory dysfunction of Alzheimer's disease (AD) is accompanied by marked cortical pathology in medial temporal lobe (MTL) gray matter. In contrast, changes in white matter (WM) of pathways associated with the MTL have rarely been studied. We used diffusion tensor imaging (DTI) to examine regional patterns of WM tissue changes in individuals with AD. Alterations of diffusion properties with AD were found in several regions including parahippocampal WM, and in regions with direct and secondary connections to the MTL. A portion of the changes measured, including effects in the parahippocampal WM, were independent of gray matter degeneration as measured by hippocampal volume. Examination of regional changes in unique diffusion parameters including anisotropy and axial and radial diffusivity demonstrated distinct zones of alterations, potentially stemming from differences in underlying pathology, with a potential myelin specific pathology in the parahippocampal WM. These results demonstrate that deterioration of neocortical connections to the hippocampal formation results in part from the degeneration of critical MTL and associated fiber pathways. (C) 2008 Elsevier Inc. All rights reserved. C1 [Salat, D. H.] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, MGH Dept Radiol, Charlestown, MA 02129 USA. [Salat, D. H.; Tuch, D. S.; van der Kouwe, A. J. W.; Greve, D. N.; Fischl, B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Pappu, V.; Lee, S. Y.; Hevelone, N. D.; Zaleta, A. K.; Growdon, J. H.; Rosas, H. D.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Corkin, S.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Salat, DH (reprint author), MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, MGH Dept Radiol, Bldg 149,13th St,Mail Code 149 2301, Charlestown, MA 02129 USA. EM salat@nmr.mgh.harvard.edu OI Hevelone, Nathanael/0000-0003-4740-2085 FU NIH [K01 AG024898]; Massachusetts Alzheimer's Disease Research Center Pilot [AG05886]; National Center for Research Resources [P41RR14075]; Mental Illness and Neuroscience Discovery (MIND) Institute; National Alliance for Medical Image Computing (NAMIC) [U54 EB05149] FX This work was supported in part by NIH K01 AG024898, a Massachusetts Alzheimer's Disease Research Center Pilot Grant 2001/2002 (AG05886), the National Center for Research Resources (P41RR14075), the Mental Illness and Neuroscience Discovery (MIND) Institute, and a grant from the National Alliance for Medical Image Computing (NAMIC U54 EB05149). We thank Dr. Francine Grodstein and the Nurses' Health Study for a portion of the participant recruitment and imaging. NR 90 TC 148 Z9 150 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2010 VL 31 IS 2 BP 244 EP 256 DI 10.1016/j.neurobiolaging.2008.03.013 PG 13 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 584NN UT WOS:000276759400006 PM 18455835 ER PT J AU Lopez-Meraz, ML Wasterlain, CG Rocha, LL Allen, S Niquet, J AF Lopez-Meraz, Maria-Leonor Wasterlain, Claude G. Rocha, Luisa L. Allen, Suni Niquet, Jerome TI Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Necrosis; Apoptosis; Caspase; Doublecortin; Hippocampus; Status epilepticus; Pilocarpine; Development ID PILOCARPINE STATUS EPILEPTICUS; LONG-TERM POTENTIATION; Q-VD-OPH; CELL-DEATH; RAT HIPPOCAMPUS; DENTATE GYRUS; CASPASE INHIBITOR; IMMATURE RATS; NEONATAL-RAT; CA1 REGION AB The mechanism of status epilepticus-induced neuronal death in the immature brain is not fully understood. In the present study, we examined the contribution of caspases in our lithium-pilocarpine model of status epilepticus in 14 days old rat pups. In CA1, upregulation of caspase-8, but not caspase-9, preceded caspase-3 activation in morphologically necrotic cells. Pretreatment with a pan-caspase inhibitor provided neuroprotection, showing that caspase activation was not an epiphenomenon but contributed to neuronal necrosis. By contrast, upregulation of active caspase-9 and caspase-3, but not caspase-8, was detected in apoptotic dentate gyrus neurons. which were immunoreactive for doublecortin and calbindin-negative, two features of immature neurons. These results suggest that, in cells which are aligned in series as parts of the same excitatory hippocampal circuit, the same seizures induce neuronal death through different mechanisms. The regional level of neuronal maturity may be a determining factor in the execution of a specific death program. (c) 2009 Elsevier Inc. All rights reserved. C1 [Lopez-Meraz, Maria-Leonor; Wasterlain, Claude G.; Allen, Suni; Niquet, Jerome] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Lopez-Meraz, Maria-Leonor; Wasterlain, Claude G.; Allen, Suni; Niquet, Jerome] VA Greater Los Angeles Healthcare Syst, Epilepsy Res Lab, Los Angeles, CA 90073 USA. [Wasterlain, Claude G.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Rocha, Luisa L.] Ctr Res & Adv Studies, Pharmacobiol Dept, Mexico City, DF, Mexico. [Lopez-Meraz, Maria-Leonor] Univ Veracruzana, Programa Neurobiol, Xalapa 91000, Veracruz, Mexico. RP Niquet, J (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. EM jniquet@ucla.edu FU Epilepsy Foundation; VHA Research Service; NINDS [R01 NS13515]; UC MEXUS-CONACyT FX This work is supported by Epilepsy Foundation (JN), VHA Research Service (CW), NINDS (grant R01 NS13515; CW), and UC MEXUS-CONACyT (CW and LR). MLLM received a UC MEXUS-CONACYT postdoctoral fellowship. NR 44 TC 24 Z9 25 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2010 VL 37 IS 2 SI SI BP 394 EP 402 DI 10.1016/j.nbd.2009.10.019 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 551QP UT WOS:000274224400019 PM 19879360 ER PT J AU Sheth, KN Cushing, TA Wendell, L Lev, MH Romero, JM Schwab, K Smith, EE Greenberg, SM Rosand, J Goldstein, JN AF Sheth, Kevin N. Cushing, Tracy A. Wendell, Lauren Lev, Michael H. Romero, Javier M. Schwab, Kristin Smith, Eric E. Greenberg, Steven M. Rosand, Jonathan Goldstein, Joshua N. TI Comparison of Hematoma Shape and Volume Estimates in Warfarin Versus Non-Warfarin-Related Intracerebral Hemorrhage SO NEUROCRITICAL CARE LA English DT Article DE Cerebral hemorrhage; Tomography; X-ray computed; Warfarin ID ABC/2 ESTIMATION TECHNIQUE; ACTIVATED FACTOR-VII; ENLARGEMENT; PREDICTORS; SCORE AB Background Hematoma volume is a major determinant of outcome in patients with intracerebral hemorrhage (ICH). Accurate volume measurements are critical for predicting outcome and are thought to be more difficult in patients with oral anticoagulation-related ICH (OAT-ICH) due to a higher frequency of irregular shape. We examined hematoma shape and methods of volume assessment in patients with OAT-ICH. Methods We performed a case-control analysis of a prospectively identified cohort of consecutive patients with ICH. We retrospectively reviewed 50 consecutive patients with OAT-ICH and 50 location-matched non-OAT-ICH controls. Two independent readers analyzed CT scans for hematoma shape and volume using both ABC/2 and ABC/3 methods. Readers were blinded to all clinical variables including warfarin status. Gold-standard ICH volumes were determined using validated computer-assisted planimetry. Results Within this cohort, median INR in patients with OAT-ICH was 3.2. Initial ICH volume was not significantly different between non-OAT-ICH and OAT-ICH (35 +/- 38 cc vs. 53 +/- 56 cc, P = 0.4). ICH shape did not differ by anticoagulation status (round shape in 10% of OAT-ICH vs. 16% of non-OAT-ICH, P = 0.5). The ABC/3 calculation underestimated median volume by 9 (3-28) cc, while the ABC/2 calculation did so by 4 (0.8-12) cc. Conclusions Hematoma shape was not statistically significantly different in patients with OAT-ICH. Among bedside approaches, the standard ABC/2 method offers reasonable approximation of hematoma volume in OAT-ICH and non-OAT-ICH. C1 [Sheth, Kevin N.] Univ Maryland, Med Ctr, Div Neurol, Baltimore, MD 21201 USA. [Wendell, Lauren; Schwab, Kristin; Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cushing, Tracy A.] Mt Auburn Hosp, Dept Emergency Med, Boston, MA USA. [Lev, Michael H.; Romero, Javier M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Smith, Eric E.; Rosand, Jonathan] Univ Calgary, Dept Clin Neurosci, Calgary Stroke Program, Calgary, AB, Canada. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Sheth, KN (reprint author), Univ Maryland, Med Ctr, Div Neurol, Baltimore, MD 21201 USA. EM ksheth@som.umaryland.edu RI Goldstein, Joshua/H-8953-2016; OI Smith, Eric/0000-0003-3956-1668 FU National Institute of Neurological Disorders and Stroke [R01 NS059727, K23NS059774]; Deane Institute for Integrative Study of Atrial Fibrillation and Stroke FX Funding was provided by The National Institute of Neurological Disorders and Stroke (NIH R01 NS059727 and K23NS059774), American Heart Association Grant-in-Aid # 0755984T, and the Deane Institute for Integrative Study of Atrial Fibrillation and Stroke. NR 21 TC 16 Z9 17 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 J9 NEUROCRIT CARE JI Neurocrit. Care PD FEB PY 2010 VL 12 IS 1 BP 30 EP 34 DI 10.1007/s12028-009-9296-7 PG 5 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA 571HL UT WOS:000275742800006 PM 19859832 ER PT J AU Parkman, HP Camilleri, M Farrugia, G McCallum, RW Bharucha, AE Mayer, EA Tack, JF Spiller, R Horowitz, M Vinik, AI Galligan, JJ Pasricha, PJ Kuo, B Szarka, LA Marciani, L Jones, K Parrish, CR Sandroni, P Abell, T Ordog, T Hasler, W Koch, KL Sanders, K Norton, NJ Hamilton, F AF Parkman, H. P. Camilleri, M. Farrugia, G. McCallum, R. W. Bharucha, A. E. Mayer, E. A. Tack, J. F. Spiller, R. Horowitz, M. Vinik, A. I. Galligan, J. J. Pasricha, P. J. Kuo, B. Szarka, L. A. Marciani, L. Jones, K. Parrish, C. R. Sandroni, P. Abell, T. Ordog, T. Hasler, W. Koch, K. L. Sanders, K. Norton, N. J. Hamilton, F. TI Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Review DE functional dyspepsia; gastric emptying; gastroparesis ID NITRIC-OXIDE SYNTHASE; GASTRIC-ELECTRICAL-STIMULATION; IRRITABLE-BOWEL-SYNDROME; CARDINAL SYMPTOM INDEX; UPPER GASTROINTESTINAL DISORDERS; DEPENDENT DIABETES-MELLITUS; GLYCATION END-PRODUCTS; ENTERIC NERVOUS-SYSTEM; QUALITY-OF-LIFE; INTERSTITIAL-CELLS AB P>Background Despite the relatively high prevelance of gastroparesis and functional dyspepsia, the aetiology and pathophysiology of these disorders remain incompletely understood. Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders. Purpose This manuscript reviews the advances in the understanding of the epidemiology, pathophysiology, diagnosis, and treatment of gastroparesis and functional dyspepsia as discussed at a recent conference sponsored by the American Gastroenterological Association (AGA) and the American Neurogastroenterology and Motility Society (ANMS). Particular focus is placed on discussing unmet needs and areas for future research. C1 [Parkman, H. P.] Temple Univ, Sch Med, Gastroenterol Sect, Dept Med, Philadelphia, PA 19140 USA. [Camilleri, M.; Farrugia, G.; Bharucha, A. E.; Szarka, L. A.] Mayo Clin, Coll Med, Dept Med, Rochester, MN USA. [McCallum, R. W.] Univ Texas El Paso, Dept Med, El Paso, TX 79968 USA. [Mayer, E. A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Tack, J. F.] Univ Hosp, Dept Med, Louvain, Belgium. [Spiller, R.] Univ Hosp, Dept Med, Nottingham, England. [Horowitz, M.; Jones, K.] Univ Adelaide, Dept Med, Adelaide, SA 5001, Australia. [Vinik, A. I.] Eastern Virginia Med Sch, Dept Med, Norfolk, VA 23501 USA. [Galligan, J. J.] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA. [Pasricha, P. J.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Kuo, B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Marciani, L.] Queens Med Ctr, Dept Radiol, Nottingham NG7 2UH, England. [Parrish, C. R.] Univ Virginia Hlth Syst, Dept Nutr, Charlottesville, VA USA. [Sandroni, P.] Mayo Clin, Coll Med, Dept Neurol, Rochester, MN USA. [Abell, T.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Ordog, T.] Mayo Clin, Coll Med, Dept Physiol, Rochester, MN USA. [Hasler, W.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Koch, K. L.] Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Winston Salem, NC 27103 USA. [Sanders, K.] Univ Nevada, Dept Physiol, Reno, NV USA. [Norton, N. J.] Int Fdn Funct Disorders, Milwaukee, MN USA. [Hamilton, F.] NIH, Bethesda, MD 20892 USA. RP Parkman, HP (reprint author), Temple Univ, Sch Med, Gastroenterol Sect, Dept Med, Parkinson Pavil,8th Floor,3401 N Broad St, Philadelphia, PA 19140 USA. EM henry.parkman@temple.edu OI spiller, robin/0000-0001-6371-4500; Marciani, Luca/0000-0001-9092-4300; Jones, Karen/0000-0002-1155-5816 FU NIDDK NIH HHS [R01 DK058185, P01 DK068055, R01 DK058185-08] NR 187 TC 58 Z9 63 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD FEB PY 2010 VL 22 IS 2 BP 113 EP 133 DI 10.1111/j.1365-2982.2009.01434.x PG 21 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 540WH UT WOS:000273370800004 PM 20003077 ER PT J AU Mulert, C Leicht, G Hepp, P Kirsch, V Karch, S Pogarell, O Reiser, M Hegerl, U Jager, L Moller, HJ McCarley, RW AF Mulert, C. Leicht, G. Hepp, P. Kirsch, V. Karch, S. Pogarell, O. Reiser, M. Hegerl, U. Jaeger, L. Moller, H. J. McCarley, R. W. TI Single-trial coupling of the gamma-band response and the corresponding BOLD signal SO NEUROIMAGE LA English DT Article ID ANTERIOR CINGULATE CORTEX; SIMULTANEOUS EEG-FMRI; EVENT-RELATED POTENTIALS; BRAIN ACTIVITY; AUDITORY-CORTEX; ALPHA-RHYTHM; SIMULTANEOUS EEG/FMRI; SELECTIVE ATTENTION; TARGET DETECTION; TASK-DIFFICULTY AB Oscillations in the gamma-band frequency range have been described to be more closely connected to hemodynamic changes as assessed with functional magnetic resonance imaging (fMRI) than other aspects of neuronal activity. In addition. gamma-band oscillations have attracted much interest during the last few years since they are thought to play a Crucial role in many aspects of brain function related to perception and cognition. It was the aim of the present simultaneous EEG-fMRI Study to identify brain regions specifically involved in the generation of the auditory gamma-band response (GBR) using single-trial coupling of EEG and fMRI. Ten healthy Subjects participated in this study Three different runs of an auditory choice reaction task with increasing difficulty were performed Brain activity was recorded simultaneously with high density FEG (61 channels) and fMRI (1.5 T). BOLD correlates of the GBR have been predicted using the sing-le-trial amplitude of the GBR Reaction times (p<0.001). error rates (p<005) and self-ratings of task difficulty and effort demands (p<0.001) were related to the level of difficulty in the task In addition,we found a significant influence of task difficulty oil the amplitude of the GBR at Cz (p<0.05). Using single-trial Coupling of EEG and fMRI GBR-specific activations were found only in the auditory cortex, the thalamus and the anterior cingulate cortex (ACC) in the most difficult run. Single-trial coupling might be a useful method in order to increase our knowledge about the functional neuroanatomy of "neural ensembles" coupled by 40 Hz oscillations (C) 2009 Elsevier Inc. All rights reserved C1 [Mulert, C.; Leicht, G.; Hepp, P.; Kirsch, V.; Karch, S.; Pogarell, O.; Hegerl, U.; Moller, H. J.] Univ Munich, Dept Psychiat & Psychotherapy, D-80336 Munich, Germany. [Mulert, C.; Kirsch, V.; McCarley, R. W.] Harvard Univ, Dept Psychiat, Sch Med, Brockton, MA 02401 USA. [Mulert, C.; Kirsch, V.; McCarley, R. W.] VA Boston Healthcare Syst, Brockton, MA USA. [Mulert, C.] Univ Med Ctr Hamburg Eppendorf, Ctr Psychosocial Med, Dept Psychiat & Psychotherapy, Hamburg, Germany. [Reiser, M.; Jaeger, L.] Univ Munich, Inst Clin Radiol, D-80336 Munich, Germany. [Hegerl, U.] Univ Leipzig, Dept Psychiat & Psychotherapy, Leipzig, Germany. RP Mulert, C (reprint author), Univ Munich, Dept Psychiat, Nussbaumstr 7, D-80336 Munich, Germany. RI Mulert, Christoph/F-2576-2012; McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Hegerl, Ulrich/0000-0002-3039-7470 NR 58 TC 43 Z9 44 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2010 VL 49 IS 3 BP 2238 EP 2247 DI 10.1016/j.neuroimage.2009.10.058 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 544BN UT WOS:000273626400030 PM 19878729 ER PT J AU Upadhyay, J Pendse, G Anderson, J Schwarz, AJ Baumgartner, R Coimbra, A Bishop, J Knudsen, J George, E Grachev, I Iyengar, S Bleakman, D Hargreaves, R Borsook, D Becerra, L AF Upadhyay, Jaymin Pendse, Gautam Anderson, Julie Schwarz, Adam J. Baumgartner, Richard Coimbra, Alexandre Bishop, James Knudsen, Jamie George, Ed Grachev, Igor Iyengar, Smriti Bleakman, David Hargreaves, Richard Borsook, David Becerra, Lino TI Improved characterization of BOLD responses for evoked sensory stimuli SO NEUROIMAGE LA English DT Article DE Somatosensory cortex; Pain; fMRI; Biphasic response ID PRIMARY SOMATOSENSORY CORTEX; NOXIOUS THERMAL STIMULI; REGIONAL PAIN SYNDROME; BRAIN ACTIVITY; HEMODYNAMIC-RESPONSE; FUNCTIONAL MRI; TEMPORAL ANALYSIS; FMRI; ACTIVATION; MODULATION AB Pain and somatosensory processing involves an interaction of multiple neuronal networks One result Of these complex interactions is the presence of differential responses across brain regions that may be incompletely modeled by a straightforward application of standard general linear model (GLM) approaches based solely on the applied stimulus We examined temporal blood oxygenation-level dependent (BOLD) signatures elicited by two Stimulation paradigms (brush and hear) providing innocuous and noxious stimuli Data were acquired from 32 healthy male subjects (2 independent cohorts) Regional time courses and model-free analyses of the first cohort revealed distinct temporal features of the BOLD responses elicited during noxious versus innocuous Stimulation Specifically. a biphasic (dual peak) BOLD signal was observed in response to heat but much less so in response to brush Stimuli This signal was characterized by a stimulus-locked response along with a second peak delayed by similar to 12.5 s A cross-validation error analysis determined a modified design matrix comprising two explanatory variables (EVs) as a parsimonious means to model the biphasic responses within a GLM framework. One EV was directly derived from the stimulation paradigm (EVI), while the second EV (EV2) was EVI shifted by 12 5 s. The 2EV GLM analysis enabled a more detailed characterization of the elicited BOLD responses. particularly during pain processing This was confirmed by application of the model to a second. independent cohort[ALI] Further more, the delayed component of the biphasic response was strongly associated with the noxious heat stimuli. suggesting that this may represent a sensitive fMRI link of pain processing (C) 2009 Elsevier Inc All rights reserved C1 [Upadhyay, Jaymin] Harvard Univ, McLean Hosp, Sch Med, Brain Imaging Ctr,PAIN Grp, Belmont, MA 02478 USA. [Schwarz, Adam J.; Iyengar, Smriti; Bleakman, David] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Baumgartner, Richard] Merck Res Labs, Biometr Res Dept, Rahway, NJ 07065 USA. [Coimbra, Alexandre] Merck Res Labs, Dept Imaging, West Point, PA 19486 USA. [George, Ed; Grachev, Igor] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol & Crit Care, Boston, MA 02129 USA. [Hargreaves, Richard] Merck Res Labs, Basic Neurosci Dept, West Point, PA 19486 USA. [Borsook, David; Becerra, Lino] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Upadhyay, J (reprint author), Harvard Univ, McLean Hosp, Sch Med, Brain Imaging Ctr,PAIN Grp, 115 Mill St, Belmont, MA 02478 USA. FU Imaging Consortium for Drug Development FX The authors would like to thank the MR technical staff at the Mclean Hospital Brain Imaging Center, Eric Moulton, PhD and Diana Wallin, BS for assistance during the preparation of this manuscript. This work was supported by the Imaging Consortium for Drug Development. NR 52 TC 14 Z9 14 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2010 VL 49 IS 3 BP 2275 EP 2286 DI 10.1016/j.neuroimage.2009.10.053 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 544BN UT WOS:000273626400033 PM 19854280 ER PT J AU Anderson, A Dinov, ID Sherin, JE Quintana, J Yuille, AL Cohen, MS AF Anderson, Ariana Dinov, Ivo D. Sherin, Jonathan E. Quintana, Javier Yuille, A. L. Cohen, Mark S. TI Classification of spatially unaligned fMRI scans SO NEUROIMAGE LA English DT Article DE Classification; FMRI; Discrimination; Schizophrenia; Dementia; Machine learning; Independent components analysis ID SCHIZOPHRENIA; MRI AB The analysis of fMRI data is challenging because they consist generally of a relatively modest signal contained in a high-dimensional space: a single scan can contain millions of voxel recordings over space and time We present a method for classification and discrimination among fMRI that is based on modeling the scans as distance matrices, where each matrix measures the divergence of spatial network signals that fluctuate over time. We used single-subject independent components analysis (ICA). decomposing an fMRI scan into a set of statistically independent spatial networks, to extract spatial networks and time courses front each Subject unique relationship with the other components within that Subject Mathematical properties of that have these relationships reveal information about the infrastructure of the brain by measuring the interaction between and strength of the components Our technique IS unique, in that it does not require spatial alignment of the scans across subjects Instead, the classifications are made solely on the temporal activity taken by the subject's unique ICs. Multiple scans are not required and multivariate classification is implementable, and the algorithm is effectively blind to the subject-uniform underlying task paradigm Classification accuracy of Lip to 90% was realized on a resting-scanned schizophrenia/normal dataset and a tasked multivariate Alzheimer's/old/young dataset We propose that the ICs represent a plausible set of imaging basis functions consistent with network-driven theories Of Mural activity in which the observed signal is an aggregate of independent spatial networks having possibly dependent temporal activity (C) 2009 Elsevier Inc. All rights reserved C1 [Anderson, Ariana; Dinov, Ivo D.; Yuille, A. L.] Univ Calif Los Angeles, Dept Stat, Los Angeles, CA 90095 USA. [Anderson, Ariana; Cohen, Mark S.] Univ Calif Los Angeles, Ctr Cognit Neurosci, Los Angeles, CA 90095 USA. [Sherin, Jonathan E.; Quintana, Javier; Cohen, Mark S.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Anderson, Ariana; Dinov, Ivo D.; Sherin, Jonathan E.; Quintana, Javier; Cohen, Mark S.] UCLA Sch Med, Los Angeles, CA 90095 USA. [Dinov, Ivo D.] Univ Calif Los Angeles, Ctr Computat Biol, Los Angeles, CA 90095 USA. [Sherin, Jonathan E.; Quintana, Javier] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA 90073 USA. [Yuille, A. L.] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. [Yuille, A. L.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Cohen, MS (reprint author), UCLA Ctr Cognit Neurosci, Suite C8-881,740 Westwood Plaza, Los Angeles, CA 90095 USA. RI Cohen, Mark/C-6610-2011; OI Cohen, Mark/0000-0001-6731-4053; Dinov, Ivo/0000-0003-3825-4375 FU NCRR NIH HHS [U54 RR021813]; NIDA NIH HHS [R21 DA026109-01, R21 DA026109, R21 DA026109-02, R21DA026109, R33 DA026109, R90 DA023422, R90 DA023422-01, T90 DA022768, T90DA022768] NR 22 TC 12 Z9 12 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2010 VL 49 IS 3 BP 2509 EP 2519 DI 10.1016/j.neuroimage.2009.08.036 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 544BN UT WOS:000273626400053 PM 19712744 ER PT J AU Zivkovic, SA Abdel-Hamid, H AF Zivkovic, Sasa A. Abdel-Hamid, Hoda TI Neurologic Manifestations of Transplant Complications SO NEUROLOGIC CLINICS LA English DT Article DE Posttransplant recovery; Neurotoxicity; Opportunistic infections; Transplant complications ID BONE-MARROW-TRANSPLANTATION; SOLID-ORGAN TRANSPLANTATION; STEM-CELL TRANSPLANTATION; INDUCED PAIN SYNDROME; LIVER-TRANSPLANTATION; LUNG TRANSPLANTATION; CARDIAC TRANSPLANTATION; RENAL-TRANSPLANTATION; PEDIATRIC-PATIENTS; TACROLIMUS FK506 AB Neurologic complications affect posttransplant recovery of more than 20% of transplant recipients. Etiology is usually related to surgical procedure of transplantation, primary disorders causing failure of transplanted organ, opportunistic infections, and neurotoxicity of immunosuppressive medications. Risk of opportunistic infections and immunosuppressant neurotoxicity is greatest within the first six months, but it persists along with long-term maintenance immunosuppression required to prevent graft rejection. Neurotoxicity may require alteration of immunosuppressive regimen, and prompt therapy of opportunistic infections improves outcomes. C1 [Zivkovic, Sasa A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Zivkovic, Sasa A.] VA Pittsburgh Healthcare Syst, Neurol Serv, Pittsburgh, PA 15240 USA. [Abdel-Hamid, Hoda] Univ Pittsburgh, Div Pediat Neurol, Childrens Hosp Pittsburgh, Sch Med, Pittsburgh, PA 15201 USA. RP Zivkovic, SA (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, PUH F878,200 Lothrop St, Pittsburgh, PA 15213 USA. EM zivkovics@upmc.edu FU Health Resources and Services Administration [231-00-0115] FX This work was supported in part by Health Resources and Services Administration contract 231-00-0115. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 97 TC 7 Z9 7 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 0733-8619 J9 NEUROL CLIN JI Neurol. Clin. PD FEB PY 2010 VL 28 IS 1 BP 235 EP + DI 10.1016/j.ncl.2009.09.011 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 617CL UT WOS:000279258300014 PM 19932384 ER PT J AU Belanto, JJ Diaz-Perez, SV Magyar, CE Maxwell, MM Yilmaz, Y Topp, K Boso, G Jamieson, CH Cacalano, NA Jamieson, CAM AF Belanto, Joseph J. Diaz-Perez, Silvia V. Magyar, Clara E. Maxwell, Michele M. Yilmaz, Yasemin Topp, Kasey Boso, Guney Jamieson, Catriona H. Cacalano, Nicholas A. Jamieson, Christina A. M. TI Dexamethasone induces dysferlin in myoblasts and enhances their myogenic differentiation SO NEUROMUSCULAR DISORDERS LA English DT Article DE Dysferlinopathy; Limb-girdle muscular dystrophy type 2B; Miyoshi myopathy; Glucocorticoid; Myotube; C2C12; Myoblast differentiation; Dysferlin; Dexamethasone ID GIRDLE MUSCULAR-DYSTROPHY; MUSCLE STEM-CELLS; SKELETAL-MUSCLE; GENE-EXPRESSION; MESSENGER-RNA; IN-VITRO; INFLAMMATION; DEFICIENCY; MYOPATHY; RECEPTOR AB Glucocorticoids are beneficial in many muscular dystrophies but they are ineffective in treating dysferlinopathy, a rare muscular dystrophy caused by loss of dysferlin. We sought to understand the molecular basis for this disparity by studying the effects Of a glucocorticoid on differentiation of the myoblast cell line, C2C12, and dysferlin-deficient C2C12s. We found that pharmacologic doses of dexamethasone enhanced the myogenic fusion efficiency of C2C12s and increased the induction of dysferlin, along with specific myogenic transcription factors, sarcolemmal and structural proteins. In contrast, the dysferlin-deficient C2C12 cell line demonstrated a reduction in long myotubes and early induction of particular muscle differentiation proteins, most notably, myosin heavy chain. Dexamethasone partially reversed the defect in myogenic fusion in the dysferlin-deficient C2C12 cells. We hypothesize that a key therapeutic benefit Of glucocorticoids may be the up-regulation of dysferlin as an important component of glucocorticoid-enhanced myogenic differentiation. (C) 2009 Elsevier B.V. All rights reserved. C1 [Belanto, Joseph J.; Yilmaz, Yasemin; Jamieson, Christina A. M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Belanto, Joseph J.; Diaz-Perez, Silvia V.; Topp, Kasey; Boso, Guney; Jamieson, Christina A. M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Magyar, Clara E.] Univ Calif Los Angeles, David Geffen Sch Med, Translat Pathol Core Lab, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Maxwell, Michele M.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA USA. [Jamieson, Catriona H.] Univ Calif San Diego, Sch Med, Dept Med, Div Hematol Oncol, La Jolla, CA 92093 USA. [Cacalano, Nicholas A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiat Oncol, Los Angeles, CA 90095 USA. RP Jamieson, CAM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, 4554 Gonda Ctr 708822,695 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM CJamieson@mednet.ucla.edu FU C.B. Day Investment Company; ViaCell, Inc.; Thayer family; Jain Foundation, Inc; NIH-NCRR [CJX1-443835-WS-29646, CBRP U19]; NSF [CHE-0722519]; University of California at Los Angeles Center for Biological Radioprotectors [U19 A1067769/NIAID] FX We thank Drs. Michele M. Maxwell and Robert H. Brown, Jr. for generously providing the dysferlin-deficient C2C12 cells the development of which was supported by the C.B. Day Investment Company, ViaCell, Inc., the Thayer family and the Jain Foundation, Inc. We are grateful to Dr. Matthew J. Schibler for help with confocal microscopy. Confocal laser scanning microscopy was performed at the CNSI Advanced Light Microscopy/Spectroscopy Shared Resource Facility at UCLA, supported with funding from NIH-NCRR shared resources grant (CJX1-443835-WS-29646) and NSF Major Research Instrumentation grant (CHE-0722519). This work was supported by a grant from the Jain Foundation, Inc. (C.A.M. Jamieson) and NIH CBRP U19 (C.A.M. Jamieson, N. Cacalano) University of California at Los Angeles Center for Biological Radioprotectors grant U19 A1067769/NIAID. NR 62 TC 23 Z9 23 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD FEB PY 2010 VL 20 IS 2 BP 111 EP 121 DI 10.1016/j.nmd.2009.12.003 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 563RP UT WOS:000275151400005 PM 20080405 ER PT J AU Kubrusly, RCC Bhide, PG AF Kubrusly, Regina C. C. Bhide, Pradeep G. TI Cocaine exposure modulates dopamine and adenosine signaling in the fetal brain SO NEUROPHARMACOLOGY LA English DT Article DE Cocaine; Dopamine; Adenosine; Brain development ID ADENYLYL-CYCLASE ACTIVITY; GABA NEURON MIGRATION; PRENATAL COCAINE; CEREBRAL-CORTEX; RECEPTOR INTERACTIONS; GANGLIONIC EMINENCE; A(2A) RECEPTORS; GENE-EXPRESSION; MOUSE MODEL; RAT-BRAIN AB Exposure to cocaine during the fetal period can produce significant lasting changes in the structure and function of the brain. Cocaine exerts its effects on the developing brain by blocking monoamine transporters and impairing monoamine receptor signaling. Dopamine is a major central target of cocaine. In a mouse model, we show that cocaine exposure from embryonic day 8 (E8) to EA produces significant reduction in dopamine transporter activity, attenuation of dopamine D1-receptor function and upregulation of dopamine D2-receptor function. Cocaine's effects on the D1-receptor are at the level of protein expression as well as activity. The cocaine exposure also produces significant increases in basal cAMP levels in the striatum and cerebral cortex. The increase in the basal cAMP levels was independent of dopamine receptor activity. In contrast, blocking the adenosine A2a receptor down regulated the basal CAMP levels in the cocaine-exposed brain to physiological levels, suggesting the involvement of adenosine receptors in mediating cocaine's effects on the embryonic brain. In support of this suggestion, we found that the cocaine exposure downregulated adenosine transporter function. We also found that dopamine D2- and adenosine A2a-receptors antagonize each other's function in the embryonic brain in a manner consistent with their interactions in the mature brain. Thus, our data show that prenatal cocaine exposure produces direct effects on both the dopamine and adenosme systems. Furthermore, the dopamine D2 and adenosine A2a receptor interactions in the embryonic brain discovered in this study unveil a novel substrate for cocaine's effects on the developing brain. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Kubrusly, Regina C. C.; Bhide, Pradeep G.] Massachusetts Gen Hosp, Dev Neurobiol Neurol Dept, Boston, MA 02129 USA. [Kubrusly, Regina C. C.; Bhide, Pradeep G.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Kubrusly, Regina C. C.] Univ Fed Fluminense, Dept Fisiol & Farmacol, Lab Neurofarmacol, Rio De Janeiro, Brazil. RP Bhide, PG (reprint author), Massachusetts Gen Hosp, 149,13th St, Charlestown, MA 02129 USA. EM bhide@helix.mgh.harvard.edu RI Neurociencia, Inct/I-1011-2013; OI Bhide, Pradeep/0000-0003-4236-9415 FU USPHS [R01 DA020796, P30NS045776]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil FX Supported by USPHS grants R01 DA020796 and P30NS045776 to PGB and a fellowship from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil to RCCK. We gratefully acknowledge advice and assistance from our colleagues Deirdre McCarthy, Jia-Qian Ren and John Sims in the course of this work. NR 48 TC 14 Z9 15 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2010 VL 58 IS 2 BP 436 EP 443 DI 10.1016/j.neuropharm.2009.09.007 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 557MX UT WOS:000274674500015 PM 19765599 ER PT J AU Costello, MR Mandelkern, MA Shoptaw, S Shulenberger, S Baker, SK Abrams, AL Xia, C London, ED Brody, AL AF Costello, Matthew R. Mandelkern, Mark A. Shoptaw, Stephen Shulenberger, Stephanie Baker, Stephanie K. Abrams, Anna L. Xia, Catherine London, Edythe D. Brody, Arthur L. TI Effects of Treatment for Tobacco Dependence on Resting Cerebral Glucose Metabolism SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE tobacco dependence; nicotine; cigarette; 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET); statistical parametric mapping; bupropion HCl ID SUSTAINED-RELEASE BUPROPION; SMOKING-CESSATION; CIGARETTE-SMOKING; CONTROLLED-TRIAL; DOPAMINE TRANSPORTER; RELAPSE PREVENTION; PLASMA NICOTINE; DEFAULT MODE; HUMAN BRAIN; BLOOD-FLOW AB While bupropion HCl and practical group counseling (PGC) are commonly used treatments for tobacco dependence, the effects of these treatments on brain function are not well established. For this study, 54 tobacco-dependent cigarette smokers underwent resting (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning before and after 8 weeks of treatment with bupropion HCl, PGC, or pill placebo. Using Statistical Parametric Mapping (SPM 2), changes in cerebral glucose metabolism from before to after treatment were compared between treatment groups and correlations were determined between amount of daily cigarette usage and cerebral glucose metabolism. Compared with placebo, the two active treatments (bupropion HCl and PGC) had reductions in glucose metabolism in the posterior cingulate gyrus. Further analysis suggested that PGC had a greater effect than bupropion HCl on glucose metabolism in this region. We also found positive correlations between daily cigarette use and glucose metabolism in the left occipital gyrus and parietal-temporal junction. There were no significant negative correlations between daily cigarette use and glucose metabolism. Our findings suggest that bupropion HCl and PGC reduce neural activity much as the performance of a goal-oriented task does in the default mode network of the brain, including the posterior cingulate gyrus. Thus, this study supports the theory that active treatments for tobacco dependence move the brain into a more goal-oriented state. Neuropsychopharmacology (2010) 35, 605-612; doi:10.1038/npp.2009.165; published online 28 October 2009 C1 [Shoptaw, Stephen; London, Edythe D.; Brody, Arthur L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Costello, Matthew R.; Mandelkern, Mark A.; Shulenberger, Stephanie; Baker, Stephanie K.; Abrams, Anna L.; Xia, Catherine; Brody, Arthur L.] Greater Los Angeles Vet Adm Healthcare Syst, Los Angeles, CA USA. [Mandelkern, Mark A.] UCI, Dept Phys, Irvine, CA USA. [London, Edythe D.; Brody, Arthur L.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. [London, Edythe D.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. RP Brody, AL (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, 300 UCLA Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. EM abrody@ucla.edu FU National Institute on Drug Abuse [R01 DA20872]; Veterans Administration; Tobacco-Related Disease Research Program [16RT-0098]; Office of National Drug Control Policy [DABT 63-00C-1003]; National Alliance for Research on Schizophrenia and Depression FX Supported by the National Institute on Drug Abuse ( ALB ( R01 DA20872)), the Veterans Administration ( ALB ( Merit Review Type I Award)), the Tobacco-Related Disease Research Program ( ALB ( 16RT-0098)), the Office of National Drug Control Policy ( EDL ( DABT 63-00C-1003)), and the National Alliance for Research on Schizophrenia and Depression ( ALB). Initial study results were presented at the 2008 Society for Research on Nicotine and Tobacco meeting. We thank Josephine Ribe and Michael Clark for technical support in performing positron emission tomography and magnetic resonance imaging scans, respectively. NR 54 TC 4 Z9 4 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2010 VL 35 IS 3 BP 605 EP 612 DI 10.1038/npp.2009.165 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 544EK UT WOS:000273635100002 PM 19865076 ER PT J AU Blake, KD Viswanath, K Blendon, RJ Vallone, D AF Blake, Kelly D. Viswanath, K. Blendon, Robert J. Vallone, Donna TI The role of tobacco-specific media exposure, knowledge, and smoking status on selected attitudes toward tobacco control SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID UNITED-STATES; CANCER; SUPPORT; SMOKERS; BEHAVIOR; RESTRICTIONS; INDIVIDUALS; NONSMOKERS; RISKS; AIR AB Background: In August 2007, the President's Cancer Panel urged the leadership of the nation to "summon the political will to address the public health crisis caused by tobacco use" (President's Cancer Panel, N, 2007, Promoting healthy lifestyles: Policy, program, and personal recommendations for reducing cancer risk. http://deainfo.nci.nih.gov/advisory/pcp/pcp07rpt/pcp07rpt.pdf). While some research has examined predictors of public support for tobacco control measures, little research has examined modifiable factors that may influence public attitudes toward tobacco control. Methods: We used the American Legacy Foundation's 2003 American Smoking and Health Survey 2 to examine the contribution of smoking status, knowledge of the negative effects of tobacco, and tobacco-specific media exposure (antitobacco messages, news coverage of tobacco issues, and protobacco advertising) on U. S. adults' attitudes toward tobacco control. In addition, we assessed whether smoking status moderates the relationship between tobacco-specific media exposure and policy attitudes. Weighted multivariable logistic regression models were employed. Results: Results suggest that knowledge of the negative effects of tobacco and smoking status are associated with attitudes toward tobacco control and that exposure to tobacco-specific information in the media plays a role only in some instances. We found no evidence of effect modification by smoking status on the impact of exposure to tobacco-specific media on attitudes toward tobacco control. Discussion: Understanding the impact of readily modifiable factors that shape policy attitudes is essential if we are to target outreach and education in a way that is likely to sway public support for tobacco control. C1 [Blake, Kelly D.; Viswanath, K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Blake, Kelly D.; Viswanath, K.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Blendon, Robert J.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Vallone, Donna] Amer Legacy Fdn, Washington, DC USA. RP Blake, KD (reprint author), Dana Farber Canc Inst, 44 Binney St,MS LW703, Boston, MA 02115 USA. EM kellyblake@post.harvard.edu FU National Cancer Institute [5R25CA057711-14] FX This study was made possible by the Harvard Education Program in Cancer Prevention and Control, grant 5R25CA057711-14 from the National Cancer Institute. NR 31 TC 18 Z9 18 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2010 VL 12 IS 2 BP 117 EP 126 DI 10.1093/ntr/ntp184 PG 10 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 553CQ UT WOS:000274342900005 PM 20018944 ER PT J AU Gray, KM DeSantis, SM Carpenter, MJ Saladin, ME LaRowe, SD Upadhyaya, HP AF Gray, Kevin M. DeSantis, Stacia M. Carpenter, Matthew J. Saladin, Michael E. LaRowe, Steven D. Upadhyaya, Himanshu P. TI Menstrual cycle and cue reactivity in women smokers SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SMOKING-BEHAVIOR; CIGARETTE-SMOKING; PHASE; NICOTINE; ABSTINENCE; CESSATION; SESSIONS; RELAPSE AB Introduction: Emerging research suggests potential effects of the menstrual cycle on various aspects of smoking behavior in women, but results to date have been mixed. The present study sought to explore the influence of menstrual cycle phase on reactivity to smoking in vivo and stressful imagery cues in a sample of non-treatment-seeking women smokers. Methods: Via a within-subjects design, nicotine-dependent women (N = 37) participated in a series of four cue reactivity sessions, each during a distinct biologically verified phase of the menstrual cycle (early follicular [EF], mid-follicular [MF], midluteal [ML], and late luteal [LL]). Subjective (Questionnaire of Smoking Urges-Brief; QSU-B) and physiological (skin conductance and heart rate) measures of craving and reactivity were collected and compared across phases. Results: Subjective reactive craving (QSU-B) to smoking in vivo cues varied significantly across the menstrual cycle (p = .02) and was higher in both EF and MF phases versus ML and LL phases, but this finding was not sustained when controlling for reactivity to neutral cues. Heart rate reactivity to stressful imagery cues (p = .01) and skin conductance reactivity to smoking in vivo cues (p = .05) varied significantly across the menstrual cycle upon controlling for reactivity to neutral cues, with highest reactivity during the MF phase. Discussion: Menstrual cycle phase may have an effect on reactivity to smoking-related and stressful cues among women smokers. These findings contribute to an expanding literature, suggesting menstrual cycle effects on smoking behaviors in women. C1 [Gray, Kevin M.] Med Univ S Carolina, Youth Div, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [DeSantis, Stacia M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Carpenter, Matthew J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Saladin, Michael E.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [LaRowe, Steven D.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Gray, KM (reprint author), Med Univ S Carolina, Youth Div, Dept Psychiat & Behav Sci, 67 President St,POB 250861, Charleston, SC 29425 USA. EM graykm@musc.edu FU National Institute on Drug Abuse [P50 DA016511, K12 DA000357, K23 DA020482]; United States Public Health Service [M01 RR01070] FX This research was supported by National Institute on Drug Abuse grants P50 DA016511 (HPU, component PI; Drs. Kathleen T. Brady and Ronald See, Center PIs), K12 DA000357 (KMG), and K23 DA020482 (MJC) as well as United States Public Health Service grant M01 RR01070 (Medical University of South Carolina Clinical and Translational Research Center). NR 27 TC 11 Z9 11 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2010 VL 12 IS 2 BP 174 EP 178 DI 10.1093/ntr/ntp179 PG 5 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 553CQ UT WOS:000274342900013 PM 19996146 ER PT J AU Lattanzi, R Grant, AK Polimeni, JR Ohliger, MA Wiggins, GC Wald, LL Sodickson, DK AF Lattanzi, Riccardo Grant, Aaron K. Polimeni, Jonathan R. Ohliger, Michael A. Wiggins, Graham C. Wald, Lawrence L. Sodickson, Daniel K. TI Performance evaluation of a 32-element head array with respect to the ultimate intrinsic SNR SO NMR IN BIOMEDICINE LA English DT Article DE Magnetic Resonance Imaging; RE coils; phased-array; coil performance; coil design; parallel imaging; electrodynamics; ultimate intrinsic SNR ID TO-NOISE RATIO; PHASED-ARRAY; COIL ARRAYS; MRI; SENSE; DESIGN; IMAGES AB The quality of an RF detector coil design is commonly judged on how it compares with other coil configurations. The aim of this article is to develop a tool for evaluating the absolute performance of RF coil arrays. An algorithm to calculate the ultimate intrinsic signal-to-noise ratio (SNR) was implemented for a spherical geometry. The same imaging tasks modeled in the calculations were reproduced experimentally using a 32-element head array. Coil performance maps were then generated based on the ratio of experimentally measured SNR to the ultimate intrinsic SNR, for different acceleration factors associated with different degrees of parallel imaging. The relative performance in all cases was highest near the center of the samples (where the absolute SNR was lowest). The highest performance was found in the unaccelerated case and a maximum of 85% was observed with a phantom whose electrical properties are consistent with values in the human brain. The performance remained almost constant for 2-fold acceleration, but deteriorated at higher acceleration factors, suggesting that larger arrays are needed for effective highly-accelerated parallel imaging. The method proposed here can serve as a tool for the evaluation of coil designs, as well as a tool to guide the development of original designs which may begin to approach the optimal performance. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Lattanzi, Riccardo; Wiggins, Graham C.; Sodickson, Daniel K.] NYU, Langone Med Ctr, Ctr Biomed Imaging, Dept Radiol, New York, NY 10016 USA. [Grant, Aaron K.] Beth Israel Deaconess Med Ctr, Dept Radiol, Div Magnet Resonance Res, Boston, MA 02215 USA. [Grant, Aaron K.] Harvard Univ, Sch Med, Boston, MA USA. [Polimeni, Jonathan R.; Wald, Lawrence L.] MGH HMS MIT, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Polimeni, Jonathan R.; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ohliger, Michael A.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Sodickson, DK (reprint author), NYU, Med Ctr, Dept Radiol, 660 1st Ave,4th Floor, New York, NY 10016 USA. EM Daniel.Sodickson@nyumc.org RI Polimeni, Jonathan/P-1395-2014; Wald, Lawrence/D-4151-2009; OI Polimeni, Jonathan/0000-0002-1348-1179; , Riccardo/0000-0002-8240-5903; Sodickson, Daniel/0000-0002-2436-4664 FU AIIH [R01-EB000447, R01-EB002468, R01-1EB00684, P41-RR14075]; Siemens Medical Solutions FX Contract/grant sponsor: AIIH; contract/grant numbers: R01-EB000447, RO1-EB002468, R01-1EB00684, P41-RR14075.; Contract/grant sponsor: Siemens Medical Solutions. NR 29 TC 7 Z9 7 U1 1 U2 9 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD FEB PY 2010 VL 23 IS 2 BP 142 EP 151 DI 10.1002/nbm.1435 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 570VQ UT WOS:000275706800004 PM 19904727 ER PT J AU Espana, S Fraile, LM Herraiz, JL Udias, JM Desco, M Vaquero, JJ AF Espana, S. Fraile, L. M. Herraiz, J. L. Udias, J. M. Desco, M. Vaquero, J. J. TI Performance evaluation of SiPM photodetectors for PET imaging in the presence of magnetic fields SO NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT LA English DT Article DE Silicon photomultiplier; Positron emission tomography; Magnetic resonance imaging ID DETECTOR MODULE; IDENTIFICATION; READOUT; LSO AB The multi-pixel photon counter (MPPC) or silicon photomultiplier (SiPM), recently introduced as a solid-state photodetector, consists of an array of Geiger-mode photodiodes (microcells). It is a promising device for PET due to its potential for high photon detection efficiency (PDE) and its foreseeable immunity to magnetic fields. It is also easy to use with simple read-outs, has a high gain and a small size. In this work we evaluate the in field performance of three I X I mm(2) (With 100, 400 and 1600 microcells, respectively) and one 6 x 6 mm(2) (arranged as a 2 x 2 array) Hamamatsu MPPCs for their use in PET imaging. We examine the dependence of the energy resolution and the gain of these devices on the temperature and reverse bias voltage, when coupled to LYSO scintillator crystals under conditions that one would find in a PET system. We find that the 400 and 1600 microcells models and the 2 x 2 array are suitable for small-size crystals, like those employed in high resolution small animal scanners. We have confirmed the good performance of these devices up to magnetic fields of 7T as well as their suitability for performing PET acquisitions in the presence of fast switching gradients and high duty radiofrequency MRI sequences. Crown Copyright (C) 2009 Published by Elsevier B.V. All rights reserved. C1 [Espana, S.; Fraile, L. M.; Herraiz, J. L.; Udias, J. M.] Univ Complutense Madrid, Dpto Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. [Desco, M.; Vaquero, J. J.] Hosp Gen Univ Gregorio Maranon, Unidad Med & Cirugia Expt, Madrid, Spain. RP Espana, S (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM samuel@nuclear.fis.ucm.es RI LOPEZ HERRAIZ, JOAQUIN/E-9234-2010; Fraile, Luis/B-8668-2011; Udias, Jose/A-7523-2010; Vaquero, Juan Jose/D-3033-2009; Desco, Manuel/D-2822-2009; Espana, Samuel/E-9240-2010 OI LOPEZ HERRAIZ, JOAQUIN/0000-0001-7208-8863; Fraile, Luis/0000-0002-6281-3635; Udias, Jose/0000-0003-3714-764X; Vaquero, Juan Jose/0000-0001-9200-361X; Desco, Manuel/0000-0003-0989-3231; Espana, Samuel/0000-0001-9092-4597 FU Ministerio de Ciencia e Innovacion [FPA2007-62216TEC2008-06715-C02-01]; UCM [910059]; CPAN [CSPD-200700042]; UE FX This work was supported in part by the CDTEAM project of the CENIT program, and by Ministerio de Ciencia e Innovacion under projects FPA2007-62216TEC2008-06715-C02-01, UCM (Grupos UCM: 910059), CPAN (Consolider-Ingenio 2010) CSPD-200700042 projects, and project SENSORCZT-S-0505/MAT/000279, Comunidad de Madrid. Part of the computations of this work were done at the "High Capacity Cluster for Physical Techniques" of UCM, funded in part by the UE under the FEDER program and in part by UCM. NR 17 TC 36 Z9 36 U1 4 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-9002 J9 NUCL INSTRUM METH A JI Nucl. Instrum. Methods Phys. Res. Sect. A-Accel. Spectrom. Dect. Assoc. Equip. PD FEB 1 PY 2010 VL 613 IS 2 BP 308 EP 316 DI 10.1016/j.nima.2009.11.066 PG 9 WC Instruments & Instrumentation; Nuclear Science & Technology; Physics, Nuclear; Physics, Particles & Fields SC Instruments & Instrumentation; Nuclear Science & Technology; Physics GA 560DK UT WOS:000274882000020 ER PT J AU Brubaker, L Rickey, L Xu, Y Markland, A Lemack, G Ghetti, C Kahn, MA Nagaraju, P Norton, P Chang, TD Stoddard, A AF Brubaker, Linda Rickey, Leslie Xu, Yan Markland, Alayne Lemack, Gary Ghetti, Chiara Kahn, Margie A. Nagaraju, Pradeep Norton, Peggy Chang, T. Debuene Stoddard, Anne CA Urinary Incontinence Treatment Net TI Symptoms of Combined Prolapse and Urinary Incontinence in Large Surgical Cohorts SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PELVIC ORGAN PROLAPSE; QUALITY-OF-LIFE; UROGENITAL DISTRESS INVENTORY; STRESS-INCONTINENCE; IMPACT QUESTIONNAIRE; FLOOR DISORDERS; WOMEN; PREVALENCE; SEVERITY; STANDARDIZATION AB OBJECTIVE: To estimate whether prolapse severity is a major contributor to urinary incontinence severity, as measured by validated incontinence questionnaires. METHODS: We analyzed data from two large female stress urinary incontinence (SUI) surgical cohorts: the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) study (N=655) and the subsequent Trial of Mid-Urethral Slings (TOMUS) study (N=597). All participants completed a standardized baseline assessment including validated measures of symptom severity, quality of life, objective measures of urine loss (Urogenital Distress Inventory [UDI], Medical, Epidemiologic, and Social Aspects of Aging questionnaire, Incontinence Impact Questionnaire, and pad test), as well as the Pelvic Organ Prolapse Quantification assessment. Groups were compared using the) chi(2); test (categorical measures) or the one-way analysis of variance (continuous measures). Statistical significance was defined as P<.05. RESULTS: The SISTEr and TOMUS samples were similar for many variables including age (52 and 53 years, respectively), nulliparity (9% and 12%), prior urinary incontinence (UI) surgery (14% and 13%), and prior hysterectomy (31% and 28%), but other differences necessitated separate analysis of the two cohorts. There was not a statistically significant difference in UDI scores according to prolapse stage in either study population. Patients with prior surgery for pelvic organ prolapse and SUI had more incontinence symptoms and were more bothered by their UI regardless of prolapse stage. CONCLUSION: Prolapse stage is not strongly or consistently associated with incontinence severity in women who select surgical treatment of SUI. Prior pelvic organ prolapse and UI surgery is associated with worse UI severity and bother. C1 Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Loyola Univ, Stritch Sch Med, Dept Urol, Chicago, IL 60611 USA. Univ Maryland, Dept Urol, Baltimore, MD 21201 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Birmingham VA Med Ctr, Birmingham, AL USA. Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. Kaiser Permanente, San Diego, CA USA. William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. NIDDK, NIH, Bethesda, MD USA. RP Brubaker, L (reprint author), Loyola Univ Chicago, Stritch Sch Med, 2160 S 1st Ave,Bldg 103, Maywood, IL 60153 USA. EM LBrubaker@lumc.edu FU Pfizer (New York, AT); Allergan (Irvine, CA) FX Dr. Brubaker has received research funding from Pfizer (New York, AT) and Allergan (Irvine, CA) and. has been a research consultant for Pfizer. Dr. Lemak has been a clinical trial participant for Allergan, a consultant and lecturer for Astellas (Deerfield, IL) and Pfizer, and a lecturer for Novartis (Basel, Switzerland). Dr. Ghetti served as a co-investigator for the Bridges study with the University of California, San Francisco, which was partially funded by Pfizer. The other authors did not report any potential conflicts of interest. NR 24 TC 4 Z9 5 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2010 VL 115 IS 2 BP 310 EP 316 PN 1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 547FS UT WOS:000273872500015 PM 20093904 ER PT J AU Huang, YJ Kim, E Cox, MJ Brodie, EL Brown, R Wiener-Kronish, JP Lynch, SV AF Huang, Yvonne J. Kim, Eugenia Cox, Michael J. Brodie, Eoin L. Brown, Ron Wiener-Kronish, Jeanine P. Lynch, Susan V. TI A Persistent and Diverse Airway Microbiota Present during Chronic Obstructive Pulmonary Disease Exacerbations SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID PSEUDOMONAS-AERUGINOSA; CYSTIC-FIBROSIS; NOSOCOMIAL PNEUMONIA; GASTRIC COLONIZATION; BACTERIAL DIVERSITY; INFECTIONS; DNA; IDENTIFICATION; BACTEREMIA; CHILDREN AB Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major source of morbidity and contribute significantly to healthcare costs. Although bacterial infections are implicated in nearly 50% of exacerbations, only a handful of pathogens have been consistently identified in COPD airways, primarily by culture-based methods, and the bacterial microbiota in acute exacerbations remains largely uncharacterized. The aim of this study was to comprehensively profile airway bacterial communities using a culture-independent microarray, the 16S rRNA PhyloChip, of a cohort of COPD patients requiring ventilatory support and antibiotic therapy for exacerbation-related respiratory failure. PhyloChip analysis revealed the presence of over 1,200 bacterial taxa representing 140 distinct families, many previously undetected in airway diseases; bacterial community composition was strongly influenced by the duration of intubation. A core community of 75 taxa was detected in all patients, many of which are known pathogens. Bacterial community diversity in COPD airways is substantially greater than previously recognized and includes a number of potential pathogens detected in the setting of antibiotic exposure. Comprehensive assessment of the COPD airway microbiota using high-throughput, culture-independent methods may prove key to understanding the relationships between airway bacterial colonization, acute exacerbation, and clinical outcomes in this and other chronic inflammatory airway diseases. C1 [Huang, Yvonne J.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Kim, Eugenia; Cox, Michael J.; Brown, Ron; Lynch, Susan V.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Brodie, Eoin L.] Lawrence Berkeley Natl Lab, Dept Ecol, Div Earth Sci, Berkeley, CA USA. [Wiener-Kronish, Jeanine P.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Lynch, SV (reprint author), Univ Calif San Francisco, Dept Med, Div Gastroenterol, 513 Parnassus Ave,S-357, San Francisco, CA 94143 USA. EM susan.lynch@ucsf.edu RI Cox, Michael/A-6959-2010; Lynch, Susan/B-6272-2009; Brodie, Eoin/A-7853-2008; OI Brodie, Eoin/0000-0002-8453-8435; Cox, Michael/0000-0002-4002-1506 FU University of California [DOE DE-AC02-05CH11231]; American Lung Association; NIH [AI075410] FX The authors thank Yvette Piceno, Todd DeSantis, and Gary Andersen at Lawrence Berkeley National Laboratory for their advice and technical support in this study, and to Homer Boushey, M.D., for his critique of the manuscript. Part of this work was performed at Lawrence Berkeley National Laboratory under the auspices of the University of California under contract number DOE DE-AC02-05CH11231. Research was supported by a Tobacco-Related Disease Research Program (Univ. of California) fellowship to Y.J.H. and an American Lung Association grant to S.V.L. S.V.L. and E.L.B. are funded also by NIH Award (AI075410). NR 43 TC 93 Z9 97 U1 1 U2 13 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD FEB PY 2010 VL 14 IS 1 BP 9 EP 59 DI 10.1089/omi.2009.0100 PG 51 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 554GO UT WOS:000274423700002 PM 20141328 ER PT J AU Borgaonkar, SP Hocker, H Shin, HJ Markey, MK AF Borgaonkar, Sanket P. Hocker, Harrison Shin, Hyunjin Markey, Mia K. TI Comparison of Normalization Methods for the Identification of Biomarkers Using MALDI-TOF and SELDI-TOF Mass Spectra SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID ENHANCED LASER-DESORPTION; SPECTROMETRY DATA; BREAST-CANCER; CLINICAL PROTEOMICS; COLORECTAL-CANCER; FEATURE-SELECTION; BLOOD-SERUM; CLASSIFICATION; DISEASE; SAMPLES AB Proteomic profiling by mass spectrometry has tremendous potential for identifying disease biomarkers. A key limitation of mass spectrometry is that the information provided on the abundance of the various peptides is only relative. Thus, normalization is typically employed. Several normalization methods have been proposed and implemented in the literature. However, it is not clear if there is any reason to prefer one method over another. The goal of this study was to investigate the effect of normalization strategy on the identification of putative biomarkers from MALDI-TOF and SELDI-TOF mass spectra. Our results demonstrate that many of the putative biomarkers identified by mass spectrometry will be the same regardless of which data normalization scheme is applied. However, there can be substantial differences in the m/z values identified as being most discriminatory based on choice of normalization method. As there is no consistent pattern as to which normalization method yields the most promising targets for follow up study, we recommend that investigators routinely repeat their analysis with multiple normalization methods and consider the top several candidates identified in each case. C1 [Borgaonkar, Sanket P.; Hocker, Harrison; Markey, Mia K.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Shin, Hyunjin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Borgaonkar, SP (reprint author), Univ Texas Austin, Dept Biomed Engn, 1 Univ Stn C0800, Austin, TX 78712 USA. EM sanborg@gmail.comM OI Markey, Mia/0000-0001-8186-4959 NR 44 TC 11 Z9 11 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD FEB PY 2010 VL 14 IS 1 BP 115 EP 126 DI 10.1089/omi.2009.0082 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 554GO UT WOS:000274423700008 PM 20141334 ER PT J AU Henderson, BA Kim, JY Golnik, KC Oetting, TA Lee, AG Volpe, NJ Aaron, M Uhler, TA Arnold, A Dunn, JP Prajna, NV Lane, AM Loewenstein, JI AF Henderson, Bonnie An Kim, Jae Yong Golnik, Karl C. Oetting, Thomas A. Lee, Andrew G. Volpe, Nicholas J. Aaron, Maria Uhler, Tara A. Arnold, Anthony Dunn, James P. Prajna, N. Venkatesh Lane, Anne Marie Loewenstein, John I. TI Evaluation of the Virtual Mentor Cataract Training Program SO OPHTHALMOLOGY LA English DT Article ID NONTECHNICAL SKILLS; TECHNICAL SKILLS; SURGEONS; PHACOEMULSIFICATION; RESIDENTS; SIMULATOR; TOOL AB Objective: Evaluate the effectiveness of an interactive cognitive computer simulation for teaching the hydrodissection portion of cataract surgery compared with standard teaching and to assess the attitudes of residents about the teaching tools and their perceived confidence in the knowledge gained after using the tools. Design: Case-control study. Participants and Controls: Residents at academic institutions. Methods: Prospective, multicenter, single-masked, controlled trial was performed in 7 academic departments of ophthalmology (Harvard Medical School/Massachusetts Eye and Ear Infirmary, University of Iowa, Emory University, University of Cincinnati, University of Pennsylvania/Scheie Eye Institute, Jefferson Medical College of Thomas Jefferson University/Wills Eye Institute, and the Aravind Eye Institute). All residents from these centers were asked to participate and were randomized into 2 groups. Group A (n = 30) served as the control and received traditional teaching materials; group B (n = 38) received a digital video disc of the Virtual Mentor program. This program is an interactive cognitive simulation, specifically designed to separate cognitive aspects (such as decision making and error recognition) from the motor aspects. Both groups took online anonymous pretests (n = 68) and posttests (n = 58), and answered satisfaction questionnaires (n = 53). Wilcoxon tests were completed to compare pretest and posttest scores between groups. Analysis of variance was performed to assess differences in mean scores between groups. Main Outcome Measures: Scores on pretests, posttests, and satisfaction questionnaires. Results: There was no difference in the pretest scores between the 2 groups (P = 0.62). However, group B (Virtual Mentor [VM]) scored significantly higher on the posttest (P = 0.01). Mean difference between pretest and posttest scores were significantly better in the VM group than in the traditional learning group (P = 0.04). Questionnaire revealed that the VM program was "more fun" to use (24.1% vs 4.2%) and residents were more likely to use this type of program again compared with the likelihood of using the traditional tools (58.6% vs 4.2%). Conclusions: The VM, a cognitive computer simulation, augmented teaching of the hydrodissection step of phacoemulsification surgery compared with traditional teaching alone. The program was more enjoyable and more likely to be used repetitively by ophthalmology residents. Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references. Ophthalmology 2010; 117: 253-258 (C) 2010 by the American Academy of Ophthalmology. C1 [Lane, Anne Marie; Loewenstein, John I.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Cambridge, MA 02138 USA. [Kim, Jae Yong] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Golnik, Karl C.] Univ Cincinnati, Cincinnati, OH USA. [Golnik, Karl C.] Cincinnati Eye Inst, Cincinnati, OH USA. [Oetting, Thomas A.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Oetting, Thomas A.] Vet Affairs Med Ctr, Cincinnati, OH 45267 USA. [Lee, Andrew G.] Methodist Hosp, Dept Ophthalmol, Houston, TX 77030 USA. [Volpe, Nicholas J.] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Aaron, Maria] Emory Univ, Sch Med, Atlanta, GA USA. [Uhler, Tara A.] Thomas Jefferson Univ, Jefferson Med Coll, Wills Eye Inst, Philadelphia, PA 19107 USA. [Arnold, Anthony] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Dunn, James P.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Prajna, N. Venkatesh] Aravind Eye Hosp, Madurai, Tamil Nadu, India. RP Henderson, BA (reprint author), Ophthalm Consultants Boston, Wollongong, NSW 2500, Australia. EM bahenderson@eyeboston.com FU Massachusetts Lions Club; Norman Knight Ophthalmology Fund FX Sponsored in part by a grant from the Massachusetts Lions Club and the Norman Knight Ophthalmology Fund. NR 19 TC 7 Z9 7 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2010 VL 117 IS 2 BP 253 EP 258 DI 10.1016/j.ophtha.2009.07.009 PG 6 WC Ophthalmology SC Ophthalmology GA 555RB UT WOS:000274530300010 PM 19969355 ER PT J AU Pujari, SS Kempen, JH Newcomb, CW Gangaputra, S Daniel, E Suhler, EB Thorne, JE Jabs, DA Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Foster, CS AF Pujari, Siddharth S. Kempen, John H. Newcomb, Craig W. Gangaputra, Sapna Daniel, Ebenezer Suhler, Eric B. Thorne, Jennifer E. Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Foster, C. Stephen TI Cyclophosphamide for Ocular Inflammatory Diseases SO OPHTHALMOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; KOYANAGI-HARADA-SYNDROME; WEGENERS-GRANULOMATOSIS; INTRAVENOUS CYCLOPHOSPHAMIDE; RHEUMATOID-ARTHRITIS; IMMUNOSUPPRESSIVE THERAPY; PULSE CYCLOPHOSPHAMIDE; FOLLOW-UP; DRUGS; MANAGEMENT AB Purpose: To evaluate the outcomes of cyclophosphamide therapy for noninfectious ocular inflammation. Design: Retrospective cohort study. Participants: Two hundred fifteen patients with noninfectious ocular inflammation observed from initiation of cyclophosphamide. Methods: Patients initiating cyclophosphamide, without other immunosuppressive drugs (other than corticosteroids), were identified at 4 centers. Dose of cyclophosphamide, response to therapy, corticosteroid-sparing effects, frequency of discontinuation, and reasons for discontinuation were obtained by medical record review of every visit. Main Outcome Measures: Control of inflammation, corticosteroid-sparing effects, and discontinuation of therapy. Results: The 215 patients (381 involved eyes) meeting eligibility criteria carried diagnoses of uveitis (20.4%), scleritis (22.3%), ocular mucous membrane pemphigoid (45.6%), or other forms of ocular inflammation (11.6%). Overall, approximately 49.2% (95% confidence interval [CI], 41.7%-57.2%) gained sustained control of inflammation (for at least 28 days) within 6 months, and 76% (95% CI, 68.3%-83.7%) gained sustained control of inflammation within 12 months. Corticosteroid-sparing success (sustained control of inflammation while tapering prednisone to 10 mg or less among those not meeting success criteria initially) was gained by 30.0% and 61.2% by 6 and 12 months, respectively. Disease remission leading to discontinuation of cyclophosphamide occurred at the rate of 0.32/person-year (95% CI, 0.24-0.41), and the estimated proportion with remission at or before 2 years was 63.1% (95% CI, 51.5%-74.8%). Cyclophosphamide was discontinued by 33.5% of patients within 1 year because of side effects, usually of a reversible nature. Conclusions: The data suggest that cyclophosphamide is effective for most patients for controlling inflammation and allowing tapering of systemic corticosteroids to 10 mg prednisone or less, although 1 year of therapy may be needed to achieve these goals. Unlike with most other immunosuppressive drugs, disease remission was induced by treatment in most patients who were able to tolerate therapy. To titrate therapy properly and to minimize the risk of serious potential side effects, a systematic program of laboratory monitoring is required. Judicious use of cyclophosphamide seems to be beneficial for severe ocular inflammation cases where the potentially vision-saving benefits outweigh the substantial potential side effects of therapy, or when indicated for associated systemic inflammatory diseases. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2010; 117: 356-365 (C) 2010 by the American Academy of Ophthalmology. C1 [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA. [Pujari, Siddharth S.; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Dept Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Dept Epidemiol, Philadelphia, PA 19104 USA. [Gangaputra, Sapna] Univ Wisconsin, Dept Ophthalmol, Fundus Photograph Reading Ctr, Madison, WI USA. [Gangaputra, Sapna; Daniel, Ebenezer; Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Suhler, Eric B.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU National Eye Institute, Bethesda, Maryland [EY014943]; Research to Prevent Blindness, Inc., New York; Paul and Evanina Mackall Foundation, New York; National Eye Institute; Veterans' Administration, Washington, DC FX Supported primarily by the National Eye Institute, Bethesda, Maryland (grant no.: EY014943 [JHK]). Additional support was provided by Research to Prevent Blindness, Inc., New York, New York, and the Paul and Evanina Mackall Foundation, New York, NY. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Drs. Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Dr Levy- Clarke previously was supported by and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute. Dr Suhler also received support from the Veterans' Administration, Washington, DC. None of the sponsors had any role in the design and conduct of the report; collection, management, analysis, and interpretation of the data; nor in the preparation, review, and approval of this manuscript. NR 65 TC 51 Z9 52 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2010 VL 117 IS 2 BP 356 EP 365 DI 10.1016/j.ophtha.2009.06.060 PG 10 WC Ophthalmology SC Ophthalmology GA 555RB UT WOS:000274530300024 PM 19969366 ER PT J AU Zaidi, AA Ying, GS Daniel, E Gangaputra, S Rosenbaum, JT Suhler, EB Thorne, JE Foster, CS Jabs, DA Levy-Clarke, GA Nussenblatt, RB Kempen, JH AF Zaidi, Ali A. Ying, Gui-Shuang Daniel, Ebenezer Gangaputra, Sapna Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Kempen, John H. CA Systemic Immunosuppressive Therapy TI Hypopyon in Patients with Uveitis SO OPHTHALMOLOGY LA English DT Article ID BEHCETS-DISEASE AB Purpose: To evaluate the risk of and risk factors for hypopyon among patients with uveitis and to evaluate the risk of visual changes and complications after hypopyon. Design: Retrospective cohort study. Participants: Patients with uveitis at 4 academic ocular inflammation subspecialty practices. Methods: Data were ascertained by standardized chart review. Main Outcome Measures: Prevalence and incidence of hypopyon, risk factors for hypopyon, and incidence of visual acuity changes and ocular complications after hypopyon. Results: Among 4911 patients with uveitis, 41 (8.3/1000) cases of hypopyon were identified at the time of cohort entry. Of these, 2885 initially free of hypopyon were followed over 9451 person-years, during which 81 patients (2.8%) developed hypopyon (8.57/1000 person-years). Risk factors for incident hypopyon included Behcet's disease (adjusted relative risk [RR] = 5.30; 95% confidence interval [CI], 2.76-10.2), spondyloarthropathy (adjusted RR = 2.86; 95% CI, 1.48-5.52), and human leukocyte antigen (HLA)-B27 positivity (adjusted RR = 2.04; 95% CI, 1.17-3.56). Patients with both a spondyloarthropathy and HLA-B27 had a higher risk than either factor alone (crude RR = 4.39; 95% CI, 2.26-8.51). Diagnosis of intermediate uveitis (+/- anterior uveitis) was associated with a lower risk of hypopyon (with respect to anterior uveitis only, adjusted RR = 0.35; 95% CI, 0.15-0.85). Hypopyon incidence tended to be lower among patients with sarcoidosis (crude RR = 0.22; 95% CI, 0.06-0.90; adjusted RR = -0.28; 95% CI, 0.07-1.15). Post-hypopyon eyes and eyes not developing hypopyon had a similar incidence of band keratopathy, posterior synechiae, ocular hypertension, hypotony, macular edema, epiretinal membrane, cataract surgery, or glaucoma surgery. Post-hypopyon eyes were more likely than eyes not developing hypopyon to gain 3 lines of vision (crude RR = 1.54; 95% CI, 1.05-2.24) and were less likely to develop 20/200 or worse visual acuity (crude RR = 0.41; 95% CI, 0.17-0.99); otherwise, visual outcomes were similar in these groups. Conclusions: Hypopyon is an uncommon occurrence in patients with uveitis. Risk factors included Behcet's disease, HLA-B27 positivity, and spondyloarthropathy. Intermediate uveitis cases (+/- anterior uveitis) had a lower risk of hypopyon. On average, post-hypopyon eyes were no more likely than other eyes with uveitis to develop structural ocular complications or lose visual acuity. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2010; 117: 366-372 (C) 2010 by the American Academy of Ophthalmology. C1 [Zaidi, Ali A.; Ying, Gui-Shuang; Daniel, Ebenezer; Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA. [Zaidi, Ali A.; Ying, Gui-Shuang; Daniel, Ebenezer; Kempen, John H.] Univ Penn, Ocular Inflammat Serv, Philadelphia, PA 19104 USA. [Ying, Gui-Shuang; Kempen, John H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Biostat, Philadelphia, PA 19104 USA. [Ying, Gui-Shuang; Kempen, John H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Epidemiol, Philadelphia, PA 19104 USA. [Daniel, Ebenezer; Gangaputra, Sapna; Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gangaputra, Sapna] Univ Wisconsin, Dept Ophthalmol, Fundus Photograph Reading Ctr, Madison, WI USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU National Eye Institute [EY014943]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; Prevent Blindness James S. Adams Special Scholar Award; National Eye Institute FX Supported primarily by National Eye Institute Grant EY014943 (Dr. Kempen). Additional support was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Drs. Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Dr. Suhler also received support from the Veteran's Affairs Administration. Dr. Levy-Clarke was previously supported by and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute. NR 12 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2010 VL 117 IS 2 BP 366 EP 372 DI 10.1016/j.ophtha.2009.07.025 PG 7 WC Ophthalmology SC Ophthalmology GA 555RB UT WOS:000274530300025 PM 20006905 ER PT J AU Srinivasan, VJ Sakadzic, S Gorczynska, I Ruvinskaya, S Wu, WC Fujimoto, JG Boas, DA AF Srinivasan, Vivek J. Sakadzic, Sava Gorczynska, Iwona Ruvinskaya, Svetlana Wu, Weicheng Fujimoto, James G. Boas, David A. TI Quantitative cerebral blood flow with Optical Coherence Tomography SO OPTICS EXPRESS LA English DT Article ID IN-VIVO; DOPPLER TOMOGRAPHY; MICRO-ANGIOGRAPHY; SCATTERING MEDIA; RAT NEOCORTEX; PERFUSION; VELOCITY; SPECKLE; HEMODYNAMICS; ARTIFACTS AB Absolute measurements of cerebral blood flow (CBF) are an important endpoint in studies of cerebral pathophysiology. Currently no accepted method exists for in vivo longitudinal monitoring of CBF with high resolution in rats and mice. Using three-dimensional Doppler Optical Coherence Tomography and cranial window preparations, we present methods and algorithms for regional CBF measurements in the rat cortex. Towards this end, we develop and validate a quantitative statistical model to describe the effect of static tissue on velocity sensitivity. This model is used to design scanning protocols and algorithms for sensitive 3D flow measurements and angiography of the cortex. We also introduce a method of absolute flow calculation that does not require explicit knowledge of vessel angles. We show that OCT estimates of absolute CBF values in rats agree with prior measures by autoradiography, suggesting that Doppler OCT can perform absolute flow measurements in animal models. (C) 2010 Optical Society of America C1 [Srinivasan, Vivek J.; Sakadzic, Sava; Ruvinskaya, Svetlana; Wu, Weicheng; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Photon Migrat Imaging Lab,Sch Med, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Gorczynska, Iwona; Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Gorczynska, Iwona; Fujimoto, James G.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. RP Srinivasan, VJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Photon Migrat Imaging Lab,Sch Med, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. EM vjsriniv@nmr.mgh.harvard.edu RI Gorczynska, Iwona/P-9367-2015 OI Gorczynska, Iwona/0000-0002-6120-8791 FU National Institutes of Health [R01-NS057476, P01NS055104, P50NS010828, K99NS067050, R01-CA075289-13]; Air Force Office of Scientific Research [FA9550-07-1-0014]; Medical Free Electron Laser Program [FA9550-07-10101] FX We would like to acknowledge scientific contributions and helpful advice from Chao Zhou at MIT, and James Jiang and Alex Cable from Thorlabs. Dr. Iwona Gorczynska's present address is the Institute of Physics, Nicolaus Copernicus University, Torun, Poland. We acknowledge support by the National Institutes of Health (R01-NS057476, P01NS055104, P50NS010828, K99NS067050 and R01-CA075289-13), the Air Force Office of Scientific Research FA9550-07-1-0014, and the Medical Free Electron Laser Program FA9550-07-10101. NR 41 TC 129 Z9 130 U1 1 U2 19 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 FEB 1 PY 2010 VL 18 IS 3 BP 2477 EP 2494 DI 10.1364/OE.18.002477 PG 18 WC Optics SC Optics GA 559AD UT WOS:000274791200068 PM 20174075 ER PT J AU Joo, C Evans, CL Stepinac, T Hasan, T de Boer, JF AF Joo, Chulmin Evans, Conor L. Stepinac, Thomas Hasan, Tayyaba de Boer, Johannes F. TI Diffusive and directional intracellular dynamics measured by field-based dynamic light scattering SO OPTICS EXPRESS LA English DT Article ID IMAGE SUBMICROSCOPIC MOTIONS; OPTICAL COHERENCE TOMOGRAPHY; PHASE MICROSCOPY; SLOW DYNAMICS; LIVE CELLS; INTERFEROMETRY; CONTRAST; DOMAIN; SPECTROSCOPY AB Quantitative measurement of diffusive and directional processes of intracellular structures is not only critical in understanding cell mechanics and functions, but also has many applications, such as investigation of cellular responses to therapeutic agents. We introduce a label-free optical technique that allows non-perturbative characterization of localized intracellular dynamics. The method combines a field-based dynamic light scattering analysis with a confocal interferometric microscope to provide a statistical measure of the diffusive and directional motion of scattering structures inside a microscopic probe volume. To demonstrate the potential of this technique, we examined the localized intracellular dynamics in human epithelial ovarian cancer cells. We observed the distinctive temporal regimes of intracellular dynamics, which transitions from random to directional processes on a timescale of similar to 0.01 sec. In addition, we observed disrupted directional processes on the timescale of 1 similar to 5 sec by the application of a microtubule polymerization inhibitor, Colchicine, and ATP depletion. (C) 2010 Optical Society of America C1 [Joo, Chulmin; Evans, Conor L.; Stepinac, Thomas; Hasan, Tayyaba; de Boer, Johannes F.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Joo, Chulmin; Evans, Conor L.; Stepinac, Thomas; Hasan, Tayyaba; de Boer, Johannes F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Joo, Chulmin] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [de Boer, Johannes F.] Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands. RP Joo, C (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM cmjoo@alum.mit.edu; jfdeboer@few.vu.nl RI de Boer, Johannes/B-7590-2012; OI de Boer, Johannes/0000-0003-1253-4950; Joo, Chulmin/0000-0002-1812-2976 FU National Institute of Health [R01 RR19768, EY14975]; U. S. Department of Defense [F4 9620-01-1-0014]; Center for Integration of Medicine and Innovative Technology; Wellman Graduate Fellowship; MIT Department of Mechanical Engineering FX This work was supported by grants from National Institute of Health (R01 RR19768, EY14975), the U. S. Department of Defense (F4 9620-01-1-0014), and the Center for Integration of Medicine and Innovative Technology. C. J. would like to thank the support through a Wellman Graduate Fellowship and a Hatsopoulos Innovation Award from the MIT Department of Mechanical Engineering. NR 40 TC 20 Z9 20 U1 0 U2 7 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 FEB 1 PY 2010 VL 18 IS 3 BP 2858 EP 2871 DI 10.1364/OE.18.002858 PG 14 WC Optics SC Optics GA 559AD UT WOS:000274791200108 PM 20174115 ER PT J AU Niedre, M Ntziachristos, V AF Niedre, Mark Ntziachristos, Vasilis TI Comparison of fluorescence tomographic imaging in mice with early-arriving and quasi-continuous-wave photons SO OPTICS LETTERS LA English DT Article ID TURBID MEDIA; MOLECULAR TOMOGRAPHY AB The highly diffuse nature of light propagation in biological tissue is a major challenge for obtaining high-fidelity fluorescence tomographic images. In this work we investigated the use of time-gated detection of early-arriving photons for reducing the effects of light scatter in mice relative to quasi-cw photons. When analyzing sinographic representations of the measured data, it was determined that early photons allowed a reduction in the measured FWHM of fluorescent targets by a factor of approximately 2-3, yielding a significant improvement in the tomographic image reconstruction quality. (C) 2010 Optical Society of America C1 [Ntziachristos, Vasilis] Tech Univ Munich, Inst Biol & Med Imaging, D-85764 Munich, Germany. [Niedre, Mark] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. [Ntziachristos, Vasilis] Helmholtz Ctr Munich, D-85764 Munich, Germany. [Niedre, Mark; Ntziachristos, Vasilis] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Lab Bioopt & Mol Imaging, Charlestown, MA 02129 USA. [Niedre, Mark; Ntziachristos, Vasilis] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Ntziachristos, V (reprint author), Tech Univ Munich, Inst Biol & Med Imaging, Ismaningerstr 21, D-85764 Munich, Germany. EM v.ntziachristos@tum.de FU National Institutes of Health (NIH) [R01 EB000750] FX This research was supported in part by the National Institutes of Health (NIH) grant R01 EB000750. The authors wish to thank Mr. Joshua Dunham and Mr. Gregory Wojtkiewicz for assistance in the experiments. NR 14 TC 25 Z9 25 U1 0 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD FEB 1 PY 2010 VL 35 IS 3 BP 369 EP 371 PG 3 WC Optics SC Optics GA 551GX UT WOS:000274196100034 PM 20125724 ER PT J AU Dodson, TB AF Dodson, Thomas B. TI Outcomes Research and the Challenge of Evidence-Based Surgery SO ORAL AND MAXILLOFACIAL SURGERY CLINICS OF NORTH AMERICA LA English DT Article DE Outcomes research; Quality assurance; Evidence-based surgical practice; Patient-oriented research ID TRIGEMINAL NERVE REPAIR; RISK-FACTORS; PATIENT SATISFACTION; COMPLICATIONS; EXTRACTION; STRATEGY AB Outcomes research is focused on measuring the results or end products of health care interventions, processes, and practices. Data derived from outcomes research informs clinical practice, quality assurance, and patient safety activities, and can be the nidus for hypothesis-driven, patient-oriented research. This article introduces a definition of outcomes research, reviews how outcomes research may guide evidence-based surgical practice and health care processes, and reviews a model for outcomes research. C1 [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest, Boston, MA 02114 USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02115 USA. RP Dodson, TB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest, 55 Fruit St,Warren Bldg Suite 1201, Boston, MA 02114 USA. EM tbdodson@partners.org FU Massachusetts General Hospital Department of Oral and Maxillofacial Surgery's Center for Applied Clinical Investigation and Education and Research; Massachusetts General Physician Organization FX Article preparation was supported by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery's Center for Applied Clinical Investigation and Education and Research Fund and Massachusetts General Physician Organization. NR 10 TC 2 Z9 2 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 1042-3699 J9 ORAL MAXIL SURG CLIN JI Oral Maxillofac. Surg. Clin. N. Am. PD FEB PY 2010 VL 22 IS 1 BP 1 EP + DI 10.1016/j.coms.2009.10.004 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 864TT UT WOS:000298263700002 PM 20159473 ER PT J AU Fernandez, C Jami, S Loredo, G Ko, F Hahn, T McDougall, S Peters, JH AF Fernandez, C. Jami, S. Loredo, G. Ko, F. Hahn, T. McDougall, S. Peters, J. H. TI Recognition of the alternatively spliced segments of fibronectin by the RCJ 3.1C5.18 chondrocytic rat cell line SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Chondrocyte; Mulipotential stem cell; Differentiation; Fibronectin alternative splicing; Cartilage ID ISOFORM DISTRIBUTION; BINDING PROTEIN-3; PROGENITOR CELLS; MESSENGER-RNA; V-SEGMENT; CARTILAGE; DIFFERENTIATION; EIIIA; IDENTIFICATION; POPULATION AB Objectives. To define, for the C5.18 chondrocyte-restricted rat cell line, (1) the capacities for recognition of alternatively spliced segments of the adhesion protein fibronectin (FN), (2) the integrin subunits required for such recognition, and (3) differences in such FN recognition vs the multipotential chondroprogenitor line, RCJ 3 1 Methods C5 18 and RCJ 3 1 cells were tested for their capacities to adhere to recombinant alternatively spliced segments of rat FN, presented on plastic surfaces either in isolation or in partial FNs spanning the 7th through 15th type III repeats (III7-15 FNs) The effects on such adhesion of cations and integrin subunit-specific antibodies were tested Results Despite significant augmentation in chondrocyte-specific gene expression in C5.18 relative to the RCJ 3 1 cells, the two lines exhibited similar recognition of FN spliced segments and partial isoforms Specifically, both lines adhered to the extra type III repeat A (EIIIA) and V, but not extra type III repeat B (EIIIB), segments There were different cation and integrin subunit requirements for adhesion to EIIIA vs V segments, and only the V segment was recognized in the context of a III7-15 FN Such recognition was mediated via a "second" arginineglycine-aspartic acid (RGD) sequence that is present in the V95 subsegment in rat, but not human, FN Conclusion The chondrocyte lineage-committed C5 18 cell line, similar to its multipotential chondroprogenitor, RCJ 3 1, recognizes the "cartilage-restricted" EIIIA and V segments of FN with cation, integrin, and molecular context requirements that are specific to each of these segments Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International C1 [Peters, J. H.] UC Davis, Med Ctr, Ctr Healthy Aging, Dept Internal Med,Sch Med, Sacramento, CA 95817 USA. [Fernandez, C.; Jami, S.; Loredo, G.; Peters, J. H.] VA No Calif Hlth Care Syst, Sacramento Med Ctr, Mather, CA 95655 USA. [Ko, F.; Hahn, T.; McDougall, S.] Greater Los Angeles VA Healthcare Syst, W LA VA Med Ctr, Los Angeles, CA USA. [Hahn, T.; McDougall, S.] Univ Calif Los Angeles, Sch Med, Dept Internal Med, Div Geriatr Med, Los Angeles, CA 90024 USA. RP Peters, JH (reprint author), UC Davis, Med Ctr, Ctr Healthy Aging, Dept Internal Med,Sch Med, Room 2351,Oak Pk Bldg,2700 StocktonBlvd, Sacramento, CA 95817 USA. OI Jami, Shekib/0000-0001-5478-1963 FU Career Development Award; Department of Veterans Affairs; Charles See Foundation; UC Davis Center for Healthy Aging FX We thank Jane Aubin of the University of Toronto for generously supplying the RCJ 3 1 and RCJ 3 1 C5 18 cell lines, Richard Hynes of M.I.T for providing the cDNA constructs used to produce the III7-15 fusion proteins. J.H.P was supported by a Career Development Award and a Merit Review Award from the Department of Veterans Affairs, a gift from the Charles See Foundation and an intramural grant from the UC Davis Center for Healthy Aging during this study NR 31 TC 1 Z9 1 U1 1 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD FEB PY 2010 VL 18 IS 2 BP 228 EP 239 DI 10.1016/j.joca.2009.09.005 PG 12 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 566HK UT WOS:000275360500011 PM 19822234 ER PT J AU Shargorodsky, J Curhan, SG Eavey, R Curhan, GC AF Shargorodsky, Josef Curhan, Sharon G. Eavey, Roland Curhan, Gary C. TI A prospective study of vitamin intake and the risk of hearing loss in men SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Otolaryngology-Head-and-Neck-Surgery-Foundation CY OCT 04-07, 2009 CL San Diego, CA SP Amer Acad Otolaryngol Head & Neck Surg Fdn ID NUTRITION EXAMINATION SURVEY; RADICAL SCAVENGERS; NATIONAL-HEALTH; OLDER-ADULTS; EXPOSURE; FOLATE AB OBJECTIVE: Hearing loss is the most common sensory disorder in the United States, afflicting more than 36 million people. Higher intakes of vitamins C, E, beta carotene, B12, and folate have been proposed to reduce the risk of hearing loss. STUDY DESIGN: We prospectively evaluated the association between intake from foods and supplements of vitamins C, E, beta carotene, B12, and folate, and the incidence of hearing loss. SETTING: Health Professionals Follow-up Study. SUBJECTS AND METHODS: A total of 26,273 men aged 40 to 74 years at baseline in 1986. Participants completed questionnaires about lifestyle and medical history every two years and diet every four years. Information on self-reported professionally diagnosed hearing loss and year of diagnosis was obtained from the 2004 questionnaire, and cases were defined as hearing loss diagnosed between 1986 and 2004. Cox proportional hazards multivariate regression was used to adjust for potential confounders. RESULTS: There were 3559 cases of hearing loss identified. Overall, there was no significant association between vitamin intake and risk of hearing loss. Among men aged 60 years, total folate intake was associated with a reduced risk of hearing loss; the relative risk for men aged >= 60 years old in the highest quintile compared with the lowest quintile of folate intake was 0.79 (95% confidence interval 0.65-0.96). CONCLUSIONS: Higher intake of vitamin C, E, beta carotene, or B12 does not reduce the risk of hearing loss in adult males. Men aged years may benefit from higher folate intake to reduce the risk of developing hearing loss. (C) 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved. C1 [Shargorodsky, Josef; Curhan, Sharon G.; Curhan, Gary C.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Curhan, Gary C.] Brigham & Womens Hosp, Div Renal, Dept Med, Boston, MA 02115 USA. [Shargorodsky, Josef] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Eavey, Roland] Vanderbilt Univ, Dept Otolaryngol, Vanderbilt Bill Wilkerson Ctr Otolaryngol & Commu, Nashville, TN USA. [Curhan, Gary C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Shargorodsky, J (reprint author), Brigham & Womens Hosp, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM Josef_Shargorodsky@meei.harvard.edu FU NCI NIH HHS [P01 CA055075-18, P01 CA055075] NR 20 TC 21 Z9 21 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD FEB PY 2010 VL 142 IS 2 BP 231 EP 236 DI 10.1016/j.otohns.2009.10.049 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 582CZ UT WOS:000276574500015 PM 20115980 ER PT J AU Lindsay, RW Hadlock, TA Cheney, ML AF Lindsay, Robin W. Hadlock, Tessa A. Cheney, Mack L. TI Upper lip elongation in Mobius syndrome SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article C1 [Lindsay, Robin W.] Massachusetts Eye & Ear Infirm, Div Facial Plast & Reconstruct Surg, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Lindsay, Robin W.; Hadlock, Tessa A.; Cheney, Mack L.] Harvard Univ, Sch Med, Boston, MA USA. [Lindsay, Robin W.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. RP Lindsay, RW (reprint author), Massachusetts Eye & Ear Infirm, Div Facial Plast & Reconstruct Surg, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM robin_lindsay@meei.harvard.edu NR 4 TC 2 Z9 2 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD FEB PY 2010 VL 142 IS 2 BP 286 EP 287 DI 10.1016/j.otohns.2009.09.034 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 582CZ UT WOS:000276574500026 PM 20115991 ER PT J AU Benoit, MM Fink, DS Brigger, MT Keamy, DG AF Benoit, Margo McKenna Fink, Daniel S. Brigger, Matthew T. Keamy, Donald G., Jr. TI Lobular capillary hemangioma of the nasal cavity in a five-year-old boy SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID PYOGENIC GRANULOMA C1 [Benoit, Margo McKenna; Fink, Daniel S.; Keamy, Donald G., Jr.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Brigger, Matthew T.] USN, Med Ctr, Dept Otolaryngol Head & Neck Surg, San Diego, CA 92152 USA. RP Benoit, MM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Margo_Benoit@meei.harvard.edu NR 5 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 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD FEB PY 2010 VL 142 IS 2 BP 290 EP 291 DI 10.1016/j.otohns.2009.09.035 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 582CZ UT WOS:000276574500028 PM 20115993 ER PT J AU Kong, J Loggia, ML Zyloney, C Tu, PC LaViolette, P Gollub, RL AF Kong, Jian Loggia, Marco L. Zyloney, Carolyn Tu, Peichi LaViolette, Peter Gollub, Randy L. TI Exploring the brain in pain: Activations, deactivations and their relation SO PAIN LA English DT Article DE fMRI; Resting state; Default network; Cross-modal interaction; Functional connectivity; Gender difference ID POSITRON-EMISSION-TOMOGRAPHY; ACUPUNCTURE ANALGESIA; PLACEBO ANALGESIA; SEX-DIFFERENCES; RATIO SCALES; DEFAULT MODE; MUSCLE PAIN; CORTEX; FMRI; INTENSITY AB The majority of neuroimaging studies on pain focuses on the study of BOLD activations, and more rarely on deactivations. In this study, in a relatively large cohort of subjects (N = 61), we assess (a) the extent of brain activation and deactivation during the application of two different heat pain levels (HIGH and LOW) and (b) the relations between these two directions of fMRI signal change. Furthermore, in a subset of our subjects (N = 12), we assess (c) the functional connectivity of pain-activated or -deactivated regions during resting states. As previously observed, we find that pain stimuli induce intensity dependent (HIGH pain > LOW pain) fMRI signal increases across the pain matrix. Simultaneously, the noxious stimuli induce activity decreases in several brain regions, including some of the 'core structures' of the default network (DMN). In contrast to what we observe with the signal increases, the extent of deactivations is greater for LOW than HIGH pain stimuli. The functional dissociation between activated and deactivated networks is further supported by correlational and functional connectivity analyses. Our results illustrate the absence of a linear relationship between pain activations and deactivations, and therefore suggest that these brain signal changes underlie different aspects of the pain experience. (C) 2009 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Kong, Jian; Loggia, Marco L.; Zyloney, Carolyn; Tu, Peichi; LaViolette, Peter; Gollub, Randy L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Kong, Jian; Loggia, Marco L.; LaViolette, Peter; Gollub, Randy L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,MIT, Charlestown, MA 02129 USA. [Gollub, Randy L.] Massachusetts Gen Hosp, MIT, CRC Biomed Imaging Core, Charlestown, MA USA. [Loggia, Marco L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. RP Kong, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Bldg 149,13th St,Suite 2661, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu OI Gollub, Randy L./0000-0002-9434-4044 FU NIH (NCCAM) [PO1-AT002048, M01-RR-01066]; National Center for Research Resources (NCRR) [UL1 RR025758-01, P41RR14075]; MIND Research Network [DE-FG03-99ER62764]; [KO1AT003883]; [R21AT004497]; [R21AT00949] FX Funding and support for this study came from KO1AT003883 and R21AT004497 to Jian Kong, R21AT00949 to Randy Gollub, NIH (NCCAM) PO1-AT002048 to Bruce Rosen, M01-RR-01066 and UL1 RR025758-01 for Clinical Research Center Biomedical Imaging Core from National Center for Research Resources (NCRR), P41RR14075 for Center for Functional Neuroimaging Technologies from NCRR and the MIND Research Network, DE-FG03-99ER62764 to Bruce Rosen. The authors have no conflicts of interest or competing financial interests to declare. NR 48 TC 77 Z9 83 U1 3 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD FEB PY 2010 VL 148 IS 2 BP 257 EP 267 DI 10.1016/j.pain.2009.11.008 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 547MV UT WOS:000273894600013 PM 20005043 ER PT J AU Vrooman, LM Supko, JG Neuberg, DS Asselin, BL Athale, UH Clavell, L Kelly, KM Laverdiere, C Michon, B Schorin, M Cohen, HJ Sallan, SE Silverman, LB AF Vrooman, Lynda M. Supko, Jeffrey G. Neuberg, Donna S. Asselin, Barbara L. Athale, Uma H. Clavell, Luis Kelly, Kara M. Laverdiere, Caroline Michon, Bruno Schorin, Marshall Cohen, Harvey J. Sallan, Stephen E. Silverman, Lewis B. TI Erwinia Asparaginase After Allergy to E. coli Asparaginase in Children With Acute Lymphoblastic Leukemia SO PEDIATRIC BLOOD & CANCER LA English DT Article DE asparaginase; childhood; Erwinia; leukemia ID ESCHERICHIA-COLI; DANA-FARBER; INTENSIVE ASPARAGINASE; CEREBROSPINAL-FLUID; ONCOLOGY-GROUP; CHILDHOOD; THERAPY; ANTIBODIES; CANCER; PHARMACOKINETICS AB Background. Escherichia coli asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity develops in up to 30% of patients. We assessed the nadir enzyme activity and tolerability of Erwinia asparaginase, an alternative preparation, in E. coli asparaginase-allergic patients. Patients and Methods. Between 2000 and 2002, 215 children with newly diagnosed ALL were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 and were to receive 30 weekly doses of intramuscular E. coli asparaginase. If E. coli asparaginase allergy developed, patients were switched to twice-weekly intramuscular Erwinia asparaginase (25,000 IU/m(2)). Nadir serum asparaginase activity (NSAA) was measured every 3 weeks. Results. Forty-two patients (20%) developed E. coli asparaginase allergy and switched to Erwinia. Of 38 patients with evaluable samples, 34 (89%) Erwinia-treated patients had at least one therapeutic NSAA (>= 0.1 IU/ml). The median NSAA was 0.247 IU/ml 3 days and 0.077 IU/ml 4 days after an Erwinia dose. Associated toxicities included allergy in 14 (33%) and pancreatitis in 3 patients (7%). At a median follow-up of 5.4 years, event-free survival (+/- standard error) of the 42 patients who switched to Erwinia was 86 +/- 5% compared with 81 +/- 3% for the 170 patients without E. coli asparaginase allergy (P=0.55). Conclusions. Twice-weekly Erwinia asparaginase was well tolerated and achieved a therapeutically effective NSAA in most E. coli asparaginase-allergic patients. Development of E. coli allergy and subsequent treatment with twice-weekly Erwinia did not adversely impact event-free Survival. Erwinia asparaginase Should be considered for E. coli asparaginase-allergic patients. Pediatr Blood Cancer 2010;54:199-205. (C) 2009 Wiley-Liss, Inc. C1 [Vrooman, Lynda M.; Neuberg, Donna S.; Sallan, Stephen E.; Silverman, Lewis B.] Dana Farber Canc Inst, Dept Pediat Oncol Biostat & Computat Biol, Boston, MA 02115 USA. [Vrooman, Lynda M.; Sallan, Stephen E.; Silverman, Lewis B.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Supko, Jeffrey G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Asselin, Barbara L.] Univ Rochester, Med Ctr, Div Pediat Oncol, Rochester, NY 14642 USA. [Athale, Uma H.] McMaster Univ, Div Pediat Hematol Oncol, Hamilton, ON, Canada. [Clavell, Luis] San Jorge Childrens Hosp, Div Pediat Oncol, San Juan, PR USA. [Kelly, Kara M.] Columbia Univ, Med Ctr, Div Pediat Oncol, Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY USA. [Laverdiere, Caroline] Univ Montreal, Hop St Justine, Div Hematol & Oncol, Montreal, PQ H3T 1C5, Canada. [Michon, Bruno] Ctr Hosp U Quebec, Div Hematol Oncol, Quebec City, PQ, Canada. [Schorin, Marshall] Inova Fairfax Hosp, Falls Church, VA USA. [Cohen, Harvey J.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. RP Vrooman, LM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Binney St, Boston, MA 02115 USA. EM lynda_vrooman@dfci.harvard.edu FU National Cancer Institute [5 P01CA068484] FX This work was supported in part by grant 5 P01CA068484 from the National Cancer Institute. NR 34 TC 57 Z9 62 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2010 VL 54 IS 2 BP 199 EP 205 DI 10.1002/pbc.22225 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 538TK UT WOS:000273206700006 PM 19672973 ER PT J AU Bergmann, AK Campagna, DR McLoughlin, EM Agarwal, S Fleming, MD Bottomley, SS Neufeld, EJ AF Bergmann, Anke K. Campagna, Dean R. McLoughlin, Erin M. Agarwal, Suneet Fleming, Mark D. Bottomley, Sylvia S. Neufeld, Ellis J. TI Systematic Molecular Genetic Analysis of Congenital Sideroblastic Anemia: Evidence for Genetic Heterogeneity and Identification of Novel Mutations SO PEDIATRIC BLOOD & CANCER LA English DT Article DE iron; microcytic anemia; ringed sideroblasts; sideroblastic anemia ID MARROW PANCREAS SYNDROME; MITOCHONDRIAL MYOPATHY; MEGALOBLASTIC-ANEMIA; MISSENSE MUTATION; PUS1 GENE; ATAXIA; DISORDER; ABC7; POLYMORPHISM; TRANSPORTER AB Background. Sideroblastic anemias are heterogeneous congenital and acquired bone marrow disorders characterized by pathologic iron deposits in mitochondria of erythroid precursors. Among the congenital sideroblastic anemias (CSAs), the most common form is X-linked sideroblastic anemia, due to Mutations in 5-aminolevulinate synthase (ALAS2). A novel autosomal recessive CSA, caused by mutations in the erythroid specific mitochondrial transporter SLC25A38, was recently defined. Other known etiologies include mutations in genes encoding the thiamine transporter SLC19A2, the RNA-modifying enzyme pSeLldouridine synthase 1 (PUS1), a mitochondrial ATP-binding cassette transporter (ABCB7), glutaredoxin 5 (GLRX5), as well as mitochondrial DNA deletions. Despite these known diverse causes, in a Substantial portion of CSA cases a presumed genetic defect remains unknown. Procedure. In the context of the recent discovery of SLC25A38 as a major novel cause, we systematically analyzed a large cohort of previously unreported CSA patients. Sixty CSA probands (28 females, 32 males) were examined for ALAS2, SLC25A38, PUS1, GLRX5, and ABCB7 mutations. SLC19A2 and mitochondrial DNA were only analyzed if characteristic syndromic features were apparent. Results. Twelve probands had biallelic mutations in SLC25A38. Seven ALAS2 mutations were detected in eight sporadic CSA cases, two being novel. We also identified a novel homozygous null PUSI mutation and novel mitochondrial DNA deletions in two patients with Pearson syndrome. No mutations were encountered in GLRX5, ABCB7, or SLC19A2. Conclusions. The remaining undefined probands (43%) can be grouped according to gender, family, and clinical characteristics, suggesting novel X-linked and autosomal recessive forms of CSA. Pediatr Blood Cancer 2010;54:273-278. (C) 2009 Wiley-Liss, Inc. C1 [Campagna, Dean R.; Fleming, Mark D.] Harvard Univ, Dept Pathol, Childrens Hosp Boston, Sch Med, Boston, MA 02115 USA. [Bergmann, Anke K.; McLoughlin, Erin M.; Agarwal, Suneet; Neufeld, Ellis J.] Harvard Univ, Div Hematol Oncol, Childrens Hosp Boston, Sch Med, Boston, MA 02115 USA. [Agarwal, Suneet; Neufeld, Ellis J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bottomley, Sylvia S.] Univ Oklahoma, Coll Med, Hematol Oncol Sect, Oklahoma City, OK 73190 USA. RP Fleming, MD (reprint author), Harvard Univ, Dept Pathol, Childrens Hosp Boston, Sch Med, 300 Longwood Ave,Enders 1116-1, Boston, MA 02115 USA. EM mark.fleming@childrens.harvard.edu RI Neufeld, Ellis/F-9331-2011 FU NIH [R01 DK080011, K08 HL089150, K24 HL004184]; The U.S. Department of Veterans, Affairs, University of Oklahoma Health Sciences Center Provost's Fund; The Oklahoma Center for Advancement of Science and Technology FX We express our gratitude to the patients, their families and referring physicians. We thank Mathew Heeney for help with consenting some of the patients, Philip Wise and Eric Wasson for technical assistance, and Mark Samuels and his colleagues at the Atlantic Medical Genetics and Genomics Initiative for discussions concerning SLC25A38 in advance Of publication. This work was supported in part by NIH grant R01 DK080011 (M.D.F.); The U.S. Department of Veterans, Affairs, University of Oklahoma Health Sciences Center Provost's Fund and The Oklahoma Center for Advancement of Science and Technology (S.S.B.); NIH grant K08 HL089150 (S.A.), and NIH grant K24 HL004184 (E.J.N.). NR 34 TC 51 Z9 59 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2010 VL 54 IS 2 BP 273 EP 278 DI 10.1002/pbc.22244 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 538TK UT WOS:000273206700019 PM 19731322 ER PT J AU Adams, EE Aluquin, VPR Bingham, CA Stone, JR Pauliks, LB AF Adams, Elizabeth E. Aluquin, Vincent P. R. Bingham, C. April Stone, James R. Pauliks, Linda B. TI Cardiac Tumor in Juvenile Onset Behcet's Disease: Case Report and Review of the Literature SO PEDIATRIC CARDIOLOGY LA English DT Review DE Behcet's disease; Child; Echocardiography; Heart neoplasm; Pulmonary embolism ID THROMBUS AB Beh double dagger et's disease is a chronic multisystemic inflammatory disorder characterized by orogenital ulcerations, uveitis, and occasional cardiac involvement. This report describes an atypical presentation of pediatric Beh double dagger et's disease with pulmonary emboli and a cardiac mass. A 16-year-old boy with a 2-year history of oral ulcers presented with weight loss, fever, joint pain, and a large tumor adhering to the free wall of the heart's right ventricle. Surgical biopsy demonstrated endomyocarditis with thrombus formation and led to the diagnosis. At the 2-year follow-up evaluation, intracardiac thrombus and pulmonic emboli had not recurred. Symptom control with immunosuppressive therapy was good. C1 [Adams, Elizabeth E.; Aluquin, Vincent P. R.; Bingham, C. April; Pauliks, Linda B.] Penn State Hershey Childrens Hosp, Dept Pediat Cardiol, Hershey, PA 17033 USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Pauliks, LB (reprint author), Penn State Hershey Childrens Hosp, Dept Pediat Cardiol, Mailbox HP14,500 Univ Dr, Hershey, PA 17033 USA. EM lpauliks@hmc.psu.edu OI Pauliks, Linda/0000-0003-1031-3994 NR 12 TC 3 Z9 4 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0172-0643 J9 PEDIATR CARDIOL JI Pediatr. Cardiol. PD FEB PY 2010 VL 31 IS 2 BP 277 EP 279 DI 10.1007/s00246-009-9565-4 PG 3 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA 552ZN UT WOS:000274333900017 PM 19859764 ER PT J AU Profit, J Petersen, LA McCormick, MC Escobar, GJ Coleman-Phox, K Zheng, Z Pietz, K Zupancic, JAF AF Profit, Jochen Petersen, Laura A. McCormick, Marie C. Escobar, Gabriel J. Coleman-Phox, Kim Zheng, Zheng Pietz, Kenneth Zupancic, John A. F. TI Patient-to-Nurse Ratios and Outcomes of Moderately Preterm Infants SO PEDIATRICS LA English DT Article DE infant; newborn; health services research; nurse-staffing; outcomes ID NEONATAL INTENSIVE-CARE; BIRTH-WEIGHT INFANTS; STAFF RATIOS; MORTALITY; RISK; UNIT; WORKLOAD; QUALITY AB OBJECTIVE: Moderately preterm infants (30-346/7 weeks' gestational age) represent the largest population of NICU residents. Whether their clinical outcomes are associated with differences in NICU nurse-staffing arrangements has not been assessed. The objective of this study was to test the influence of patient-to-nurse ratios (PNRs) on outcomes of care provided to moderately preterm infants. PATIENTS AND METHODS: Using data from a prospective, multicenter, observational cohort study of 850 moderately preterm infants from 10 NICUs in California and Massachusetts, we tested for associations between PNR and several important clinical outcomes by using multivariate random-effects models. To correct for the influence of NICU size, we dichotomized the sample into those with an average daily census of <20 or >= 20 infants. RESULTS: Overall, we found few clinically significant associations between PNR and clinical outcomes of care. Mean PNRs were higher in large compared with small NICUs (2.7 vs 2.1; P < .001). In bivariate analyses, an increase in PNR was associated with a slightly higher daily weight gain (5 g/day), greater gestational age at discharge, any intraventricular hemorrhage, and severe retinopathy of prematurity. After controlling for case mix, NICU size, and site of care, an additional patient per nurse was associated with a decrease in daily weight gain by 24%. Other variables were no longer independently associated with PNR. CONCLUSIONS: In this population of moderately preterm infants, the PNR was associated with a decrease in daily weight gain, but was not associated with other measures of quality. In contrast with findings in the adult intensive care literature, measured clinical outcomes were similar across the range of nurse-staffing arrangements among participating NICUs. We conclude that the PNR is not useful for profiling hospitals' quality of care delivery to moderately preterm infants. Pediatrics 2010; 125: 320-326 C1 [Profit, Jochen] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Profit, Jochen; Petersen, Laura A.; Pietz, Kenneth] Texas Childrens Hosp, Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Profit, Jochen; Petersen, Laura A.; Pietz, Kenneth] Houston Vet Affairs Hlth Serv, Res & Dev Ctr Excellence, Hlth Policy & Qual Program, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [McCormick, Marie C.; Zheng, Zheng; Zupancic, John A. F.] Beth Israel Deaconess Med Ctr, Dept Neonatol, Boston, MA 02215 USA. [McCormick, Marie C.; Zupancic, John A. F.] Harvard Univ, Sch Med, Div Newborn Med, Boston, MA USA. [McCormick, Marie C.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Escobar, Gabriel J.; Coleman-Phox, Kim] Kaiser Permanente Med Care Program, Perinatal Res Unit, Oakland, CA USA. RP Profit, J (reprint author), Houston Vet Affairs Hlth Serv, Res & Dev Ctr Excellence 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM profit@bcm.edu OI Zupancic, John/0000-0003-1734-7193; McCormmick, Marie/0000-0002-3938-1707 FU Agency for Healthcare Research and Quality [5 R01 HS 10131-02, T32 HS 000063]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [K23 HD056298-01]; American Heart Association [0540043N]; Veterans Administration Center [CoE HFP90-20] FX This project was supported by the Agency for Healthcare Research and Quality (grant 5 R01 HS 10131-02, "Unstudied Infants: Low Risk Babies in a High Risk Place" [to Dr McCormick]). Dr Profit's contribution is supported in part by the Agency for Healthcare Research and Quality (grant T32 HS 000063) and Eunice Kennedy Shriver National Institute of Child Health and Human Development grant K23 HD056298-01. Dr Petersen is a recipient of the American Heart Association Established Investigator Award (grant 0540043N). Drs Petersen and Profit also receive support from a Veterans Administration Center grant (Veterans Affairs Health Services Research and Development CoE HFP90-20). NR 18 TC 14 Z9 14 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2010 VL 125 IS 2 BP 320 EP 326 DI 10.1542/peds.2008-3140 PG 7 WC Pediatrics SC Pediatrics GA 573VH UT WOS:000275942900017 PM 20064868 ER PT J AU Prosser, LA Kong, CY Rusinak, D Waisbren, SL AF Prosser, Lisa A. Kong, Chung Yin Rusinak, Donna Waisbren, Susan L. TI Projected Costs, Risks, and Benefits of Expanded Newborn Screening for MCADD SO PEDIATRICS LA English DT Article DE newborn screening; cost-effectiveness; economic; QALY ID TANDEM MASS-SPECTROMETRY; COA DEHYDROGENASE-DEFICIENCY; INFLUENZA VACCINATION; ECONOMIC-EVALUATION; HEALTH STATES; CHILDREN; DISORDERS; PREFERENCES; PHENYLKETONURIA; INTERVENTIONS AB OBJECTIVE: To evaluate the cost-effectiveness of newborn screening for medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) incorporating quality-of-life effects for false-positive newborn screens and recommended dietary treatment. METHODS: A computer simulation model was developed to predict costs and health outcomes for expanded newborn screening for MCADD compared with clinical identification. The modeled target population was a hypothetical cohort of 100 000 newborns in the United States. Probabilities, costs, and quality-of-life weights were derived from a long-term follow-up study of newborn screening compared with clinical identification, primary data collection, published data, and expert opinion. We used a lifetime time horizon and the societal perspective. The main outcome measure was the incremental cost-effectiveness ratio in dollars per quality-adjusted life-year (QALY) gained. Secondary outcomes included averted deaths and hospitalizations. RESULTS: Using base-case assumptions, the cost-effectiveness of newborn screening for MCADD was $21 273 per QALY gained. The cost-effectiveness ratio increased to $21 278/QALY when the loss in quality of life associated with false-positive test results was incorporated and to $27 423/QALY when the quality of life associated with lifelong dietary recommendations for treating MCADD was incorporated. Results were sensitive to the false-positive rate for the newborn screening test and the cost of the initial screen. CONCLUSIONS: Expanded newborn screening for MCADD is cost-effective compared with well-accepted pediatric health interventions. Losses in quality of life associated with dietary treatment for MCADD, however, may offset some of the gains in QALYs from newborn screening. Consideration of new disorders for expanded newborn screening panels should include the potential reduction in quality of life associated with treatments. Pediatrics 2010; 125:e286-e294 C1 [Prosser, Lisa A.] Univ Michigan, Sch Med, Div Gen Pediat, Child Hlth Evaluat & Res Unit, Ann Arbor, MI USA. [Prosser, Lisa A.; Rusinak, Donna] Harvard Univ, Sch Med, Ctr Child Hlth Care Studies, Boston, MA USA. [Prosser, Lisa A.; Rusinak, Donna] Harvard Pilgrim Hlth Care, Boston, MA USA. [Kong, Chung Yin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Waisbren, Susan L.] Childrens Hosp Boston, Dept Genet, Boston, MA USA. RP Prosser, LA (reprint author), Univ Michigan Hlth Syst, Div Gen Pediat, Child Hlth Evaluat & Res Unit, 300 N Ingalls St,Room 6E14, Ann Arbor, MI 48109 USA. EM lisapros@med.umich.edu FU National Human Genome Research Institute, Division of Ethical, Legal and Social Implications [2R01HG002085-04] FX Funding for this study was provided by the National Human Genome Research Institute, Division of Ethical, Legal and Social Implications (grant 2R01HG002085-04). NR 46 TC 24 Z9 24 U1 2 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2010 VL 125 IS 2 BP E286 EP E294 DI 10.1542/peds.2009-0605 PG 9 WC Pediatrics SC Pediatrics GA 573VH UT WOS:000275942900042 PM 20123779 ER PT J AU Inhoff, T Stengel, A Peter, L Goebel, M Tache, Y Bannert, N Wiedenmann, B Klapp, BF Monnikes, H Kobelt, P AF Inhoff, Tobias Stengel, Andreas Peter, Lisa Goebel, Miriam Tache, Yvette Bannert, Norbert Wiedenmann, Bertram Klapp, Burghard F. Moennikes, Hubert Kobelt, Peter TI Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats SO PEPTIDES LA English DT Article DE Arcuate nucleus; Rat; Nesfatin-1; Phospho-mTOR; CART; NPY ID AMPHETAMINE-REGULATED TRANSCRIPT; NEUROPEPTIDE-Y; FEEDING-BEHAVIOR; CART NEURONS; SPINAL-CORD; FOOD-INTAKE; PEPTIDE; PROTEIN; GHRELIN; BRAIN AB Recently, two proteins have been localized in the arcuate nucleus (ARC) and implicated in the regulation of food intake: the serine-threonine-kinase mammalian target of rapamycin (mTOR) as part of the TOR signaling complex 1 (TORC1), and nesfatin-1 derived from the precursor protein nucleobindin2. However, the exact cell types are not well described. Therefore, we performed double-labeling studies for NPY, CART, nesfatin-1 and pmTOR in the ARC. In this study, we showed that nesfatin-1 is not only intracellularly co-localized with cocaine- and amphetamine-regulated transcript (CART) peptide as reported before, but also with phospho-mTOR (pmTOR) and neuropeptide Y (NPY) in ARC neurons. Quantification revealed that 59 +/- 5% of the pmTOR-immunoreactive (it) neurons were immunoreactive for nesfatin-1. Moreover, double labeling for nesfatin-1 and NPY exhibited that 19 +/- 5% of the NPY positive cells were also immunoreactive for nesfatin-1. Furthermore, we could also confirm results from previous studies, showing that the majority of nesfatin-1 neurons are also positive for CART peptide, whereas most of the pmTOR is co-localized with NPY and only to a lesser extent with CART. (C) 2009 Elsevier Inc. All rights reserved. C1 [Inhoff, Tobias; Peter, Lisa; Wiedenmann, Bertram; Kobelt, Peter] Univ Med Berlin, Dept Med, Div Hepatol Gastroenterol & Endocrinol, Charite, D-10117 Berlin, Germany. [Klapp, Burghard F.; Kobelt, Peter] Univ Med Berlin, Dept Med, Div Psychosomat Med & Psychotherapy, Charite, D-10117 Berlin, Germany. [Stengel, Andreas; Goebel, Miriam; Tache, Yvette] Univ Calif Los Angeles, Dept Med, Div Digest Dis, CURE Digest Dis Res Ctr, Los Angeles, CA 90024 USA. [Stengel, Andreas; Goebel, Miriam; Tache, Yvette] Univ Calif Los Angeles, Ctr Neurobiol Stress, Los Angeles, CA 90024 USA. [Stengel, Andreas; Goebel, Miriam; Tache, Yvette] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Bannert, Norbert] Robert Koch Inst, D-1000 Berlin, Germany. [Moennikes, Hubert] Martin Luther Hosp, Dept Med, Berlin, Germany. [Moennikes, Hubert] Martin Luther Hosp, Inst Neurogastroenterol, Berlin, Germany. RP Kobelt, P (reprint author), Univ Med Berlin, Dept Med, Div Hepatol Gastroenterol & Endocrinol, Charite, Campus Virchow, D-10117 Berlin, Germany. EM peter.kobelt@charite.de FU German Research Foundation [DFG KO 3864/2-1, DFG STE 1765/1-1, GO 1718/1-1]; Charite-Universitatsmedizin Berlin [UFF 09/41730, 09/42458]; Veterans Administration Research Career Scientist Award; Veterans Administration Merit Award; NIHDK [33061]; [DK-41301] FX This work was supported by grants from the German Research Foundation to PX (DFG KO 3864/2-1), A.S. (DFG STE 1765/1-1), M.G. (GO 1718/1-1), and from Charite-Universitatsmedizin Berlin to PX (UFF 09/41730 and 09/42458) as well as Veterans Administration Research Career Scientist Award (Y.T.), Veterans Administration Merit Award (Y.T.), NIHDK 33061 (Y.T.), Center Grant DK-41301 (Animal Core) (Y.T.). NR 32 TC 40 Z9 44 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD FEB PY 2010 VL 31 IS 2 BP 257 EP 262 DI 10.1016/j.peptides.2009.11.024 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 560BQ UT WOS:000274877200010 PM 19961888 ER PT J AU Yuan, PQ Wu, SV Wang, L Tache, Y AF Yuan, P. -Q Wu, S. V. Wang, L. Tache, Y. TI Corticotropin releasing factor in the rat colon: Expression, localization and upregulation by endotoxin SO PEPTIDES LA English DT Article DE Corticotropin releasing factor; Enterochromaffin cells; Enteric nervous system; Lipopolysaccharide; Colon; Stress; Defecation; Corticosterone ID ENTERIC NERVOUS-SYSTEM; IRRITABLE-BOWEL-SYNDROME; MYENTERIC NEURONS; INTESTINAL INFLAMMATION; CONSCIOUS RATS; MAST-CELLS; TRYPTOPHAN-HYDROXYLASE; ENTEROCHROMAFFIN CELLS; 5-HT3 RECEPTORS; CHALLENGED RATS AB Little is known about CRF expression and regulation in the rat colon compared to the brain. We investigated CRF gene expression, cellular location, and regulation by endotoxin and corticosterone in the male rat colon at 6 h after intraperitoneal (ip) injection. CRF mRNA level, detected by reverse transcription-polymerase chain reaction (RT-PCR) was 1.3-fold higher in the distal than proximal colon and 3.4-fold higher in the proximal colonic submucosa plus muscle layers than in mucosa. CRF immunoreactivity was located in the epithelia, lamina propria and crypts, and co-localized with tryptophan hydroxylase. a marker for enterochromaffin (EC) cells, and in enteric neurons. Lipopolysaccharide (LPS, 100 mu g/kg, ip) increased defecation by 2.9-fold and upregulated CRF mRNA by 2.5-fold in the proximal and 1.1-fold in the distal colon while there was no change induced by corticosterone as monitored by quantitative PCR. LPS-induced increased CRF mRNA expression occurred in the submucosa plus muscle layers (1.5-fold) and the mucosa of proximal colon (0.9-fold). LIPS increased significantly CRF immunoreactivity in the submucosal and myenteric plexuses of proximal and distal colon compared to saline groups. These results indicate that in rats, CRF is expressed in both proximal and distal colon and more prominently in enteric neurons of the submucosa plus muscle layers and subject to upregulation at the gene and protein levels by LPS through corticosteroid independent pathways. These data suggests that colonic CRF may be part of the local effector limb of the CRF, receptor mediated colonic alterations induced by acute stress. (C) 2009 Elsevier Inc. All rights reserved. C1 [Yuan, P. -Q] Univ Calif Los Angeles, CURE, DDRC, VA GLAHS, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Ctr Neurobiol Stress, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Div Digest Dis, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90073 USA. RP Yuan, PQ (reprint author), Univ Calif Los Angeles, CURE, DDRC, VA GLAHS, Bldg 115,Rm 213B,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM pqyuan@mednet.ucla.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK-57238]; VA Career Scientist Award and Merit Award [DK-41301]; [P01-DK 33506] FX We thank Drs. Wylie W. Vale and jean Rivier(Salk institute, San Diego, CA) for the generous donation of the rabbit anti-CRF antiserum, and rat CRF, respectively and Ms Honghui Liang for technical assistance. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, grants R01 DK-57238 (YT), VA Career Scientist Award and Merit Award (YT), DK-41301 (Animal Core, YT), P01-DK 33506 (C. Pothoulakis, PI). NR 55 TC 20 Z9 20 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD FEB PY 2010 VL 31 IS 2 BP 322 EP 331 DI 10.1016/j.peptides.2009.11.012 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 560BQ UT WOS:000274877200020 PM 19944726 ER PT J AU Stengel, A Goebel, M Wang, LX Tache, Y AF Stengel, Andreas Goebel, Miriam Wang, Lixin Tache, Yvette TI Ghrelin, des-acyl ghrelin and nesfatin-1 in gastric X/A-like cells: Role as regulators of food intake and body weight SO PEPTIDES LA English DT Review DE Body weight; Endocrine cell; Food intake; Ghrelin; Nesfatin-1; NUCB2; Obesity; Stomach ID GROWTH-HORMONE SECRETAGOGUE; GLUCAGON-LIKE PEPTIDE-1; STIMULATES LOCOMOTOR-ACTIVITY; O-ACYLTRANSFERASE GOAT; COUPLED RECEPTOR GPR39; AGOUTI-RELATED PROTEIN; RAT ARCUATE NUCLEUS; PLASMA GHRELIN; PERIPHERAL GHRELIN; SLEEVE GASTRECTOMY AB Numerous peptides released from endocrine cells in the intestinal mucosa were established early on to be involved in the physiological regulation of food intake with a prominent role in termination of food ingestion when nutrients pass along the intestinal tract. Recently, peptides released from X/A-like endocrine cells of the gastric oxyntic mucosa were recognized as additional key players in the regulation of feeding and energy expenditure. Gastric X/A-like cells release the octanoylated peptide, ghrelin, the only known peripherally produced hormone stimulating food intake through interaction with growth hormone secretagogue I a receptor(GHS-R1a). Additionally, non-octanoylated (des-acyl) ghrelin present in the circulation at higher levels than ghrelin is currently discussed as potential modulator of food intake by opposing ghrelin's action independent from GHS-R1a although the functional significance remains to be established. Obestatin, a ghrelin-associated peptide was initially reported as anorexigenic modulator of ghrelin's orexigenic action. However, subsequent reports did not support this contention. Interesting is the recent identification of nesfatin-1, a peptide derived from the nucleobindin2 gene prominently expressed in gastric X/A-like cells in different vesicles than ghrelin. Circulating nesfatin-1 levels vary with metabolic state and peripheral or central injection inhibits dark phase feeding in rodents. Overall, these data point to an important role of gastric X/A-like cells in food intake regulation through the expression of the orexigenic peptide ghrelin along with des-acyl ghrelin and nesfatin-1 capable of reducing food intake upon exogenous injection although their mechanisms of action and functional significance remain to be established. Published by Elsevier Inc C1 [Tache, Yvette] Univ Calif Los Angeles, Digest Dis Res Ctr, CURE, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Div Digest Dis, David Geffen Sch Med, Los Angeles, CA 90073 USA. RP Tache, Y (reprint author), Univ Calif Los Angeles, Digest Dis Res Ctr, CURE, VA Greater Los Angeles Healthcare Syst, Bldg 115,Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM astengel@mednet.ucla.edu; ytache@mednet.ucla.edu FU VA Research Career Scientist Award; NIH [DK-33061, DK-57238]; VA Merit Award; German Research Foundation [STE 1765/1-1 and GO 1718/1-1] FX Y.T. is in receipt of VA Research Career Scientist Award and NIH R01 grants DK-33061, DK-57238 and VA Merit Award. A.S. and M.G. are supported by the German Research Foundation grants STE 1765/1-1 and GO 1718/1-1 respectively. We thank Ms. Eugenia Hu for careful reading of the manuscript. NR 170 TC 57 Z9 61 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD FEB PY 2010 VL 31 IS 2 BP 357 EP 369 DI 10.1016/j.peptides.2009.11.019 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 560BQ UT WOS:000274877200025 PM 19944123 ER PT J AU Blais, MA AF Blais, Mark A. TI The common structure of normal personality and psychopathology: Preliminary exploration in a non-patient sample SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE Normal personality; Psychopathology; Common structure; Factor analysis ID HIGHER-ORDER FACTORS; MENTAL-DISORDERS; MODEL; INSTRUMENTS; TRAITS; SCALES AB Normal personality and psychopathology have traditionally been conceptualized as separate or distinct areas of inquiry. However recent research exploring the hierarchical nature of personality traits suggests the possibility of integrating findings across these domains. This study used the Personality Assessment Inventory (Morey, 1991) and NEO-Personality Inventory-Revised (Costa & McCrae, 1992) to investigate the joint factor structure of normal personality and psychopathology. Factor analysis revealed a well defined three factor structure with scales from both instruments having prominent loadings on all the factors. The first joint PAI-NEO factor was marked by Neuroticism, Anxiety, Depression and Borderline Personality traits, the second factor had negative loadings for Agreeableness and Conscientiousness and positive loadings for Drug Abuse and Antisocial Personality traits. The third joint factor had positive loadings for Extraversion, Openness and Mania plus a secondary negative loading for Depression. The joint PAI-NEO factor structure bore a clear resemblance to the Big Three model of personality traits depicted in Markon, Krueger, and Watson's (2005) personality hierarchy. While preliminary the current findings suggest that normal personality and psychopathology may share a common latent structure and their shared structure may integrate into the broader hierarchy of personality traits. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Blais, Mark A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Blais, Mark A.] Harvard Univ, Sch Med, Psychol Evaluat & Res Lab, Boston, MA 02114 USA. RP Blais, MA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM Mblais@partners.org NR 28 TC 8 Z9 8 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD FEB PY 2010 VL 48 IS 3 BP 322 EP 326 DI 10.1016/j.paid.2009.10.028 PG 5 WC Psychology, Social SC Psychology GA 557OE UT WOS:000274678000012 ER PT J AU Deo, RC Hunter, L Lewis, GD Pare, G Vasan, RS Chasman, D Wang, TJ Gerszten, RE Roth, FP AF Deo, Rahul C. Hunter, Luke Lewis, Gregory D. Pare, Guillaume Vasan, Ramachandran S. Chasman, Daniel Wang, Thomas J. Gerszten, Robert E. Roth, Frederick P. TI Interpreting Metabolomic Profiles using Unbiased Pathway Models SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID CITRIN DEFICIENCY; PROSTATE-CANCER; BREAST-CANCER; HUMAN-DISEASE; NETWORK; INSULIN; ASSOCIATION; CLASSIFICATION; PREDICTION; SIGNATURES AB Human disease is heterogeneous, with similar disease phenotypes resulting from distinct combinations of genetic and environmental factors. Small-molecule profiling can address disease heterogeneity by evaluating the underlying biologic state of individuals through non-invasive interrogation of plasma metabolite levels. We analyzed metabolite profiles from an oral glucose tolerance test (OGTT) in 50 individuals, 25 with normal (NGT) and 25 with impaired glucose tolerance (IGT). Our focus was to elucidate underlying biologic processes. Although we initially found little overlap between changed metabolites and preconceived definitions of metabolic pathways, the use of unbiased network approaches identified significant concerted changes. Specifically, we derived a metabolic network with edges drawn between reactant and product nodes in individual reactions and between all substrates of individual enzymes and transporters. We searched for "active modules''-regions of the metabolic network enriched for changes in metabolite levels. Active modules identified relationships among changed metabolites and highlighted the importance of specific solute carriers in metabolite profiles. Furthermore, hierarchical clustering and principal component analysis demonstrated that changed metabolites in OGTT naturally grouped according to the activities of the System A and L amino acid transporters, the osmolyte carrier SLC6A12, and the mitochondrial aspartate-glutamate transporter SLC25A13. Comparison between NGT and IGT groups supported blunted glucose- and/or insulin-stimulated activities in the IGT group. Using unbiased pathway models, we offer evidence supporting the important role of solute carriers in the physiologic response to glucose challenge and conclude that carrier activities are reflected in individual metabolite profiles of perturbation experiments. Given the involvement of transporters in human disease, metabolite profiling may contribute to improved disease classification via the interrogation of specific transporter activities. C1 [Deo, Rahul C.; Hunter, Luke; Roth, Frederick P.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Deo, Rahul C.; Lewis, Gregory D.; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Lewis, Gregory D.; Gerszten, Robert E.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Pare, Guillaume; Chasman, Daniel] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA. [Pare, Guillaume; Chasman, Daniel] Harvard Univ, Brigham & Womens Hosp, Sch Med, Donald W Reynolds Ctr Cardiovasc Res, Boston, MA 02115 USA. [Vasan, Ramachandran S.; Wang, Thomas J.] NHLBI, Framingham Heart Study, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. RP Deo, RC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM fritz_roth@hms.harvard.edu RI Roth, Frederick/H-6308-2011; OI Ramachandran, Vasan/0000-0001-7357-5970; Roth, Frederick/0000-0002-6628-649X FU NIH [T32 HL007208, HL096738, DK081572-02, HL081341, HG004233, HG0017115, NS035611, HG003224]; AHA; Leducq Foundation; Canadian Institute for Advanced Research FX RCD was supported by NIH grant T32 HL007208; REG was supported by NIH Grants HL096738, DK081572-02, the AHA Established Investigator Award and the Leducq Foundation; and FPR was supported by NIH grants HL081341, HG004233, HG0017115, NS035611, HG003224 and by the Canadian Institute for Advanced Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 32 Z9 32 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2010 VL 6 IS 2 AR e1000692 DI 10.1371/journal.pcbi.1000692 PG 14 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 565AI UT WOS:000275260000012 PM 20195502 ER PT J AU Kim, SY Dunn, IF Firestein, R Gupta, P Wardwell, L Repich, K Schinzel, AC Wittner, B Silver, SJ Root, DE Boehm, JS Ramaswamy, S Lander, ES Hahn, WC AF Kim, So Young Dunn, Ian F. Firestein, Ron Gupta, Piyush Wardwell, Leslie Repich, Kara Schinzel, Anna C. Wittner, Ben Silver, Serena J. Root, David E. Boehm, Jesse S. Ramaswamy, Sridhar Lander, Eric S. Hahn, William C. TI CK1 epsilon Is Required for Breast Cancers Dependent on beta-Catenin Activity SO PLOS ONE LA English DT Article ID WNT SIGNALING PATHWAY; COLON-CANCER; EXPRESSION; ACTIVATION; GENE; INHIBITOR; GROWTH; CELLS; MEMBRANE; ONCOGENE AB Background: Aberrant beta-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate beta-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active beta-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized beta-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1 epsilon) as required specifically for the proliferation of breast cancer cells with activated beta-catenin and confirm its role as a positive regulator of beta-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated beta-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/beta-catenin signaling. We also find that expression of CK1e is able to promote oncogenic transformation of human cells in a beta-catenin-dependent manner. Conclusions/Significance: These studies identify CK1 epsilon as a critical contributor to activated beta-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active beta-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors. C1 [Kim, So Young; Dunn, Ian F.; Firestein, Ron; Wardwell, Leslie; Repich, Kara; Schinzel, Anna C.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wittner, Ben; Ramaswamy, Sridhar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dunn, Ian F.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Firestein, Ron] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kim, So Young; Schinzel, Anna C.; Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Kim, So Young; Firestein, Ron; Schinzel, Anna C.; Boehm, Jesse S.; Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Kim, So Young; Dunn, Ian F.; Firestein, Ron; Gupta, Piyush; Repich, Kara; Schinzel, Anna C.; Silver, Serena J.; Root, David E.; Boehm, Jesse S.; Ramaswamy, Sridhar; Lander, Eric S.; Hahn, William C.] Broad Inst, Cambridge, MA USA. [Wittner, Ben; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Ramaswamy, Sridhar] Harvard Stem Cell Inst, Cambridge, MA USA. RP Kim, SY (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM William_Hahn@dfci.harvard.edu OI Boehm, Jesse/0000-0002-6795-6336 FU Department of Defense postdoctoral fellowship; National Institutes of Health (NIH) [K08 CA134836-01]; Mentored Clinical Scientist Award [P50 CA127003]; GI SPORE Career Development [R33 CA128625, R01 CA130988]; Department of Defense Idea Award [W81XWH-07-1-0408]; Dana-Farber Harvard Cancer Center SPORE in Breast Cancer [P50 CA89393] FX This work was supported in part by a Department of Defense postdoctoral fellowship (S.Y.K.), the Brain Science Foundation and Warren-Whitman-Richardson Foundation (I. D.), K08 CA134836-01 from National Institutes of Health (NIH): Mentored Clinical Scientist Award and P50 CA127003: GI SPORE Career Development Grant (R.F.), R33 CA128625 (W.C.H.), R01 CA130988 (W.C.H.), Department of Defense Idea Award W81XWH-07-1-0408 (W.C.H.), Dana-Farber Harvard Cancer Center SPORE in Breast Cancer P50 CA89393 (S.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 46 Z9 49 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 1 PY 2010 VL 5 IS 2 AR e8979 DI 10.1371/journal.pone.0008979 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 551LF UT WOS:000274209700008 PM 20126544 ER PT J AU Evans, CT Li, K Burns, SP Smith, B Lee, TA Weaver, FM AF Evans, Charlesnika T. Li, Keran Burns, Stephen P. Smith, Bridget Lee, Todd A. Weaver, Frances M. TI Antibiotic Prescribing for Acute Respiratory Infection and Subsequent Outpatient and Hospital Utilization in Veterans With Spinal Cord Injury and Disorder SO PM&R LA English DT Article AB Objective: To assess the association between antibiotic prescribing for acute respiratory infection (ARI) and subsequent health-care utilization in veterans with spinal cord injury and disorder (SCI/D). Design: Retrospective cohort of veterans with SCI/D. Setting: Veterans Affairs medical facilities that provide outpatient care. Patients: Veterans with SCI/D with a diagnosis of acute bronchitis or upper respiratory infection during an outpatient visit between fiscal year 2006 and 2007 that did not result in same-clay hospitalization. Independent Variable: Receipt of a new antibiotic prescription occurring within 3 clays before or after an ARI visit. Main Outcome Measure: Subsequent outpatient visit or hospitalization within 30 days of the index ARI visit. Results: A total of 1277 patients were identified with ARI; 53.2% were prescribed an antibiotic. An outpatient clinic visit within 30 days of the index ARI visit occurred in 47.0% of patients. Receipt of an antibiotic prescription was not associated with a subsequent outpatient visit. However, in those with certain chronic respiratory conditions (cough, shortness of breath, bronchitis not specified as acute or chronic, and allergic rhinitis), those prescribed antibiotics were less likely to return for an outpatient visit than those not prescribed antibiotics (adjusted relative risk = 0.77, 95% confidence interval = 0.61-0.97); no association was observed in those patients without these conditions. A total of 7.9% of patients were hospitalized within 30 days and did not differ by prescribing group. The 30-day mortality rate was 0.6%. Conclusions: Certain chronic respiratory conditions in veterans with SCI/D may be risk factors for increased health-care utilization and potentially poor outcomes if a patient is not treated with antibiotics for ARI. However, in those without these conditions, those with ARI who were prescribed antibiotics have similar utilization to those not prescribed antibiotics. These data suggest that in the absence of chronic respiratory conditions, antibiotic use for ARI can be curbed in this population that is at high risk for respiratory complications. PM R 2010;2:101-109 C1 [Evans, Charlesnika T.] Vet Affairs Edward Hines Jr Hosp, Ctr Management Complex Chron Care Spinal Cord Inj, Dept Vet Affairs VA, Hines, IL USA. [Evans, Charlesnika T.; Li, Keran; Smith, Bridget; Weaver, Frances M.] Northwestern Univ, Feinberg Sch Med, Inst Healthcare Studies, Chicago, IL 60611 USA. [Li, Keran] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Burns, Stephen P.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Burns, Stephen P.] Univ Washington, Seattle, WA 98195 USA. [Lee, Todd A.] Univ Illinois, Chicago, IL USA. [Weaver, Frances M.] Northwestern Univ, Sch Med, Dept Neurol, Chicago, IL 60611 USA. RP Evans, CT (reprint author), Vet Affairs Edward Hines Jr Hosp, Ctr Management Complex Chron Care Spinal Cord Inj, Dept Vet Affairs VA, 5th Ave & Roosevelt Rd,POB 5000,Room D302, Hines, IL USA. EM Charlesnika.Evans@va.gov FU Department of Veterans Affairs, Office at Research and Development, Health Services Research and Development Service Locally Initiated Project [LIP 42-503]; Paralyzed Veterans of America Research Foundation [2562] FX Supported by the Department of Veterans Affairs, Office at Research and Development, Health Services Research and Development Service Locally Initiated Project (LIP 42-503), and the Paralyzed Veterans of America Research Foundation (Project #2562). NR 39 TC 3 Z9 4 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD FEB PY 2010 VL 2 IS 2 BP 101 EP 109 DI 10.1016/j.pmrj.2009.11.002 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA V23RY UT WOS:000208361100004 PM 20117971 ER PT J AU Stirman, SW Bhar, SS Spokas, M Brown, GK Creed, TA Perivoliotis, D Farabaugh, DT Grant, PM Beck, AT AF Stirman, Shannon Wiltsey Bhar, Sunil S. Spokas, Megan Brown, Gregory K. Creed, Torrey A. Perivoliotis, Dimitri Farabaugh, Danielle T. Grant, Paul M. Beck, Aaron T. TI Training and Consultation in Evidence-Based Psychosocial Treatments in Public Mental Health Settings: The ACCESS Model SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article DE evidence-based psychotherapies; training; consultation; implementation ID EMPIRICALLY SUPPORTED TREATMENTS; COGNITIVE-BEHAVIORAL THERAPY; STAFF TURNOVER; IMPLEMENTATION; DISSEMINATION; PSYCHOTHERAPY; ADHERENCE; COMMUNITY; YOUTH; INTERVENTIONS AB We present a model of training in evidence-based psychosocial treatments (EBTs). The ACCESS (assess and adapt, convey basics, consult, evaluate. study outcomes, sustain) model integrates principles and findings from adult education and training literatures, research. and practical suggestions based on a community-based clinician training program. Descriptions of the steps are provided as a means of guiding implementation efforts and facilitating training partnerships between public mental health agencies and practitioners of EBTs. C1 [Stirman, Shannon Wiltsey] Boston Univ, Womens Hlth Sci Div, Natl Ctr PTSD, Med Ctr, Boston, MA 02130 USA. [Bhar, Sunil S.] Swinbourne Univ Technol, Melbourne, Vic, Australia. [Spokas, Megan] La Salle Univ, Philadelphia, PA USA. [Perivoliotis, Dimitri] Univ Penn, Dept Psychiat, Psychopathol Res Unit, Philadelphia, PA 19104 USA. [Grant, Paul M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Creed, Torrey A.] Childrens Hosp Philadelphia, Ctr Family Intervent Sci, Philadelphia, PA USA. [Creed, Torrey A.] Univ Penn, Beck Initiat, Philadelphia, PA 19104 USA. [Farabaugh, Danielle T.] Coatesville Vet Affairs Med Ctr, Inpatient Posttraumat Stress Disorder Program, Coatesville, PA USA. RP Stirman, SW (reprint author), Boston Univ, Womens Hlth Sci Div, Natl Ctr PTSD, Med Ctr, 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. EM Shannon.Wiltsey-Stirman@va.gov FU NIMH NIH HHS [K99 MH080100, K99 MH080100-01A1, P20 MH071905, R00 MH080100] NR 63 TC 24 Z9 24 U1 2 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD FEB PY 2010 VL 41 IS 1 BP 48 EP 56 DI 10.1037/a0018099 PG 9 WC Psychology, Multidisciplinary SC Psychology GA 554ZL UT WOS:000274475600007 PM 22872783 ER PT J AU Conklin, SM Runyan, CA Leonard, S Reddy, RD Muldoon, MF Yao, JK AF Conklin, Sarah M. Runyan, Caroline A. Leonard, Sherry Reddy, Ravinder D. Muldoon, Matthew F. Yao, Jeffrey K. TI Age-related changes of n-3 and n-6 polyunsaturated fatty acids in the anterior cingulate cortex of individuals with major depressive disorder SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE Depression; Anterior cingulate cortex; Postmortem; n-6 fatty acids; Arachidonic acid; n-3 fatty acids; Eicosapentaenoic acid; Docosahexaenoic acid; Age ID OMEGA-3-FATTY-ACID DOCOSAHEXAENOIC ACID; POSTMORTEM ORBITOFRONTAL CORTEX; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; PRELIMINARY DOUBLE-BLIND; BLOOD-CELL MEMBRANES; ARACHIDONIC-ACID; BIPOLAR DISORDER; FISH CONSUMPTION; FRONTAL-CORTEX AB Accumulating evidence finds a relative deficiency of peripheral membrane fatty acids in persons with affective disorders such as unipolar and bipolar depression. Here we sought to investigate whether postmortem brain fatty acids within the anterior cingulate cortex (BA-24) varied according to the presence of major depression at the time of death. Using capillary gas chromatography we measured fatty acids in a depressed group (n = 12), and in a control group without lifetime history of psychiatric diagnosis (n = 14). Compared to the control group, the depressed group showed significantly lower concentrations of numerous saturated and polyunsaturated fatty acids including both the n-3 and n-6 fatty acids. Additionally, significant correlations between age at death and precursor (or metabolites) in the n-3 fatty acid pathway were demonstrated in the depressed group but not in control subjects. In the n-6 fatty acid family, the ratio of 20:3(n-6)/18:2(n-6) was higher in patients than in control groups, whereas the ratio of 20A(n-6)/20:3(n-6) was relatively decreased in patients. Lastly, a significant negative correlation between age and the ratio of 20:4(n-6) to 22:6(n-3) was found in patients, but not in controls. Taken together, decreases in 22:6(n-3) may be caused, at least in part, by the diminished formation of 20:5(n-3), which is derived from 20:4(n-3) through a Delta 5 desaturase reaction. The present findings from postmortem brain tissue raise the possibility that an increased ratio of 20:4(n-6) to 22:6(n-3) may provide us with a biomarker for depression. Future research should further investigate these relationships. Published by Elsevier Ltd. C1 [Conklin, Sarah M.; Reddy, Ravinder D.; Muldoon, Matthew F.; Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA USA. [Conklin, Sarah M.] Allegheny Coll, Neurosci Program, Meadville, PA 16335 USA. [Conklin, Sarah M.] Allegheny Coll, Dept Psychol, Meadville, PA 16335 USA. [Runyan, Caroline A.] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Leonard, Sherry] Univ Colorado, Hlth Sci Ctr, Denver VA Med Ctr, Denver, CO USA. [Leonard, Sherry] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. [Leonard, Sherry] Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. [Reddy, Ravinder D.; Yao, Jeffrey K.] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. [Muldoon, Matthew F.] Univ Pittsburgh, Sch Med, Ctr Clin Pharmacol, Pittsburgh, PA USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA USA. EM jkyao@pitt.edu FU Office of Research and Development, Department of Veterans Affairs; NIH [T32 HL007560]; Highland Drive VA Pittsburgh Healthcare System FX This study was supported in parts by the Office of Research and Development, Department of Veterans Affairs [Merit Reviews (JKY,SL) and Research Career Scientist Awards (JKY,SL)], NIH T32 HL007560 (SMC, MFM), and the Highland Drive VA Pittsburgh Healthcare System. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 57 TC 28 Z9 28 U1 6 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD FEB-MAR PY 2010 VL 82 IS 2-3 BP 111 EP 119 DI 10.1016/j.plefa.2009.12.002 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 569RQ UT WOS:000275617500007 PM 20060277 ER PT J AU Vera, M Perez-Pedrogo, C Huertas, SE Reyes-Rabanillo, ML Juarbe, D Huertas, A Reyes-Rodriguez, ML Chaplin, W AF Vera, Mildred Perez-Pedrogo, Coralee Huertas, Sarah Enid Reyes-Rabanillo, Maria Leticia Juarbe, Deborah Huertas, Aracelis Reyes-Rodriguez, Mae Lynn Chaplin, William TI Collaborative Care for Depressed Patients With Chronic Medical Conditions: A Randomized Trial in Puerto Rico SO PSYCHIATRIC SERVICES LA English DT Article ID COMORBID DEPRESSION; HEALTH-SERVICES; CHRONIC DISEASE; TERM OUTCOMES; MANAGEMENT; METAANALYSIS; POPULATION; VALIDATION; SYMPTOMS; VALIDITY AB Objective: This study examined whether a collaborative care model for depression would improve clinical and functional outcomes for depressed patients with chronic general medical conditions in primary care practices in Puerto Rico. Methods: A total of 179 primary care patients with major depression and chronic general medical conditions were randomly assigned to receive collaborative care or usual care. The collaborative care intervention involved enhanced collaboration among physicians, mental health specialists, and care managers paired with depression-specific treatment guidelines, patient education, and follow-up. In usual care, study personnel informed the patient and provider of the diagnosis and encouraged patients to discuss treatment options with their provider. Depression severity was assessed with the Hopkins Symptom Checklist; social functioning was assessed with the 36-item Short Form. Results: Compared with usual care, collaborative care significantly reduced depressive symptoms and improved social functioning in the six months after randomization. Integration of collaborative care in primary care practices considerably increased depressed patients' use of mental health services. Conclusions: Collaborative care significantly improved clinical symptoms and functional status of depressed patients with coexisting chronic general medical conditions receiving treatment for depression in primary care practices in Puerto Rico. These findings highlight the promise of the collaborative care model for strengthening the relationship between mental health and primary care services in Puerto Rico. (Psychiatric Services 61:144-150, 2010) C1 [Vera, Mildred; Perez-Pedrogo, Coralee; Juarbe, Deborah] Univ Puerto Rico, Ctr Evaluat & Sociomed Res, Grad Sch Publ Hlth, San Juan, PR 00936 USA. [Huertas, Aracelis] Univ Puerto Rico, Sch Hlth Profess, San Juan, PR 00936 USA. [Huertas, Sarah Enid] Univ Puerto Rico, Dept Psychiat, Sch Med, San Juan, PR 00936 USA. [Vera, Mildred] Univ Puerto Rico, Dept Hlth Serv Adm, San Juan, PR 00936 USA. [Reyes-Rabanillo, Maria Leticia] US Dept Vet Affairs, VA Caribbean Healthcare Syst, San Juan, PR USA. [Reyes-Rodriguez, Mae Lynn] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Chaplin, William] St Johns Univ, Dept Psychol, New York, NY USA. RP Vera, M (reprint author), Univ Puerto Rico, Ctr Evaluat & Sociomed Res, Grad Sch Publ Hlth, Med Sci Campus,POB 365067, San Juan, PR 00936 USA. EM mildred.vera@upr.edu FU National Institute of General Medical Sciences [S06-GM008224]; Pfizer, Inc [WS297211]; National Center for Research Resources [P20-RR11126] FX This project was supported by grant S06-GM008224 from the National Institute of General Medical Sciences, grant WS297211 from Pfizer, Inc., and grant P20-RR11126 from the National Center for Research Resources. NR 36 TC 19 Z9 19 U1 2 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD FEB PY 2010 VL 61 IS 2 BP 144 EP 150 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 550VN UT WOS:000274160300008 PM 20123819 ER PT J AU Gonzalez, JM Bowden, CL Berman, N Frank, E Bauer, MS Kogan, JN Alegria, M Miklowitz, DJ AF Gonzalez, Jodi M. Bowden, Charles L. Berman, Nancy Frank, Ellen Bauer, Mark S. Kogan, Jane N. Alegria, Margarita Miklowitz, David J. TI One-Year Treatment Outcomes of African-American and Hispanic Patients With Bipolar I or II Disorder in STEP-BD SO PSYCHIATRIC SERVICES LA English DT Article ID NATIONAL-COMORBIDITY-SURVEY; R PSYCHIATRIC-DISORDERS; SEVERE MENTAL-ILLNESS; UNITED-STATES; RACIAL-DIFFERENCES; 12-MONTH PREVALENCE; CULTURAL MISTRUST; WHITE PATIENTS; RATING-SCALE; DIAGNOSIS AB Objective: Few studies have compared treatment outcomes of African-American, Hispanic, and non-Hispanic white patients with bipolar disorder. The U. S. Systematic Treatment Enhancement Program for Bipolar Disorder compared one-year outcomes for bipolar I or II disorder from each of these racial-ethnic groups. Methods: African Americans (N=155) were retrospectively compared with a matched group of non-Hispanic whites (N=729), and Hispanics (N=152) were compared with a separate matched group of non-Hispanic whites (N=822). Response and recovery outcomes were examined. Survival analysis was used to compare time to treatment response for depression (Montgomery-Asberg Depression Rating Scale) and mania (Young Mania Rating Scale) as well as global assessment of functioning (Global Assessment of Functioning). Results: For manic and depressive symptoms, time to response and proportion of responders were similar across groups. Over the study year the proportion of days well was similar across groups. A smaller proportion of African Americans met criteria for improved global functioning. Depression response among African Americans with psychotic symptoms was slower than the response among African Americans without psychotic symptoms and among non-Hispanic whites with or without psychotic symptoms. No differences between Hispanics and non-Hispanic whites in response times and recovery were observed. Conclusions: Results are consistent with U. S. clinical trials for other psychiatric disorders, which have reported similar outcomes for ratings of primary symptoms. Baseline psychotic symptoms are likely a significant contributor when African Americans with bipolar disorder are slow to recover. These results may be less generalizable to uninsured patients. (Psychiatric Services 61:164-172, 2010) C1 [Gonzalez, Jodi M.; Bowden, Charles L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Berman, Nancy] MIT, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02139 USA. [Frank, Ellen; Kogan, Jane N.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Bauer, Mark S.] Harvard Univ, Sch Med, Harvard S Shore Psychiat Residency Training Progr, Cambridge, MA 02138 USA. [Bauer, Mark S.] VA Boston Healthcare Syst, Boston, MA USA. [Alegria, Margarita] Cambridge Hlth Alliance, Ctr Multicultural Mental Hlth Res, Cambridge, MA USA. [Miklowitz, David J.] Univ Calif Los Angeles, Sch Med, Div Child & Adolescent Psychiat, Los Angeles, CA 90024 USA. RP Gonzalez, JM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM gonzalezjm1@uthscsa.edu FU National Institute of Mental Health (NIMH) [1MH-80001, P20-MH068662] FX This study was conducted with the support of contracts 1MH-80001 and P20-MH068662 from the National Institute of Mental Health (NIMH). Opinions, findings, and conclusions or recommendations expressed in this article are those of the authors and do not necessarily reflect the views of the NIMH. This article was approved by the STEP-BD Publication Committee. NR 41 TC 9 Z9 9 U1 2 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD FEB PY 2010 VL 61 IS 2 BP 164 EP 172 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 550VN UT WOS:000274160300011 PM 20123822 ER PT J AU Leuchter, AF Husain, MM Cook, IA Trivedi, MH Wisniewski, SR Gilmer, WS Luther, JF Fava, M Rush, AJ AF Leuchter, A. F. Husain, M. M. Cook, I. A. Trivedi, M. H. Wisniewski, S. R. Gilmer, W. S. Luther, J. F. Fava, M. Rush, A. J. TI Painful physical symptoms and treatment outcome in major depressive disorder: a STAR*D (Sequenced Treatment Alternatives to Relieve Depression) report SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Antidepressant medication; major depression; pain; treatment response ID DIAGNOSTIC SCREENING QUESTIONNAIRE; REPORT QIDS-SR; QUICK INVENTORY; RATING-SCALE; PRIMARY-CARE; PSYCHOMETRIC EVALUATION; BACK-PAIN; SYMPTOMATOLOGY; TRIAL; ANTIDEPRESSANTS AB Background. Painful physical symptoms (PPS) are both common and reduce the likelihood of remission in major depressive disorder (MDD), based upon results of clinical trials in selected populations. Whether PI'S significantly contribute to poorer treatment outcome overall in primary or specialty psychiatric care settings remains Unclear. Method. Out-patients (n = 2876) with MDD were treated in the first step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial with citalopram up to 60 mg/day for LIP to 14 weeks. Presence of painful symptoms, as well as severity of depression, physical illness, and demographic and treatment factors were examined. Time to and overall rates of remission were analysed in relation to the presence of PPS. Results. Of the participants, 80% complained of PPS. These patients, both in primary and specialty psychiatric settings, had significantly, lower remission rates and took longer to remit. Increasing severity of PIS was associated with greater physical illness burden, lower socio-economic status, absence of private insurance and being female, African-American or Hispanic. After adjustment for these factors, patients with PPS no longer had significantly poorer treatment outcomes. Conclusions. Presence and severity of PPS is an indicator of MDD that may have poorer treatment outcome with in initial selective serotonin reuptake inhibitor. These poorer treatment outcomes are multifactorial, however, and are not explained by the presence and severity of pain per se. C1 [Leuchter, A. F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Lab Brain Behav & Pharmacol,Semel Inst Neurosci &, Los Angeles, CA 90024 USA. [Husain, M. M.; Trivedi, M. H.; Rush, A. J.] Univ Texas SW Med Sch, Dept Psychiat, Dallas, TX 75230 USA. [Wisniewski, S. R.; Luther, J. F.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Gilmer, W. S.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Fava, M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Leuchter, AF (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Lab Brain Behav & Pharmacol,Semel Inst Neurosci &, 760 Westwood Plaza,Room 37-452, Los Angeles, CA 90024 USA. EM afl@ucla.edu FU NIMH; National Institutes of Health [N01MH90003] FX This project has been funded with Federal funds from the NIMH, National Institutes of Health, under contract N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (principal investigator AJR) [ClinicalTrials.gov no. NCT000215281. NR 44 TC 42 Z9 45 U1 2 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD FEB PY 2010 VL 40 IS 2 BP 239 EP 251 DI 10.1017/S0033291709006035 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 554GD UT WOS:000274422600007 PM 19493369 ER PT J AU Jha, AK Prasopa-Plaizier, N Larizgoitia, I Bates, DW AF Jha, A. K. Prasopa-Plaizier, N. Larizgoitia, I. Bates, D. W. CA WHO World Alliance Patient Safety TI Patient safety research: an overview of the global evidence SO QUALITY & SAFETY IN HEALTH CARE LA English DT Article ID ADVERSE DRUG EVENTS; INTENSIVE-CARE UNITS; SURGICAL-SITE INFECTIONS; AUSTRALIAN HEALTH-CARE; HOSPITALIZED-PATIENTS; RISK-FACTORS; NOSOCOMIAL INFECTIONS; NURSING-HOMES; WORK HOURS; INTERNS AB Background Unsafe medical care may cause substantial morbidity and mortality globally, despite imprecise estimates of the magnitude of the problem. To better understand the extent and nature of the problem of unsafe care, the WHO World Alliance for Patient Safety commissioned an overview of the world's literature on patient safety research. Methods Major patient safety topics were identified through a consultative and investigative process and were categorised into the framework of structure, process and outcomes of unsafe care. Lead experts examined current evidence and identified major knowledge gaps relating to topics in developing, transitional and developed nations. The report was reviewed by internal and external experts and underwent improvements based on the feedback. Findings Twenty-three major patient safety topics were examined. Much of the evidence of the outcomes of unsafe care is from developed nations, where prevalence studies demonstrate that between 3% and 16% of hospitalised patients suffer harm from medical care. Data from transitional and developing countries also suggest substantial harm from medical care. However, considerable gaps in knowledge about the structural and process factors that underlie unsafe care globally make solutions difficult to identify, especially in resource-poor settings. Interpretation Harm from medical care appears to pose a substantial burden to the world's population. However, much of the evidence base comes from developed nations. Understanding the scope of and solutions for unsafe care for the rest of the world is a critical component of delivering safe, effective care to all of the world's citizens. C1 [Jha, A. K.; Bates, D. W.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Jha, A. K.; Bates, D. W.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Jha, A. K.] VA Boston Healthcare Syst, Boston, MA USA. [Prasopa-Plaizier, N.; Larizgoitia, I.] WHO, WHO World Alliance Patient Safety, CH-1211 Geneva, Switzerland. RP Jha, AK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 665 Huntington Ave, Boston, MA 02115 USA. EM ajha@hsph.harvard.edu RI Bright, Roselie/D-2240-2016 FU WHO World Alliance for Patient Safety, World Health Organization, Geneva, Switzerland FX Funding The project was funded by the WHO World Alliance for Patient Safety, World Health Organization, Geneva, Switzerland. NR 77 TC 57 Z9 63 U1 1 U2 13 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1475-3898 J9 QUAL SAF HEALTH CARE JI Qual. Saf. Health Care PD FEB PY 2010 VL 19 IS 1 BP 42 EP 47 DI 10.1136/qshc.2008.029165 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 557BC UT WOS:000274641500009 PM 20172882 ER PT J AU Feuchtner, GM Alkadhi, H Karlo, C Sarwar, A Meier, A Dichtl, W Leschka, S Blankstein, R Gruenenfelder, J Stolzmann, P Cury, RC AF Feuchtner, Gudrun M. Alkadhi, Hatem Karlo, Christoph Sarwar, Ammar Meier, Andreas Dichtl, Wolfgang Leschka, Sebastian Blankstein, Ron Gruenenfelder, Juerg Stolzmann, Paul Cury, Ricardo C. TI Cardiac CT Angiography for the Diagnosis of Mitral Valve Prolapse: Comparison with Echocardiography SO RADIOLOGY LA English DT Article ID MULTISLICE COMPUTED-TOMOGRAPHY; CARDIOVASCULAR-MAGNETIC-RESONANCE; CORONARY-ARTERY-DISEASE; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; TRANSTHORACIC ECHOCARDIOGRAPHY; REGURGITATION; ACCURACY; QUANTIFICATION; STENOSIS; SURGERY AB Purpose: To evaluate the diagnostic performance of coronary computed tomographic (CT) angiography for the diagnosis of mitral valve prolapse (MVP). Materials and Methods: The retrospective case-controlled multicenter study protocol was approved by the institutional review boards. The U. S. part of the study was HIPAA compliant. One hundred twelve patients who underwent electrocardiographically gated 64-section coronary CT angiography (n = 60) or dual-source coronary CT angiography (n = 52) and transthoracic echocardiography (TTE) were included. Fifty-three patients with MVP were matched for age and sex with 59 patients without MVP. CT images were analyzed on three-, two-, and four-chamber (CH) views by two independent observers. MVP was defined as a greater than 2-mm displacement of leaflets below the annulus plane and was subclassified as "billowing" (bowing) or "flail leaflet" (free leaflet margin displacement). Leaflet thickness was measured and defined as thickened if it was greater than 2 mm. Results: The diagnostic performance of CT when three- and two- CH views were combined for the diagnosis of MVP was as follows: sensitivity, 96%; specificity, 93%; positive predictive value (PPV), 93%; and negative predictive value, 96%. On four-CH views, the excursion of billowing was higher than it was on three- CH views (P<.001), and the PPV of the four-CH view for diagnosis of MVP was 89%. The correlation between CT and TTE for excursion of billowing was high (r = 0.80-0.91). In a subset of 32 patients, the agreement between CT and TTE for differentiation of billowing (n = 13) and flail leaflet (n = 2) was 100%. Leaflet thickening was more prevalent in patients with MVP than it was in those without (71% vs 20%, P<.001), and correlation with TTE was good (r = 0.81 [anterior leaflet] and 0.77 [posterior leaflet]). Conclusion: The combined use of three- and two-CH views allows an accurate diagnosis of MVP at coronary CT angiography. C1 [Feuchtner, Gudrun M.; Dichtl, Wolfgang] Innsbruck Med Univ, Dept Radiol 2, A-6020 Innsbruck, Austria. [Feuchtner, Gudrun M.; Sarwar, Ammar; Blankstein, Ron; Cury, Ricardo C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Alkadhi, Hatem; Karlo, Christoph; Meier, Andreas; Leschka, Sebastian; Stolzmann, Paul] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Gruenenfelder, Juerg] Univ Zurich Hosp, Cardiovasc Surg Clin, CH-8091 Zurich, Switzerland. [Cury, Ricardo C.] Baptist Miami Cardiac & Vasc Inst, Dept Radiol, Miami, FL USA. RP Feuchtner, GM (reprint author), Innsbruck Med Univ, Dept Radiol 2, Anichstr 35, A-6020 Innsbruck, Austria. EM Gudrun.Feuchtner@i-med.ac.at FU National Center of Competence in Research, Computer Aided; Image Guided Medical Interventions of the Swiss National Science Foundation FX From the Department of Radiology II, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria ( G. M. F., W. D.); Department of Radiology, Massachusetts General Hospital, Boston, Mass ( G. M. F., A. S., R. B., R. C. C.); Institute of Diagnostic Radiology ( H. A., C. K., A. M., S. L., P. S.) and Clinic for Cardiovascular Surgery (J.G.), University Hospital Zurich, Zurich, Switzerland; and Department of Radiology, Baptist ( Miami) Cardiac and Vascular Institute, Miami, Fla ( R. C. C.). Received March 4, 2009; revision requested March 30; final revision received June 16; accepted June 19; final version accepted July 24. H. A. supported by the National Center of Competence in Research, Computer Aided and Image Guided Medical Interventions of the Swiss National Science Foundation. Address correspondence to G. M. F. (e-mail: Gudrun.Feuchtner@i-med.ac.at). NR 32 TC 27 Z9 28 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2010 VL 254 IS 2 BP 374 EP 383 DI 10.1148/radiol.2541090393 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 546QF UT WOS:000273824600008 PM 20093510 ER PT J AU Rocha, JA Blankstein, R Shturman, LD Bezerra, HG Okada, DR Rogers, IS Ghoshhajra, B Hoffmann, U Feuchtner, G Mamuya, WS Brady, TJ Cury, RC AF Rocha-Filho, Jose A. Blankstein, Ron Shturman, Leonid D. Bezerra, Hiram G. Okada, David R. Rogers, Ian S. Ghoshhajra, Brian Hoffmann, Udo Feuchtner, Gudrun Mamuya, Wilfred S. Brady, Thomas J. Cury, Ricardo C. TI Incremental Value of Adenosine-induced Stress Myocardial Perfusion Imaging with Dual-Source CT at Cardiac CT Angiography SO RADIOLOGY LA English DT Article ID TOMOGRAPHY CORONARY-ANGIOGRAPHY; 64-SLICE COMPUTED-TOMOGRAPHY; AMERICAN-HEART-ASSOCIATION; ARTERY-DISEASE; DIAGNOSTIC-ACCURACY; PRETEST PROBABILITY; CLINICAL CARDIOLOGY; INTERVENTION; INTERMEDIATE; PERFORMANCE AB Purpose: First, to assess the feasibility of a protocol involving stress-induced perfusion evaluated at computed tomography (CT) combined with cardiac CT angiography in a single examination and second, to assess the incremental value of perfusion imaging over cardiac CT angio graphy in a dual-source technique for the detection of obstructive coronary artery disease ( CAD) in a high-risk population. Materials and Methods: Institutional review board approval and informed patient consent were obtained before patient enrollment in the study. The study was HIPAA compliant. Thirty-five patients at high risk for CAD were prospectively enrolled for evaluation of the feasibility of CT perfusion imaging. All patients underwent retrospectively electrocardiographically gated ( helical) adenosine stress CT perfusion imaging followed by prospectively electrocardiographically gated ( axial) rest myocardial CT perfusion imaging. Analysis was performed in three steps: ( a) Coronary arterial stenoses were scored for severity and reader confidence at cardiac CT angiography, (b) myocardial perfusion defects were identified and scored for severity and reversibility at CT perfusion imaging, and ( c) coronary stenosis severity was reclassified according to perfusion findings at combined cardiac CT angiography and CT perfusion imaging. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of cardiac CT angiography before and after CT perfusion analysis were calculated. Results: With use of a reference standard of greater than 50% stenosis at invasive angiography, all parameters of diagnostic accuracy increased after CT perfusion analysis: Sensitivity increased from 83% to 91%; specificity, from 71% to 91%; PPV, from 66% to 86%; and NPV, from 87% to 93%. The area under the receiver operating characteristic curve increased significantly, from 0.77 to 0.90 (P < .005). Conclusion: A combination protocol involving adenosine perfusion CT imaging and cardiac CT angiography in a dual-source technique is feasible, and CT perfusion adds incremental value to cardiac CT angiography in the detection of significant CAD. C1 [Rocha-Filho, Jose A.; Blankstein, Ron; Shturman, Leonid D.; Bezerra, Hiram G.; Okada, David R.; Rogers, Ian S.; Ghoshhajra, Brian; Hoffmann, Udo; Feuchtner, Gudrun; Mamuya, Wilfred S.; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Cury, RC (reprint author), Baptist Cardiac & Vasc Inst, Cardiovasc MRI & CT Program, 8900 N Kendall Dr, Miami, FL 33176 USA. EM rcury@baptisthealth.net FU Astellas Pharma; New York Cardiac Center; National Institutes of Health [1T32 HL076136] FX From the Department of Radiology, Massachusetts General Hospital, Boston, Mass. Received June 9, 2009; revision requested July 27; revision received August 26; accepted September 16; final version accepted October 1. Supported in part by a grant from Astellas Pharma and the New York Cardiac Center. R. C. C. supported by Astellas Pharma. R. B., L. D. S., I. S. R., and B. G. supported by National Institutes of Health grant 1T32 HL076136. Address correspondence to R. C. C., Cardiovascular MRI and CT Program, Baptist Cardiac and Vascular Institute, 8900 N Kendall Dr, Miami, FL 33176 (e-mail: rcury@baptisthealth.net). NR 28 TC 140 Z9 148 U1 1 U2 7 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2010 VL 254 IS 2 BP 410 EP 419 DI 10.1148/radiol.09091014 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 546QF UT WOS:000273824600012 PM 20093513 ER PT J AU Mohamed, MA Lentz, MR Lee, V Halpern, EF Sacktor, N Selnes, O Barker, PB Pomper, MG AF Mohamed, Mona A. Lentz, Margaret R. Lee, Vallent Halpern, Elkan F. Sacktor, Ned Selnes, Ola Barker, Peter B. Pomper, Martin G. TI Factor Analysis of Proton MR Spectroscopic Imaging Data in HIV Infection: Metabolite-derived Factors Help Identify Infection and Dementia SO RADIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; MAGNETIC-RESONANCE-SPECTROSCOPY; PRINCIPAL COMPONENT ANALYSIS; CENTRAL-NERVOUS-SYSTEM; COMMON FACTOR-ANALYSIS; AIDS DEMENTIA; HUMAN BRAIN; NEUROLOGICAL DISEASES; IMMUNE ACTIVATION AB Purpose: To develop a relevant pathophysiologic model of human immunodeficiency virus (HIV)-associated dementia by studying regional variations in metabolite levels measured with magnetic resonance (MR) spectroscopic imaging and their relationship to immunologic measures and cognitive dysfunction. Materials and Methods: This was a HIPAA-compliant, institutional review board-approved study involving written informed consent. Distributions of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) concentrations in 94 subjects (20 seronegative controls and 74 HIV-positive subjects; 34 of the HIV-positive subjects having HIV-associated dementia; 63 men, 31 women; mean age, 40 years) were determined with proton (hydrogen 1 [(1)H]) MR spectroscopic imaging. HIV-positive subjects underwent neuropsychological testing and blood and cerebrospinal fluid (CSF) analysis. Factor analysis was utilized to determine associations between metabolites across regions. Analysis of variance and t tests were used to isolate differences between cohorts. Results: A "Cho factor" differentiated seronegative controls from HIV-infected cohorts, indicating elevated Cho levels across deep gray and white matter regions of HIV-positive individuals. An "NAA factor" differentiated those with dementia from those without and correlated best with psychomotor and executive function tests. A "Cr factor" indicated Cr elevations correlated with CSF monocyte chemoattractant protein-1 levels. NAA and Cr factor scores were strongly weighted to metabolite changes in white matter regions. Conclusion: These results highlight the importance of white matter involvement in HIV-associated dementia and support the current pathogenesis model of glial cell proliferation in HIV infection, denoted by regional Cho elevations, and neuronal dysfunction and/or death, denoted by NAA decreases, associated with dementia. Factor analysis of MR spectroscopic imaging data is a useful method for determining regional metabolic variations in HIV infection and its neuropsychological correlates. (C) RSNA, 2010 C1 [Mohamed, Mona A.; Barker, Peter B.; Pomper, Martin G.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21231 USA. [Mohamed, Mona A.; Barker, Peter B.] Johns Hopkins Med Inst, FM Kirby Ctr Funct Brain Imaging, Baltimore, MD 21231 USA. [Sacktor, Ned; Selnes, Ola] Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21231 USA. [Lentz, Margaret R.; Lee, Vallent; Halpern, Elkan F.] Massachusetts Gen Hosp, Dept Neuroradiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Pomper, MG (reprint author), Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 1550 Orleans St,492 CRB 2, Baltimore, MD 21231 USA. EM mpomper@jhmi.edu FU National Institutes of Health [R01 MH61438, K25 NS051129] FX This research was supported by the National Institutes of Health [grants R01 MH61438 and K25 NS051129]. NR 47 TC 13 Z9 15 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2010 VL 254 IS 2 BP 577 EP 586 DI 10.1148/radiol.09081867 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 546QF UT WOS:000273824600029 PM 20093528 ER PT J AU Abujudeh, H Kaewlai, R AF Abujudeh, Hani Kaewlai, Rathachai TI E-mail Alert for Important Imaging Findings Response SO RADIOLOGY LA English DT Letter C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Abujudeh, H (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 213D, Boston, MA 02114 USA. EM habujudeh@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2010 VL 254 IS 2 BP 635 EP 636 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 546QF UT WOS:000273824600041 ER PT J AU Burns, SM Boyd, BL Hill, J Hough, S AF Burns, Shaun Michael Boyd, Briana L. Hill, Justin Hough, Sigmund TI Psychosocial Predictors of Employment Status Among Men Living With Spinal Cord Injury SO REHABILITATION PSYCHOLOGY LA English DT Article DE employment; gender; masculinity; spinal cord injury; Web-based research ID QUALITY-OF-LIFE; PROSTATE-CANCER; SOCIAL SUPPORT; HEALTH-STATUS; HELP-SEEKING; WORK; DEPRESSION; RETURN; MASCULINITY; ADJUSTMENT AB Objective: To explore the relationship between employment status and community access, perceived community discrimination, social support from significant others, depressive symptoms, and gender-related variables for 83 men living with spinal cord injury. Study Design: Correlational research. Selling: Internet-based investigation employing spinal cord injury listservs. Main Outcome Measure: Participant employment status. Results: A forced-entry hierarchical logistic regression indicated that means of injury, community access and perceived community discrimination, social support from significant others, depressive symptoms, and men's adherence to masculine norms for primacy of work, self-reliance, and emotional control significantly predicted employment status. Conclusions: Psychosocial variables such as community access, perceived discrimination. social support from significant others. depressive symptoms, and gender identity represent important and understudied predictors of employment status among men living with spinal cord injury. C1 [Burns, Shaun Michael] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Primary Care Behav Hlth Program, W Roxbury, MA 02132 USA. [Boyd, Briana L.] Univ Calif San Diego, San Diego, CA 92103 USA. RP Burns, SM (reprint author), Harvard Univ, Sch Med, VA Boston Healthcare Syst, Primary Care Behav Hlth Program, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM shaun.burns@va.gov NR 61 TC 9 Z9 9 U1 4 U2 9 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0090-5550 J9 REHABIL PSYCHOL JI Rehabil. Psychol. PD FEB PY 2010 VL 55 IS 1 BP 81 EP 90 DI 10.1037/a0018583 PG 10 WC Psychology, Clinical; Rehabilitation SC Psychology; Rehabilitation GA 563NJ UT WOS:000275139000010 PM 20175638 ER PT J AU Lee, HJ Elmoazzen, H Wright, D Biggers, J Rueda, BR Heo, YS Toner, M Toth, TL AF Lee, Ho-Joon Elmoazzen, Heidi Wright, Diane Biggers, John Rueda, Bo R. Heo, Yun Seok Toner, Mehmet Toth, Thomas L. TI Ultra-rapid vitrification of mouse oocytes in low cryoprotectant concentrations SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Article DE cryopreservation; oocyte; quartz capillary; slush nitrogen; ultra-rapid; vitrification ID HIGHLY EFFICIENT VITRIFICATION; EMBRYONIC STEM-CELLS; ASSISTED REPRODUCTION; AQUEOUS-SOLUTIONS; CRYOPRESERVATION; SURVIVAL; PERSPECTIVES; BLASTOCYSTS; NITROGEN; CULTURE AB The ideal. cryopreservation protocol would combine the benefits of slow freezing with the benefits of vitrification. This report describes a method for the ultra-rapid vitrification of oocytes using slush nitrogen in quartz capillaries. The approach minimizes the thermal mass of the vitrification vessel by using open microcapillaries made of highly conductive quartz and achieves cooling rates of 250,000 degrees C/min. The process of vitrification can be optimized by maximizing the rate at which the sample is cooled, which allows for the use of tower cryoprotectant concentrations. Mouse oocytes can be successfully vitrified using 1.5 mol/l 1,2-propanediol and 0.5 mol/l trehalose and achieve survival rates of 90.0%(36/40). Fertilization and blastocyst formation rates of vitrified-warmed and fresh oocytes were not significantly different. A total of 120 blastocysts from each of the vitrified-warmed and fresh oocytes were transferred to surrogate mothers and 23 and 27 offspring were born respectively. All offspring in both groups were healthy, grew and bred normally and gave rise to a second generation of pups. Thus, an ultra-rapid vitrification technique has been developed for mouse oocytes that uses low concentrations of cryoprotectants and slush nitrogen in quartz capillaries, which combines the benefits of slow freezing and vitrification. (C) 2009, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. C1 [Lee, Ho-Joon; Wright, Diane; Rueda, Bo R.; Toth, Thomas L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. [Heo, Yun Seok; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. [Heo, Yun Seok; Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. [Biggers, John] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Lee, HJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. EM hjlee@partners.org; tltoth@partners.org FU National Institutes of Health [R21HD061297] FX The authors would like to thank Gloria Lee and Dr. Kaisa Selesniemi for technical assistance, Dr. Jonathan Tilly for guidance of this project and critical reading and Dr Isaac Schiff for his vision and personal support. This study was partially funded by National Institutes of Health (R21HD061297) and a special thanks are due to Susan and George Domolky for providing additional financial support. NR 38 TC 22 Z9 24 U1 1 U2 8 PU REPRODUCTIVE HEALTHCARE LTD PI CAMBRIDGE PA DUCK END FARM, DRY DRAYTON, CAMBRIDGE, CB3 8DB, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD FEB PY 2010 VL 20 IS 2 BP 201 EP 208 DI 10.1016/j.rbmo.2009.11.012 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 561EO UT WOS:000274958800007 PM 20113958 ER PT J AU Chang, HL Senaratne, TN Zhang, LH Szotek, PP Stewart, E Dombkowski, D Preffer, F Donahoe, PK Teixeira, J AF Chang, Henry L. Senaratne, Tharanga N. Zhang, LiHua Szotek, Paul P. Stewart, Ethan Dombkowski, David Preffer, Frederic Donahoe, Patricia K. Teixeira, Jose TI Uterine Leiomyomas Exhibit Fewer Stem/Progenitor Cell Characteristics When Compared With Corresponding Normal Myometrium SO REPRODUCTIVE SCIENCES LA English DT Article DE Uterine leiomyomas; fibroids; stem cells ID HEMATOPOIETIC STEM-CELL; REPRODUCTIVE-TRACT FIBROBLASTS; SIDE-POPULATION CELLS; MENSTRUAL-CYCLE; CANCER-CELLS; EXPRESSION; THY-1; IDENTIFICATION; BCL-2; PROLIFERATION AB Uterine leiomyomas (also known as uterine fibroids) are the most common benign tumors of female reproductive tract and are the single most common indication for hysterectomies. Despite their high prevalence, the exact pathogenesis of these benign tumors is still unknown. One possible mechanism for leiomyoma formation. is dysregulation of mesenchymal stein cell activity. Mesenchymal stein cells have been identified in both human. and murine uteri and cancer stein cells have been identified in female reproductive malignancies. We compared stem/progenitor cell characteristics in both normal myometrium and the corresponding leiomyoma of patient's undergoing hysterectomies. We found that leiomyoma cells form fewer mesenchymal stein cell colonies and exhibit less Hoechst dye-excluding side population (SP) activity, which is a function associated with progenitor cells in other tissues, than cells isolated from normal myometrium. Whereas in normal myometrium, we observed heterogeneous expression of CD90, a cell surface marker associated the with differentiation potential of uterine fibroblasts, in leiomyomas, we observed homogenous expression of CD90, suggesting leiomyoma cells are more terminally differentiated. Furthermore, we found that while leiomyoma cells could only produce CD90 expressing cells, both CD90+ and CD90- myometrial cells could reestablish their original heterogeneous CD90 profile when expanded in vitro. These results suggest that normal myometrium contains cells with stem/progenitor cell activities that are absent in leiomyomas. C1 [Zhang, LiHua; Stewart, Ethan; Teixeira, Jose] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Vincent Ctr Reprod Biol,Dept Obstet & Gynecol, Boston, MA 02114 USA. [Chang, Henry L.; Senaratne, Tharanga N.; Szotek, Paul P.; Donahoe, Patricia K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Pediat Surg Res Labs, Boston, MA 02114 USA. [Dombkowski, David; Preffer, Frederic] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Flow Cytometry Lab,Dept Pathol, Boston, MA 02114 USA. RP Teixeira, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Vincent Ctr Reprod Biol,Dept Obstet & Gynecol, Thier 931,55 Fruit St, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064 FU NIH/MGH T32 in Cancer Biology [T32CA071345]; Harvard Stem Cell Institute Internship Program; Harvard Stem Cell Institute [DP-0010-07-00]; NICHD [HD052701] FX The authors would like to thank Dr Drucilla J. Roberts for helping us with the analysis of the immunohistochemistry and immunofluorescence and Dr David T. MacLaughlin for critically reviewing an early version of this manuscript. HLC and PPS were supported by NIH/MGH T32 in Cancer Biology T32CA071345. TNS was supported by the Harvard Stem Cell Institute Internship Program Aug-2007. PKD is supported in part from the Harvard Stem Cell Institute DP-0010-07-00. JT is supported by a grant from NICHD, HD052701. NR 34 TC 35 Z9 35 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD FEB PY 2010 VL 17 IS 2 BP 158 EP 167 DI 10.1177/1933719109348924 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 545SL UT WOS:000273757000007 PM 19805552 ER PT J AU Moorer, OW Meterko, M Alt-White, AC Sullivan, JL AF Moorer, Oyweda W. Meterko, Mark Alt-White, Anna C. Sullivan, Jennifer L. TI Adding a Nursing Information Technology Subscale to the Practice Environment Scale of the Nursing Work Index SO RESEARCH IN NURSING & HEALTH LA English DT Article DE information systems; computers technology; methodological research; instrument development and validation; work; job satisfaction; PES-NWI; nursing practice environment ID RELIABILITY; NURSES AB In the Past decade, the use of information technology (IT) to support healthcare delivery has greatly expanded. introducing new clinical information systems and updating existing systems require continued learning and training among registered nurses (RNs) and other clinicians. Consequently, a 5-item measure was designed as a subscale to the Practice Environment Scale of the Nursing Work Index. This new subscale, the Nursing Information Technology Subscale (NITS) measures RNs' Perception of the extent to which IT in their Practice environment supports Patient care delivery. A psychometric evaluation of the NITS was conducted at 8 Veterans Affairs hospitals. The findings demonstrated that this brief subscale has acceptable reliability as well as convergent and discriminant validity. (C) 2009 Wiley Periodicals, Inc. Res Nurs Health 33:48-59, 2010 C1 [Moorer, Oyweda W.] Off Qual & Safety, Dept Vet Affairs, Washington, DC 20420 USA. [Meterko, Mark] HSR&D Ctr Org Leadership & Management Res, VA Boston Hlth Care Syst, Methodol & Survey Unit, Boston, MA USA. [Alt-White, Anna C.] DVA Off Nursing Serv, Res & Acad Initiat, Washington, DC USA. [Sullivan, Jennifer L.] HSR&D Ctr Org Leadership & Management Res, VA Boston Hlth Care Syst, Boston, MA USA. RP Moorer, OW (reprint author), Off Qual & Safety, Dept Vet Affairs, 810 Vermont Ave, Washington, DC 20420 USA. OI Sullivan, Jennifer/0000-0003-2906-2232 NR 24 TC 5 Z9 5 U1 13 U2 26 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0160-6891 J9 RES NURS HEALTH JI Res. Nurs. Health PD FEB PY 2010 VL 33 IS 1 BP 48 EP 59 DI 10.1002/nur.20360 PG 12 WC Nursing SC Nursing GA 544PI UT WOS:000273670300005 PM 20014031 ER PT J AU Siobal, MS Hess, DR AF Siobal, Mark S. Hess, Dean R. TI Are Inhaled Vasodilators Useful in Acute Lung Injury and Acute Respiratory Distress Syndrome? SO RESPIRATORY CARE LA English DT Article DE acute lung injury; acute respiratory distress syndrome; inhaled nitric oxide; prostacyclin; pulmonary hypertension ID EXPERIMENTAL PULMONARY-HYPERTENSION; MECHANICALLY VENTILATED PATIENTS; RIGHT-VENTRICULAR FAILURE; NITRIC-OXIDE THERAPY; RECEPTOR ANTAGONIST LU-135252; MULTICENTER CLINICAL-TRIAL; RANDOMIZED DOUBLE-BLIND; AEROSOLIZED PROSTACYCLIN; PROSTAGLANDIN E-1; NITROGLYCERIN INHALATION AB In patients with acute respiratory distress syndrome (ARDS), inhaled vasodilator can result in important physiologic benefits (eg, improved hypoxemia, lower pulmonary arterial pressure, and improved right-ventricular function and cardiac output) without systemic hemodynamic effects. Inhaled nitric oxide (INO) and aerosolized prostacyclins are currently the most frequently used inhaled vasodilators. Inhaled prostacyclins are as effective physiologically as INO and cost less. Randomized controlled trials of INO in the treatment of ARDS have shown short-term physiologic benefits, but no benefit in long-term outcomes. No outcome studies have been reported on the use of prostacyclin in patients with ARDS. There is no role for the routine use of inhaled vasodilators in patients with ARDS. Inhaled vasodilator as a rescue therapy for severe refractory hypoxemia in patients with ARDS may be reasonable, but is controversial. C1 [Siobal, Mark S.] San Francisco Gen Hosp, Resp Care Serv, NH GA2, San Francisco, CA 94110 USA. [Siobal, Mark S.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. [Hess, Dean R.] Harvard Univ, Sch Med, Boston, MA USA. [Hess, Dean R.] Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. RP Siobal, MS (reprint author), San Francisco Gen Hosp, Resp Care Serv, NH GA2, 1001 Potrero Ave, San Francisco, CA 94110 USA. EM msiobal@sfghsom.ucsf.edu NR 132 TC 15 Z9 15 U1 0 U2 1 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 J9 RESP CARE JI Respir. Care PD FEB PY 2010 VL 55 IS 2 SI SI BP 144 EP 161 PG 18 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 561MM UT WOS:000274981600001 PM 20105341 ER PT J AU Joo, MJ Au, DH Fitzgibbon, ML Lee, TA AF Joo, Min J. Au, David H. Fitzgibbon, Marian L. Lee, Todd A. TI Inhaled corticosteroids and risk of pneumonia in newly diagnosed COPD SO RESPIRATORY MEDICINE LA English DT Article DE Chronic obstructive pulmonary disease; Pneumonia; Corticosteroids; Drug therapy; Case-control studies ID OBSTRUCTIVE PULMONARY-DISEASE; SALMETEROL/FLUTICASONE PROPIONATE; FLUTICASONE PROPIONATE; THERAPEUTIC TRIALS; EXACERBATIONS; METAANALYSIS; SALMETEROL AB Introduction: The use of inhaled corticosteroids (ICS) in COPD may be associated with an increased risk of pneumonia. Little is known of this risk in newly diagnosed COPD patients. The objective of this study was to determine if the use of ICS among newly diagnosed COPD patients is associated with an increased risk of pneumonia hospitalizations. Methods: Using data from the Department of Veterans Affairs and Centers for Medicare and Medicaid Services, a nested case-control study was performed. We identified patients 65 years of age or older with a new diagnosis of COPD from 1998 to 2002. A total of 145,586 patients were identified. Cases were defined based on hospitalization for pneumonia and exposure was prior use of ICS. Up to 10 controls were matched for each case based on age, sex, month and year of the case. The association between ICS use and pneumonia was evaluated with conditional logistic regression controlling for age, comorbidities, medication classes associated with the risk of pneumonia, and markers of COPD severity. Results: There were 13,995 cases of pneumonia. The cohort was predominantly mate with an average age of 75.1 (SD = 5.4) years. The rate of pneumonia was 6.4 per 100 person-years. After adjustment for covariates, patients with current use of ICS were 1.38 (95% CI, 1.31-1.45) times more likely to have a hospitalization for pneumonia than those without current use of ICS. Conclusions: The use of ICS among patients with newly diagnosed COPD is associated with an increased risk of hospitalization for pneumonia. Published by Elsevier Ltd. C1 [Joo, Min J.] Univ Illinois, Dept Med, Sect Pulm Crit Care & Sleep Med, Chicago, IL USA. [Joo, Min J.; Lee, Todd A.] Hines VA Hosp, Ctr Management Complex Chron Care CMC3, Hines, IL USA. [Joo, Min J.; Fitzgibbon, Marian L.] Jesse Brown VA Med Ctr, CMC3, Chicago, IL USA. [Au, David H.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Au, David H.] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [Lee, Todd A.] Univ Illinois, Dept Pharm, Chicago, IL USA. RP Joo, MJ (reprint author), 840 S Wood St,M-C 719, Chicago, IL 60612 USA. EM joo@uic.edu FU Health Services Research & Development Service, Center for Management of Complex Chronic Care, Center of Excellence, Hines VA Hospital FX This research was supported in part by the Health Services Research & Development Service, Center for Management of Complex Chronic Care, Center of Excellence, Hines VA Hospital. The views expressed in this manuscript reflect those of the authors and not necessarily those of the Department of Veterans Affairs. NR 23 TC 32 Z9 32 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD FEB PY 2010 VL 104 IS 2 BP 246 EP 252 DI 10.1016/j.rmed.2009.10.002 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 558QJ UT WOS:000274759400013 PM 19879745 ER PT J AU Klein, RS Morganroth, PA Werth, VP AF Klein, Rachel S. Morganroth, Pamela A. Werth, Victoria P. TI Cutaneous Lupus and the Cutaneous Lupus Erythematosus Disease Area and Severity Index Instrument SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Cutaneous lupus erythematosus; Disease classification; Rowell syndrome; CLASI; Clinical outcome instrument ID EPIDERMOLYSIS-BULLOSA-ACQUISITA; QUALITY-OF-LIFE; SYSTEMIC-LUPUS; CLINICAL-MANIFESTATIONS; OUTCOME INSTRUMENT; ATOPIC-DERMATITIS; REVISED CRITERIA; ROWELLS-SYNDROME; SURFACE-AREA; INVOLVEMENT AB This article provides an overview of cutaneous lupus erythematosus, including classification schemes, disease subtypes, and therapy. It also describes the Cutaneous Lupus Erythematosus Disease Area and Severity Index, a novel clinical outcome instrument that quantifies cutaneous activity and damage in cutaneous lupus erythematosus. C1 [Klein, Rachel S.; Morganroth, Pamela A.; Werth, Victoria P.] Univ Penn, Dept Dermatol, Sch Med, Philadelphia, PA 19104 USA. [Klein, Rachel S.; Morganroth, Pamela A.; Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Werth, VP (reprint author), Univ Penn, Dept Dermatol, Sch Med, Suite 1-330A,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM werth@mail.med.upenn.edu FU National Institutes of Health; NIH [K24-AR 02207, T32-AR007465-25]; Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Biomedical Laboratory Research and Development FX This material is based upon work supported by the National Institutes of Health, including NIH grant K24-AR 02207 (Werth) and NIH training grant T32-AR007465-25 (Klein). This work was also partially supported by a Merit Review Grant from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. NR 78 TC 12 Z9 13 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-857X J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD FEB PY 2010 VL 36 IS 1 BP 33 EP + DI 10.1016/j.rdc.2009.12.001 PG 20 WC Rheumatology SC Rheumatology GA 576OE UT WOS:000276153400004 PM 20202590 ER PT J AU Perlick, DA Rosenheck, RA Kaczynski, R Swartz, MS Canive, JM Lieberman, JA AF Perlick, Deborah A. Rosenheck, Robert A. Kaczynski, Richard Swartz, Marvin S. Canive, Jose M. Lieberman, Jeffrey A. TI Impact of antipsychotic medication on family burden in schizophrenia: Longitudinal results of CATIE trial SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Family burden; Second-generation antipsychotics ID BIPOLAR DISORDER; MENTAL-HEALTH; OLANZAPINE; CAREGIVERS; HALOPERIDOL; SCALE; DRUGS AB Background: This study evaluated the effectiveness of first- and second-generation antipsychotics in reducing family burden associated with schizophrenia. Methods: The family caregivers of 623 SCID-diagnosed patients enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) randomly assigned to a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetiapine, risperidone or ziprasidone) were interviewed about resources provided and stresses experienced at baseline and followed for 18 months. Patient symptoms, side effects and service use were assessed as well. Hierarchical regression analyses evaluated the effect of treatment assignment on four burden factors: problem behavior, resource demands and disruption, impairment in activities of daily living and patient helpfulness. Intention-to-treat analyses with all available observations classified based on initial treatment assignment, including observations after medications changed were followed by secondary analyses excluding observations after the first medication change, i.e. only considering initial medication. Results: Despite significant reductions on the problem behavior and resource demands/disruption factors, there were no significant differences between perphenazine and any of the second-generation medications. When only initial treatment period observations were included, patients were perceived as more helpful when medicated with perphenazine as compared to risperidone. in comparisons between second-generation drugs, patients on quetiapine were perceived as more helpful than those on risperidone (p = 0.004). Conclusion: In this 18-month randomized trial. there was no evidence of superiority of second-generation antipsychotics in relieving family burden. (C) 2009 Published by Elsevier B.V. C1 [Perlick, Deborah A.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Perlick, Deborah A.] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY 10468 USA. [Rosenheck, Robert A.] VA Connecticut Hlth Care Syst, New England Mental Illness, Res Educ & Clin Ctr, West Haven, CT 06516 USA. [Rosenheck, Robert A.; Kaczynski, Richard] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. [Rosenheck, Robert A.; Kaczynski, Richard] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Swartz, Marvin S.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27708 USA. [Canive, Jose M.] Univ New Mexico, Dept Psychiat, VA Med Ctr, Albuquerque, NM 87108 USA. [Canive, Jose M.] Univ New Mexico, New Mexico VA Hlth Care Syst, VA Med Ctr, Albuquerque, NM 87108 USA. [Lieberman, Jeffrey A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. RP Perlick, DA (reprint author), Mt Sinai Sch Med, Dept Psychiat, 1 Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM debbieperlick@aol.com; robert.rosenheck@yale.edu; richard.kaczynski@yale.edu; Marvin.swartz@duke.edu; jose.canive@va.gov; jlieberman@pi.cpmc.Columbia.edu FU NIMH NIH HHS [N01 MH90001] NR 27 TC 6 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB PY 2010 VL 116 IS 2-3 BP 118 EP 125 DI 10.1016/j.schres.2009.09.026 PG 8 WC Psychiatry SC Psychiatry GA 561AB UT WOS:000274946000003 PM 19864114 ER PT J AU Koerner, F AF Koerner, Frederick TI Papilloma and papillary carcinoma SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Papilloma; Papillary carcinoma; Breast; Diagnosis ID IN-SITU; BREAST; FORM AB Papillomas and papillary carcinomas differ in their 3 fundamental characteristics: the geometric properties of their fronds, the amount of their stroma, and the characteristics of their epithelium. Fibrosis at the edge of papillomas often entraps glands and creates the spurious impression of invasion. The proliferation of surface epithelial cells of papillomas does not give rise to unexpected diagnostic difficulties, but glandular proliferation within the stalks of papillomas often simulates the appearance of cribriform ductal carcinoma in situ. Needle biopsies of papillomas can deposit clusters of benign cells in a distribution that resembles an invasive carcinoma. Although papillomas overrun by ductal carcinoma in situ exhibit a papillary architecture, other features differentiate them from conventional papillary carcinomas. The presence of basal carcinoma cells with clear cytoplasm ("dimorphic" cells) and the formation of short stubby fronds sometimes cause pathologists to mistake papillary carcinomas for papillomas, and the bland cytologic characteristics of solid papillary carcinomas can lead to the same error. Conventional papillary carcinomas typically invade in a blunt manner. This phenomenon complicates the recognition of invasion by many papillary carcinomas and has given rise to controversy about the nature of the lesion classically known as "intracystic papillary carcinoma." (C) 2010 Elsevier Inc. All rights reserved. C1 [Koerner, Frederick] Massachusetts Gen Hosp, Pathol Serv, James Homer Wright Lab Pathol, Boston, MA 02114 USA. [Koerner, Frederick] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Koerner, F (reprint author), Massachusetts Gen Hosp, Pathol Serv, James Homer Wright Lab Pathol, Boston, MA 02114 USA. EM FKOERNER@partners.org NR 15 TC 13 Z9 14 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 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2010 VL 27 IS 1 BP 13 EP 30 DI 10.1053/j.semdp.2009.12.004 PG 18 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 642OX UT WOS:000281226700004 PM 20306827 ER PT J AU Hoshida, Y Toffanin, S Lachenmayer, A Villanueva, A Minguez, B Llovet, JM AF Hoshida, Yujin Toffanin, Sara Lachenmayer, Anja Villanueva, Augusto Minguez, Beatriz Llovet, Josep M. TI Molecular Classification and Novel Targets in Hepatocellular Carcinoma: Recent Advancements SO SEMINARS IN LIVER DISEASE LA English DT Review DE Hepatocellular carcinoma; molecular classification; meta-analysis; signaling pathway ID HEPATITIS-B-VIRUS; GENE-EXPRESSION PROFILES; TUMOR-SUPPRESSOR GENE; METHYLATOR PHENOTYPE ASSOCIATION; PHASE-II TRIAL; MICRORNA EXPRESSION; DNA METHYLATION; LIVER-CANCER; PROMOTER METHYLATION; THERAPEUTIC TARGETS AB Hepatocellular carcinoma (HCC) is one of most lethal cancers worldwide. Strategic decisions for the advancement of molecular therapies in this neoplasm require a clear understanding of its molecular classification. Studies indicate aberrant activation of signaling pathways involved in cellular proliferation (e.g., epidermal growth factor and RAS/mitogen-activated protein kinase pathways), survival (e.g., Akt/mechanistic target of rapamycin pathway), differentiation (e.g., Wnt and Hedgehog pathways), and angiogenesis (e.g., vascular endothelial growth factor and platelet-derived growth factor), which is heterogeneously presented in each tumor. Integrative analysis of accumulated genomic datasets has revealed a global scheme of molecular classification of HCC tumors observed across diverse etiologic factors and geographic locations. Such a framework will allow systematic understanding of the frequently co-occurring molecular aberrations to design treatment strategy for each specific subclass of tumors. Accompanied by a growing number of clinical trials of molecular targeted drugs, diagnostic and prognostic biomarker development will be facilitated with special attention on study design and with new assay technologies specialized for archived fixed tissues. A new class of genomic information, microRNA dysregulation and epigenetic alterations, will provide insight for more precise understanding of disease mechanism and expand the opportunity of biomarker/therapeutic target discovery. These efforts will eventually enable personalized management of HCC. C1 [Toffanin, Sara; Lachenmayer, Anja; Minguez, Beatriz; Llovet, Josep M.] Mt Sinai Sch Med, Div Liver Dis, Mt Sinai Liver Canc Program, New York, NY 10029 USA. [Hoshida, Yujin] Broad Inst, Canc Program, Cambridge, MA USA. [Hoshida, Yujin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Villanueva, Augusto; Llovet, Josep M.] IDIBAPS, Hosp Clin,CIBERehd, Liver Unit, Barcelona Clin Liver Canc Grp BCLC, Barcelona, Spain. [Llovet, Josep M.] ICREA, Barcelona, Spain. RP Llovet, JM (reprint author), Mt Sinai Sch Med, Div Liver Dis, Mt Sinai Liver Canc Program, 1425 Madison Ave,11F-70,Box 1123, New York, NY 10029 USA. EM Josep.Llovet@mssm.edu RI Augusto, Villanueva/F-9378-2012; Minguez, Beatriz/N-4456-2014; Llovet, Josep M /D-4340-2014 OI Augusto, Villanueva/0000-0003-3585-3727; Minguez, Beatriz/0000-0002-7276-9666; Llovet, Josep M /0000-0003-0547-2667 FU German Research Foundation (DFG); Programa de Estancias de Movilidad Postdoctoral en el Extranjero incluidas las ayudas MICINN/Fulbright [EX2008-P632]; National Institute of Health-NIDDK [1R01DK076986-01]; National Institute of Health (Spain) [SAF-2007-61898]; Samuel Waxman Cancer Research Foundation FX Augusto Villanueva is a recipient of a Sheila Sherlock fellowship (European Association for the Study of the Liver). Sara Toffanin is supported by a fellowship from Istituto Nazionale dei Tumori, Milan, Italy. Anja Lachenmayer is the recipient of a postdoctoral fellowship grant from German Research Foundation (DFG). Beatriz Minguez is the recipient of a grant from Programa de Estancias de Movilidad Postdoctoral en el Extranjero incluidas las ayudas MICINN/Fulbright (EX2008-P632). Josep M. Llovet has grants from National Institute of Health-NIDDK 1R01DK076986-01, National Institute of Health (Spain) grant I+D Program (SAF-2007-61898), and the Samuel Waxman Cancer Research Foundation. NR 185 TC 147 Z9 154 U1 1 U2 37 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD FEB PY 2010 VL 30 IS 1 BP 35 EP 51 DI 10.1055/s-0030-1247131 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 557JJ UT WOS:000274665100005 PM 20175032 ER PT J AU Devidas, M London, WB Anderson, JR AF Devidas, Meenakshi London, Wendy B. Anderson, James R. TI The Use of Central Laboratories and Remote Electronic Data Capture to Risk-Adjust Therapy for Pediatric Acute Lymphoblastic Leukemia and Neuroblastoma SO SEMINARS IN ONCOLOGY LA English DT Review AB The Children's Oncology Group (COG) is a National Cancer Institute (NIH)-sponsored cooperative clinical trials group with the primary mission of conducting pediatric cancer clinical trials. COG has complex risk classification systems that are used to deliver risk-stratified therapy for many pediatric cancers, including clinical trials for acute lymphoblastic leukemia (ALL) and neuroblastoma (NB). Classification of patients is based on biological, clinical, and genomic data obtained at initial diagnosis and during the initial phases of therapy. The COG Web-based remote data entry (RDE) system enables submission of data in real time from central laboratories and treating institutions. The data are then used in an automated fashion to determine the risk group and corresponding treatment assignment for individual patients enrolled in COG clinical trials. Semin Oncol 37:53-59. (C) 2010 Published by Elsevier Inc. C1 [Devidas, Meenakshi] Univ Florida, Coll Med, Dept Epidemiol & Hlth Policy Res, Gainesville, FL 32601 USA. [Anderson, James R.] Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE USA. [London, Wendy B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [London, Wendy B.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. RP Devidas, M (reprint author), Univ Florida, Coll Med, Dept Epidemiol & Hlth Policy Res, 104 N Main St,Suite 600, Gainesville, FL 32601 USA. EM mdevidas@cog.ufl.edu FU NCI NIH HHS [U10 CA029139-22, U10 CA098543-01, U10 CA098413-05, U10 CA098543, U10 CA098413] NR 4 TC 3 Z9 3 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2010 VL 37 IS 1 BP 53 EP 59 DI 10.1053/j.seminoncol.2009.12.007 PG 7 WC Oncology SC Oncology GA 601QW UT WOS:000278079300009 PM 20172365 ER PT J AU Tsapaki, V Rehani, M Saini, S AF Tsapaki, Virginia Rehani, Madan Saini, Sanjay TI Radiation Safety in Abdominal Computed Tomography SO SEMINARS IN ULTRASOUND CT AND MRI LA English DT Article ID MULTIDETECTOR CT UROGRAPHY; DOSE REDUCTION; RADIOFREQUENCY ABLATION; ACUTE APPENDICITIS; IMAGE QUALITY; CANCER-RISKS; PATIENT; EXPOSURE; DETECTABILITY; OPTIMIZATION C1 [Tsapaki, Virginia] Konstantopoulio Hosp, Med Phys Unit, Athens 14569, Greece. [Rehani, Madan] IAEA, NSRW, Radiat Protect Patients Unit, RSM, A-1400 Vienna, Austria. [Saini, Sanjay] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Tsapaki, V (reprint author), Konstantopoulio Hosp, Med Phys Unit, 1 Ifaistou St,14569 Anixi, Athens 14569, Greece. NR 72 TC 14 Z9 16 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 0887-2171 J9 SEMIN ULTRASOUND CT JI Semin. Ultrasound CT MRI PD FEB PY 2010 VL 31 IS 1 BP 29 EP 38 DI 10.1053/j.sult.2009.09.004 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 584LN UT WOS:000276753500005 PM 20102693 ER PT J AU Mayer, KH O'Cleirigh, C Skeer, M Covahey, C Leidolf, E Vanderwarker, R Safren, SA AF Mayer, K. H. O'Cleirigh, C. Skeer, M. Covahey, C. Leidolf, E. Vanderwarker, R. Safren, S. A. TI Which HIV-infected men who have sex with men in care are engaging in risky sex and acquiring sexually transmitted infections: findings from a Boston community health centre SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article ID CD4 CELL COUNTS; VIRAL LOAD; SYPHILIS INFECTION; WESTERN-EUROPE; UNITED-STATES; DISEASES; TRANSMISSION; BEHAVIOR; MSM AB Objectives The primary objective was to determine the prevalence of sexually transmitted infections (STI) in a cohort of HIV-infected men who have sex with men (MSM) in their primary care setting, and to identify the demographic and behavioural characteristics of those infected with STI and the correlates of sexual transmission risk behaviour. Methods At study entry, participants (n = 398) were tested for STI and their medical charts were reviewed for STI results in the previous year. Data on demographics, substance use, sexual behaviour and HIV disease characteristics were collected through a computer-assisted self-assessment and medical record extraction. Logistic regression analyses assessed characteristics of those with recent STI and recent transmission risk behaviour. Results The sample was predominantly white (74.6%) and college educated (51.7%). On average, participants were 41.5 years old (SD 8.4) and had been HIV infected for 8.6 years (SD 6.7); 9% of the sample had an STI, with 6.4% testing positive for syphilis, 3.1% for gonorrhoea and 0.25% for chlamydia. Age and years since HIV diagnosis were significantly associated with testing positive for an STI, as was engaging in transmission risk behaviour and using methamphetamine, ketamine and inhalants. Substance use, particularly methamphetamine use, and being more recently diagnosed with HIV were each uniquely associated with transmission risk behaviour in a multivariable model. Conclusions These results underscore the need to develop more effective secondary prevention interventions for HIV-infected MSM, tailored to more recently diagnosed patients, particularly those who are younger and substance users. C1 [Mayer, K. H.; O'Cleirigh, C.; Skeer, M.; Covahey, C.; Leidolf, E.; Vanderwarker, R.; Safren, S. A.] Fenway Inst, Boston, MA 02215 USA. [Mayer, K. H.] Miriam Hosp, Brown Med Sch, Providence, RI 02906 USA. [O'Cleirigh, C.; Safren, S. A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Skeer, M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Mayer, KH (reprint author), Fenway Inst, 1340 Boylston St, Boston, MA 02215 USA. EM Kenneth_Mayer@brown.edu FU NIMH [5R01MH068746-05]; HRSA [H97HA01293] FX Funding This study was supported by NIMH grant 5R01MH068746-05 and HRSA grant H97HA01293 awarded to KHM and SAS. NR 28 TC 42 Z9 43 U1 2 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD FEB PY 2010 VL 86 IS 1 BP 66 EP 70 DI 10.1136/sti.2009.036608 PG 5 WC Infectious Diseases SC Infectious Diseases GA 555PO UT WOS:000274525800016 PM 19720603 ER PT J AU Cryder, CE London, AJ Volpp, KG Loewenstein, G AF Cryder, Cynthia E. London, Alex John Volpp, Kevin G. Loewenstein, George TI Informative inducement: Study payment as a signal of risk SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Risk; Incentives; Ethics; Participant payments; Human Participants research; USA, informed consent ID RESEARCH PARTICIPATION; UNDUE; ETHICS AB In research involving human subjects, large participation payments often are deemed undesirable because they may provide 'undue inducement' for potential participants to expose themselves to risk. However, although large incentives may encourage participation, they also may signal the riskiness of a study's procedures. In three experiments, we measured people's interest in participating in potentially risky research studies, and their perception of the risk associated with those studies, as functions of participation payment amounts. All experiments took place 2007-2008 with an on-line nationwide sample or a sample from a northeastern U.S. city. We tested whether people judge studies that offer higher participation payments to be riskier, and, if so, whether this increased perception of risk increases time and effort spent learning about the risks. We found that high participation payments increased willingness to participate, but, consistent with the idea that people infer riskiness from payment amount, high payments also increased perceived risk and time spent viewing risk information. Moreover, when a link between payment amount and risk level was made explicit in Experiment 3, the relationship between high payments and perceived risk strengthened. Research guidelines usually prohibit studies from offering participation incentives that compensate for risks, yet these experiments' results indicate that potential participants naturally assume that the magnitude of risks and incentives are related. This discrepancy between research guidelines and participants' assumptions about those guidelines has implications for informed consent in human subjects research. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Cryder, Cynthia E.] Washington Univ, John M Olin Sch Business, St Louis, MO 63130 USA. [London, Alex John; Loewenstein, George] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Volpp, Kevin G.] Univ Penn, Sch Med, Philadelphia VA Med Ctr, CHERP, Philadelphia, PA 19104 USA. RP Cryder, CE (reprint author), Washington Univ, John M Olin Sch Business, CB 1133,1 Brookings Dr, St Louis, MO 63130 USA. EM cryder@wustl.edu OI London, Alex/0000-0002-6450-0309 NR 17 TC 30 Z9 30 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2010 VL 70 IS 3 BP 455 EP 464 DI 10.1016/j.socscimed.2009.10.047 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 552VK UT WOS:000274321500015 PM 19926187 ER PT J AU Conboy, LA Macklin, E Kelley, J Kokkotou, E Lembo, A Kaptchuk, T AF Conboy, Lisa Ann Macklin, Eric Kelley, John Kokkotou, Efi Lembo, Anthony Kaptchuk, Ted TI Which patients improve: Characteristics increasing sensitivity to a supportive patient-practitioner relationship SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; Patient-practitioner relationship; Social factors; Randomized controlled trial; False discovery rate analysis ID IRRITABLE-BOWEL-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; BECK ANXIETY INVENTORY; IMMUNE FUNCTION; SOCIAL SUPPORT; STRESS; SCALE; ALOSETRON; PARTICIPATION AB Supportive social relationships, including a positive patient-practitioner relationship, have been associated with positive health outcomes. Using the data from a randomized controlled trial (RCT) undertaken in the Boston area of the United States, this study sought to identify baseline factors predictive of patients' response to an experimentally applied supportive patient-practitioner relationship. To sort through the hundreds of potential attributes affecting the patient-practitioner relationship, we applied a false discovery rate method borrowed from the field of genomics and bioinformatics. To our knowledge such a method has not previously been applied to generate hypotheses from clinical trial data. In a previous RCT, our team investigated the effect of the patient-practitioner relationship on symptom improvement in patients with irritable Bowel syndrome (IBS). Data were collected on a sample of 289 individuals with IBS using a three-week, single blind, three arm, randomized controlled design. We found that a supportive patient-practitioner relationship significantly improved symptomatology and quality of life. A complex, multi-level measurement package was used to prospectively measure change and identify factors associated with improvement. Using a local false discovery rate procedure, we examined the association of 452 baseline subject variables with sensitivity to treatment. Out of 452 variables, only two baseline factors, reclusiveness, and previous trial experience increased sensitivity to the supportive patient-practitioner relationship. A third variable, additional opportunity during the study for subjects to discuss their illness through experiential interview, was associated with improved outcomes among subjects who did not receive the supportive patient-practitioner relationship. The few variables associated with differential benefit suggest that a patient-centered supportive patient-practitioner relationship may be beneficial for most patients. This may be especially important for reclusive individuals. Within the context of our study, additional study attention in the form of repeated experiential interviews compensated for a lack of positive patient-practitioner support. A supportive patient-practitioner relationship may also help overcome low provider expectations for subjects with previous trial experience. These results converge with the results of the parent trial, implicating the importance of the social world in healing. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Conboy, Lisa Ann; Kaptchuk, Ted] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA 02215 USA. [Macklin, Eric] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Kelley, John] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kokkotou, Efi; Lembo, Anthony] Beth Israel Hosp, Dept Gastroenterol, Boston, MA USA. RP Conboy, LA (reprint author), Harvard Univ, Sch Med, Osher Res Ctr, 401 Pk Dr,Suite 22A, Boston, MA 02215 USA. EM lisa_conboy@hms.harvard.edu RI Macklin, Eric/E-2955-2013 OI Macklin, Eric/0000-0003-1618-3502 FU NCCIH NIH HHS [1R01 AT01414-01, 1R21 AT002860-01, K24 AT004095, R01 AT001414, R01 AT001414-01, R01 AT004662, R21 AT002860, 1K24 AT004095] NR 47 TC 20 Z9 20 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2010 VL 70 IS 3 BP 479 EP 484 DI 10.1016/j.socscimed.2009.10.024 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 552VK UT WOS:000274321500018 PM 19900742 ER PT J AU Yi-Frazier, JP Smith, RE Vitaliano, PP Yi, JC Mai, S Hillman, M Weinger, K AF Yi-Frazier, Joyce P. Smith, Ronald E. Vitaliano, Peter P. Yi, Jean C. Mai, Scarlett Hillman, Matthew Weinger, Katie TI A Person-Focused Analysis of Resilience Resources and Coping in Patients with Diabetes SO STRESS AND HEALTH LA English DT Article DE diabetes; resilience; coping; HbA(1c) ID QUALITY-OF-LIFE; GLYCEMIC CONTROL; SELF-CARE; MALTREATED CHILDREN; METABOLIC-CONTROL; SEX-DIFFERENCES; ADJUSTMENT; STRESS; STYLES; HEALTH AB This study investigated the resilience resources and coping profiles of patients with diabetes. A total of 145 patients with diabetes completed a questionnaire packet including two measurements of coping (COPE and Coping Styles Questionnaires) and personal resources. Glycosylated haemoglobin (HbA(1c)) was also assessed. Resilience was defined by a factor score derived from measures of self-esteem, self-efficacy, self-mastery and optimism. All of the maladaptive coping subscales were negatively associated with resilience (r's range from -0.34 to -0.56, all p values are <0.001). Of the adaptive coping subscales, only acceptance, emotional support and pragmatism were positively associated with resilience. The upper, middle and lower tertiles of the resilience factor were identified, and the coping profiles of these groups differed significantly, with low-resilience patients favouring maladaptive strategies much more than those with high- or moderate-resilience resources do. Resilience groups did not differ in HbA(1c) levels; correlation coefficients of the coping subscales with HbA(1c) were explored. This study demonstrates a link between maladaptive coping and low resilience, suggesting that resilience impacts one's ability to manage the difficult treatment and lifestyle requirements of diabetes. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Weinger, Katie] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Behav & Mental Hlth Res, Boston, MA 02215 USA. [Yi-Frazier, Joyce P.] Seattle Childrens Res Inst, Dept Endocrinol Diabet, Seattle, WA USA. [Smith, Ronald E.; Mai, Scarlett] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Vitaliano, Peter P.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Yi, Jean C.] Fred Hutchinson Canc Res Ctr, Dept Biobehav Sci, Seattle, WA 98104 USA. [Hillman, Matthew] Univ Washington, Dept Biol, Seattle, WA 98195 USA. RP Weinger, K (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Behav & Mental Hlth Res, 1 Joslin Pl, Boston, MA 02215 USA. EM katie.weinger@joslin.harvard.edu FU National Science Foundation; National Institute of Mental Health [R01 MH57663]; Harvard Medical School Priscilla White Fellowship; National Institute of Diabetes and Digestive and Kidney Diseases [R01 NIDDK60115, P30 NIDDK36836] FX This research was supported by the National Science Foundation (National Science Foundation Graduate Research Fellowship Grant), the National Institute of Mental Health (R01 MH57663) and the Harvard Medical School Priscilla White Fellowship, National Institute of Diabetes and Digestive and Kidney Diseases (R01 NIDDK60115, P30 NIDDK36836). NR 48 TC 21 Z9 22 U1 2 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1532-3005 J9 STRESS HEALTH JI Stress Health PD FEB PY 2010 VL 26 IS 1 BP 51 EP 60 DI 10.1002/smi.1258 PG 10 WC Psychology, Applied; Psychiatry; Psychology SC Psychology; Psychiatry GA 556KR UT WOS:000274590300007 PM 20526415 ER PT J AU Smith, EE Pan, WQ Olson, D Reeves, MJ Ovbiagele, B Peterson, ED Fonarow, GC Schwamm, LH AF Smith, Eric E. Pan, Wenqin Olson, DaiWai Reeves, Mathew J. Ovbiagele, Bruce Peterson, Eric D. Fonarow, Gregg C. Schwamm, Lee H. TI Frequency and Determinants of Lipid Testing in Ischemic Stroke and Transient Ischemic Attack Findings From Get With The Guidelines-Stroke SO STROKE LA English DT Article DE cholesterol; health services research; ischemic stroke; LDL; stroke; transient ischemic attack ID HEALTH-CARE PROFESSIONALS; CARDIOVASCULAR RADIOLOGY; VASCULAR-DISEASE; CHOLESTEROL; PREVENTION; ASSOCIATION; COUNCIL; PROGRAM; STATINS; INTERVENTION AB Background and Purpose-National guidelines recommend lipid testing for all patients with ischemic stroke and transient ischemic attack. This study examined the frequency and predictors for in-hospital low-density lipoprotein testing using data from a nationwide stroke registry. Methods-Between 2003 and 2008, Get With The Guideline-Stroke (GWTG-Stroke) hospitals (n = 981) contributed 479 284 consecutive ischemic stroke or transient ischemic attack admissions. Logistic regression models were used to determine patient and hospital characteristics associated with lipid testing. Results-Frequency of LDL measurement increased from 54.3% in 2003 to 81.9% in 2008 (P < 0.001), the adjusted OR for LDL measurement was 1.23 per additional calendar year (95% CI, 1.18 to 1.29; P < 0.001). The frequency of LDL measurement also increased with longer hospital program participation; the adjusted OR was 1.17 per additional year of GWTG-Stroke participation (95% CI, 1.12 to 1.23; P < 0.001). LDL measurement was lower in women, nonsmokers, those with atrial fibrillation, those with a history of stroke or transient ischemic attack, and in those with transient ischemic attack (versus ischemic stroke; all P < 0.001). LDL >= 100 mg/dL was seen in 52.1% of those tested, including in 35.5% of patients already prescribed lipid-lowering therapy before admission. Conclusions-Rates of LDL measurement in hospitalized patients with ischemic stroke and transient ischemic attack have improved dramatically in this large quality improvement program, although disparities in testing still exist. Testing frequently revealed an LDL level that could prompt a change in clinical management. (Stroke. 2010; 41: 232-238.) C1 [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Foothills Med Ctr, Calgary Stroke Program, Calgary, AB T2N 2T9, Canada. [Pan, Wenqin; Olson, DaiWai; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Ovbiagele, Bruce] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA 90024 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. RP Smith, EE (reprint author), Univ Calgary, Dept Clin Neurosci, Foothills Med Ctr, Calgary Stroke Program, 1403 29th St NW, Calgary, AB T2N 2T9, Canada. EM eesmith@ucalgary.ca RI Smith, Eric/C-5443-2012; OI Smith, Eric/0000-0003-3956-1668; Schwamm, Lee/0000-0003-0592-9145 FU American Heart Association; American Stroke Association; Pfizer, Inc, New York, NY; Merck-Schering Plough Partnership; National Institutes of Health [R01 NS062028]; Heart and Stroke Foundation of Canada; Canadian Institutes for Health Research; Michigan Stroke Paul Coverdell Registry; BMS-Sanofi; Pfizer; National Institutes of Health FX The GWTG is funded by the American Heart Association and the American Stroke Association. The program is also supported in part by unrestricted educational grants to the American Heart Association by Pfizer, Inc, New York, NY, and the Merck-Schering Plough Partnership ( North Wales, Pa), who did not participate in the design, analysis, manuscript preparation, or approval.; E. E. S. serves as a member of the Get With The Guidelines (GWTG) Science Subcommittee and receives research support from the National Institutes of Health (National Institute of Neurological Diseases and Stroke R01 NS062028) and the Canadian Stroke Network and salary support from the Heart and Stroke Foundation of Canada and the Canadian Institutes for Health Research. W. P., E. D. P., and D. O. are members of the Duke Clinical Research Institute, which serves as the American Heart Association (AHA) GWTG data coordinating center. M. J. R. has received salary support from the Michigan Stroke Paul Coverdell Registry and serves as a member of the AHA's GWTG Quality Improvement Subcommittee. E. D. P. reports research support from BMS-Sanofi. G. C. F. chairs the AHA GWTG Steering Committee; serves as a consultant to Pfizer, Merck, Schering Plough, Bristol Myers Squibb, and Sanofi-Aventis; receives speaker honoraria from Pfizer, Merck, Schering Plough, Bristol Myers Squibb, and Sanofi-Aventis; and receives research support from Pfizer and the National Institutes of Health. L. H. S. serves as vice chair of the AHA GWTG Steering Committee; serves as a consultant to the Research Triangle Institute, CryoCath, and to the Massachusetts Department of Public Health; and has provided expert medical opinions in malpractice lawsuits regarding stroke treatment and prevention. NR 21 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2010 VL 41 IS 2 BP 232 EP 238 DI 10.1161/STROKEAHA.109.567693 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600008 PM 20035071 ER PT J AU Ziegler, PD Glotzer, TV Daoud, EG Wyse, DG Singer, DE Ezekowitz, MD Koehler, JL Hilker, CE AF Ziegler, Paul D. Glotzer, Taya V. Daoud, Emile G. Wyse, D. George Singer, Daniel E. Ezekowitz, Michael D. Koehler, Jodi L. Hilker, Christopher E. TI Incidence of Newly Detected Atrial Arrhythmias via Implantable Devices in Patients With a History of Thromboembolic Events SO STROKE LA English DT Article DE ambulatory electrocardiography; atrial fibrillation; diagnostic methods; stroke ID FOLLOW-UP; FIBRILLATION; STROKE; ABLATION; DIAGNOSTICS; CATHETER; FLUTTER AB Background and Purpose-Evidence of atrial tachycardia/atrial fibrillation (AT/AF) is often sought in patients with ischemic stroke or transient ischemic attack. We studied patients with previous thromboembolic events (TE) who were implanted with devices capable of continuous arrhythmia monitoring to comprehensively quantify the incidence and duration of newly detected AT/AF. Methods-This study represents a subgroup analysis of the TRENDS trial, which included patients with clinical indications for pacemakers or defibrillators and >= 1 stroke risk factors (heart failure, hypertension, age 65 or older, diabetes, or previous TE). A history of AF was not required. All implanted devices were capable of continuously monitoring the cumulative time spent in AT/AF each day. This analysis focuses primarily on the incidence and duration of newly detected AT/AF (defined as >= 5 minutes of AT/AF on any day) in patients with previous TE, no documented history of AF, and no warfarin or antiarrhythmic drug use. Results-A total of 319 patients had a history of TE and >= 1 day of device data. Patients with a documented history of AF (n = 80), warfarin use (n = 56), or antiarrhythmic drug use (n = 20) were excluded from analysis. Of the remaining 163 patients, newly detected AT/AF was identified via the device in 45 patients (28%) over a mean follow-up of 1.1 +/- 0.7 years. AT/AF recurred infrequently, with only 12 patients experiencing AT/AF on >10% of follow-up days. Conclusion-Newly detected episodes of AT/AF were found via continuous monitoring in 28% of patients with previous TE. Most episodes would not have been detected by standard intermittent monitoring techniques. (Stroke. 2010; 41: 256-260.) C1 [Ziegler, Paul D.; Koehler, Jodi L.; Hilker, Christopher E.] Medtronic Inc, Minneapolis, MN USA. [Glotzer, Taya V.] Hackensack Univ Med Ctr, Hackensack, NJ USA. [Daoud, Emile G.] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Wyse, D. George] Libin Cardiovasc Inst Alberta, Calgary, AB, Canada. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ezekowitz, Michael D.] Lankenau Inst Med Res, Philadelphia, PA USA. RP Ziegler, PD (reprint author), Medtron Cardiac Rhythm Dis Management, 8200 Coral Sea St NE,Mailstop MVN 41, Mounds View, MN 55112 USA. EM paul.david.ziegler@medtronic.com FU Medtronic FX This study was funded by Medtronic. NR 16 TC 75 Z9 76 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2010 VL 41 IS 2 BP 256 EP 260 DI 10.1161/STROKEAHA.109.571455 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600012 PM 20044517 ER PT J AU Hoh, BL Chi, YY Lawson, MF Mocco, J Barker, FG AF Hoh, Brian L. Chi, Yueh-Yun Lawson, Matthew F. Mocco, J. Barker, Fred G., II TI Length of Stay and Total Hospital Charges of Clipping Versus Coiling for Ruptured and Unruptured Adult Cerebral Aneurysms in the Nationwide Inpatient Sample Database 2002 to 2006 SO STROKE LA English DT Article DE aneurysm; clipping; coiling; hospital charges; length of hospitalization ID INTRACRANIAL ANEURYSMS; UNITED-STATES; SUBARACHNOID HEMORRHAGE; ENDOVASCULAR TREATMENT; RESOURCE USE; COST; MORTALITY AB Background and Purpose-We have previously reported the difference in length of stay and hospital charges for patients with cerebral aneurysms treated with either clipping or coiling at our institution. We now report an analysis of the same comparison at a national level conducted using the Nationwide Inpatient Sample database. Methods-We obtained the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project, Agency for Healthcare Quality and Research. The Nationwide Inpatient Sample is the largest all-payer inpatient care database in the US and represents approximate to 20% of all inpatient admissions to US nonfederal hospitals. Hospitalizations for clipping or coiling of ruptured and unruptured cerebral aneurysms from 2002 to 2006 were identified by cross-matching International Classification of Diseases-9 codes for diagnoses of subarachnoid hemorrhage (430) or unruptured cerebral aneurysm (437.3) with procedure codes for clipping (39.51) or coiling (39.79, 39.72, or 39.52) of cerebral aneurysms. Length of hospital stay and total hospital charges for clipping and coiling were compared using linear mixed models adjusted for the following patient and hospital-specific factors: gender, age, race/ethnicity, admission source and type, median income level in patient's postal code of residence, payer for care, comorbidities, and hospital cerebral aneurysm case volume, bed size, teaching status, rural/urban location, and geographic region. Results-There were 9635 hospitalizations for ruptured aneurysm treatments (6019 clipping, 3616 coiling) and 9399 hospitalizations for unruptured aneurysm treatments (4700 clipping, 4699 coiling). For ruptured aneurysm patients, after adjusting for the effects of patient-specific and hospital-specific factors, clipping compared to coiling was associated with significantly longer length of stay (P < 0.0001) and significantly higher total hospital charges (P < 0.0001). For unruptured aneurysm patients, clipping compared to coiling was associated with significantly longer length of stay (P < 0.0001) and significantly higher total hospital charges (P < 0.0001). After adjusting for the effects of hospital-level and patient-level characteristics, clipping as compared to coiling was associated with an average of 1.2-times more days in hospitalization for ruptured patients and was associated with an average of 1.8-times more days in hospitalization for unruptured patients. On average, clipping resulted in $15 325 more in total charge for ruptured patients and resulted in $11 263 more in total charge for unruptured patients after considering all relevant hospital and patient characteristics. Conclusions-The results of this nationwide analysis differed from the findings of our single institution study. Clipping compared to coiling was associated with significantly longer lengths of stay and significantly higher total hospital charges for both ruptured and unruptured aneurysm patients. (Stroke. 2010;41:337-342.) C1 [Hoh, Brian L.; Lawson, Matthew F.; Mocco, J.] Univ Florida, Dept Neurol Surg, Gainesville, FL 32610 USA. [Chi, Yueh-Yun] Univ Florida, Dept Epidemiol & Hlth Policy Res, Gainesville, FL 32610 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hoh, BL (reprint author), Univ Florida, Dept Neurol Surg, POB 100265, Gainesville, FL 32610 USA. EM brian.hoh@neurosurgery.ufl.edu NR 15 TC 54 Z9 57 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2010 VL 41 IS 2 BP 337 EP 342 DI 10.1161/STROKEAHA.109.569269 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600025 PM 20044522 ER PT J AU Saver, JL Liebeskind, DS Nogueira, RG Jahan, R AF Saver, Jeffrey L. Liebeskind, David S. Nogueira, Raul G. Jahan, Reza TI Need to Clarify Thrombolysis In Myocardial Ischemia (TIMI) Scale Scoring Method in the Penumbra Pivotal Stroke Trial SO STROKE LA English DT Letter ID RECANALIZATION; REPERFUSION C1 [Saver, Jeffrey L.; Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Saver, Jeffrey L.; Liebeskind, David S.; Jahan, Reza] Univ Calif Los Angeles, Stroke Ctr, Ronald Reagen Med Ctr, Los Angeles, CA 90024 USA. [Nogueira, Raul G.] Harvard Univ, Dept Radiol, Endovasc Neurosurg Intervent Neuroradiol Sect, Massachusetts Gen Hosp,Sch Med, Boston, MA 02115 USA. [Jahan, Reza] Univ Calif Los Angeles, Div Intervent Neuroradiol, Dept Radiol, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Saver, JL (reprint author), Univ Calif Los Angeles, Dept Neurol, David Geffen Sch Med, Los Angeles, CA 90024 USA. OI Saver, Jeffrey/0000-0001-9141-2251 FU NINDS NIH HHS [U01 NS 44364, K23 NS054084, P50 NS044378] NR 6 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2010 VL 41 IS 2 BP E115 EP E116 DI 10.1161/STROKEAHA.109.566406 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600056 PM 20035075 ER PT J AU Sorensen, AG Heiss, WD AF Sorensen, A. Gregory Heiss, Wolf-Dieter TI Advances in Imaging 2009 SO STROKE LA English DT Editorial Material DE imaging; advances ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; ACUTE STROKE TRIAGE; INTRAVENOUS THROMBOLYSIS; ADVANCED CT; MR; IDENTIFICATION; CONNECTIVITY; PERFORMANCE; THERAPIES AB Imaging remains a mainstay of stroke diagnosis and treatment. 2009 brought much that was new: increased scrutiny of the safety of imaging; evidence of improved technical capabilities of imaging; new findings based on imaging; and as a result of the above, evidence that the field has definite needs. We will briefly cover each of these in turn. (Stroke. 2010; 41: e91-e92.) C1 [Sorensen, A. Gregory] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Sorensen, A. Gregory] Harvard Univ, Sch Med, Boston, MA USA. [Heiss, Wolf-Dieter] Max Planck Inst Neurol Res, Cologne, Germany. RP Sorensen, AG (reprint author), Massachusetts Gen Hosp, Dept Neuroradiol, 32 Fruit St, Boston, MA 02114 USA. EM sorensen@nmr.mgh.harvard.edu NR 34 TC 0 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2010 VL 41 IS 2 BP E91 EP E92 DI 10.1161/STROKEAHA.109.575407 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600047 PM 20075337 ER PT J AU Surbone, A Baider, L Weitzman, TS Brames, MJ Rittenberg, CN Johnson, J AF Surbone, Antonella Baider, Lea Weitzman, Tammy S. Brames, Mary Jacqueline Rittenberg, Cynthia N. Johnson, Judith CA MASCC Psychosocial Study Grp TI Psychosocial care for patients and their families is integral to supportive care in cancer: MASCC position statement SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Cancer; Supportive care; Patients' psychosocial concerns; Unmetpsychosocial needs; Psychosocial interventions ID QUALITY-OF-LIFE; YOUNG-ADULT CANCER; BREAST-CANCER; PSYCHOLOGICAL DISTRESS; MULTINATIONAL-ASSOCIATION; COMMUNICATION-SKILLS; HEALTH-CARE; RISK-INDEX; LONG-TERM; SURVIVORS AB This position paper, written on behalf of the MASCC Psychosocial Study Group, reviews the most common psychosocial concerns and needs of cancer patients during all phases of the cancer continuum, from diagnosis to death or survivorship. Developments in psychosocial care at both individual and systems levels are surveyed and summarized, along with gaps in knowledge and research and needed improvements in the dissemination and application of acquired knowledge and expertise. The roles of culture, spirituality, and religion as part of psychosocial care are reviewed, along with families' and caregivers' specific psychosocial concerns and needs, and areas of needed psychosocial interventions in supportive cancer care. Deficits in recognizing and meeting patients' psychosocial needs at the system level are examined, and international guidelines and models of psychosocial care are reviewed, including their potential applications to local contexts. The paper calls for a shift to a new paradigm of care through adoption of an integrated approach to identify and meet the psychosocial needs of cancer patients and survivors as part of supportive care worldwide. C1 [Surbone, Antonella] NYU, Sch Med, Dept Med, New York, NY 10016 USA. [Baider, Lea] Hadassah Univ, Med Ctr, Sharett Inst, Dept Psychooncol, Jerusalem, Israel. [Weitzman, Tammy S.] Dana Farber Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. [Brames, Mary Jacqueline] Indiana Canc Pavil, Simon Canc Ctr, Indianapolis, IN USA. [Rittenberg, Cynthia N.] Multinatl Assoc Support Care Canc, Metairie, LA USA. [Johnson, Judith] Multinatl Assoc Support Care Canc, Minneapolis, MN USA. RP Surbone, A (reprint author), NYU, Sch Med, Dept Med, New York, NY 10016 USA. EM dr.surbone@libero.it NR 96 TC 50 Z9 50 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD FEB PY 2010 VL 18 IS 2 BP 255 EP 263 DI 10.1007/s00520-009-0693-4 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 534OA UT WOS:000272905800013 PM 19609571 ER PT J AU Sohn, DK Turner, BG Gee, DW Willingham, FF Sylla, P Cizginer, S Konuk, Y Brugge, WR Rattner, DW AF Sohn, Dae Kyung Turner, Brian G. Gee, Denise W. Willingham, Field F. Sylla, Patricia Cizginer, Sevdenur Konuk, Yusuf Brugge, William R. Rattner, David W. TI Reducing the unexpectedly high rate of injuries caused by NOTES gastrotomy creation SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-American-Gastrointestinal-and-Endoscopic-Surgeons CY APR 22-24, 2009 CL Phoenix, AZ SP Soc Amer Gastrointestinal & Endoscop Surg DE NOTES; Transgastric; Gastrotomy; Intraoperative complications ID TRANSLUMINAL ENDOSCOPIC SURGERY; PERITONEAL-CAVITY; PORCINE MODEL; DISTAL PANCREATECTOMY; TRANSGASTRIC ACCESS; SURVIVAL AB Despite the wide range of natural orifice transluminal endoscopic surgery (NOTES) procedures reported to date using a transgastric endoscopic approach, complications associated with gastrotomy creation have not been described. This study was conducted to identify the incidence and types of complications related to gastrotomy creation with the needle knife puncture and balloon dilatation technique for NOTES access to the peritoneal cavity. Between May 2007 and August 2008, transgastric procedures were performed in 76 swine at a single institution. A total of 58 gastrotomies were created using the needle knife puncture and balloon dilatation technique without laparoscopic observation and 18 gastrotomies were created under laparoscopic visualization after CO(2) insufflation through a laparoscopic port. In all cases, a needle knife with an electrosurgical current of 25-W coagulation and/or 25-W cut and a wire-guided endoscopic balloon dilated to 20 mm were used to create the gastrotomy. All complications were collected prospectively and reviewed from laboratory medical records, operative reports, and necropsy findings. NOTES gastrotomy-related complications occurred in 10/76 (13.2%) animals. Major complications occurred in six animals (7.9%), including four splenic lacerations, a mesenteric tear, and a fatal diaphragmatic injury. Minor complications occurred in four animals (5.3%), including three abdominal wall injuries and minor gastrotomy site bleeding. When pregastrotomy laparoscopic guidance was used, only one injury occurred in 18 animals (5.5%), but 9/58 (15.5%) gastrotomies performed without laparoscopic visualization caused some type of injury. The difference in rate of injury did not achieve statistical significance. No learning curve effect could be identified. Injuries to adjacent viscera occur more often than is reported with the traditional transgastric needle knife NOTES access technique. Gastric punctures should be made either with laparoscopic visualization or by other techniques such as the PEG approach or with noncutting devices to reduce the incidence of visceral injury associated with transgastric peritoneal entry. C1 [Sohn, Dae Kyung; Gee, Denise W.; Sylla, Patricia; Konuk, Yusuf; Rattner, David W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Turner, Brian G.; Willingham, Field F.; Cizginer, Sevdenur; Brugge, William R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gastrointestinal Unit, Boston, MA 02115 USA. [Sohn, Dae Kyung] Natl Canc Ctr, Res Inst & Hosp, Ctr Colorectal Canc, Goyang, South Korea. RP Rattner, DW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 15 Parkman St,WACC 460, Boston, MA 02114 USA. EM drattner@partners.org OI Willingham, Field/0000-0002-7071-3001 NR 17 TC 17 Z9 17 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 J9 SURG ENDOSC JI Surg. Endosc. PD FEB PY 2010 VL 24 IS 2 BP 277 EP 282 DI 10.1007/s00464-009-0570-8 PG 6 WC Surgery SC Surgery GA 550PW UT WOS:000274141400005 PM 19533234 ER PT J AU Silverdale, MA Kobylecki, C Hallett, PJ Li, Q Dunah, AW Ravenscroft, P Bezard, E Brotchie, JM AF Silverdale, Monty A. Kobylecki, Christopher Hallett, Penelope J. Li, Qin Dunah, Anthone W. Ravenscroft, Paula Bezard, Erwan Brotchie, Jonathan M. TI Synaptic Recruitment of AMPA Glutamate Receptor Subunits in Levodopa-Induced Dyskinesia in the MPTP-Lesioned Nonhuman Primate SO SYNAPSE LA English DT Article DE macaque; MPTP; Parkinson's disease; trafficking; Western blotting; cellular fractionation ID DOPA-INDUCED DYSKINESIA; INDUCED MOTOR COMPLICATIONS; PARKINSONS-DISEASE; MACAQUE MODEL; RAT MODEL; PHOSPHORYLATION; MONKEYS; NMDA; BLOCKADE; TRAFFICKING C1 [Silverdale, Monty A.; Kobylecki, Christopher] Salford Royal Hosp, Greater Manchester Neurosci Ctr, Salford M6 8HD, Lancs, England. [Hallett, Penelope J.; Dunah, Anthone W.] Harvard Univ, Sch Med, Charlestown, MA USA. [Hallett, Penelope J.; Dunah, Anthone W.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA USA. [Li, Qin] China Acad Med Sci, Inst Lab Anim Sci, Beijing, Peoples R China. [Ravenscroft, Paula; Bezard, Erwan] Univ Victor Segalen Bordeaux 2, CNRS, Bordeaux Inst Neurosci, UMR 5227, Bordeaux, France. [Brotchie, Jonathan M.] Toronto Western Hosp, Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada. RP Silverdale, MA (reprint author), Salford Royal Hosp, Greater Manchester Neurosci Ctr, Stott Lane, Salford M6 8HD, Lancs, England. EM monty.silverdale@srft.nhs.uk OI Hallett, Penelope/0000-0002-8858-9096; Bezard, Erwan/0000-0002-0410-4638 NR 34 TC 38 Z9 38 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD FEB PY 2010 VL 64 IS 2 BP 177 EP 180 DI 10.1002/syn.20739 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 538PD UT WOS:000273195500011 PM 19852073 ER PT J AU Saboisky, J Eckert, D Malhotra, A AF Saboisky, Julian Eckert, Danny Malhotra, Atul TI Stable breathing through deeper sleeping SO THORAX LA English DT Editorial Material ID SLOW-WAVE SLEEP; AROUSAL RESPONSE; AIRWAY OCCLUSION; APNEA; PATHOGENESIS; INSTABILITY; MECHANISMS; TRAZODONE; INCREASES; PRESSURE C1 [Malhotra, Atul] Brigham & Womens Hosp, Sleep Disorders Res Program, BIDMC, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Malhotra, A (reprint author), Brigham & Womens Hosp, Sleep Disorders Res Program, BIDMC, 75 Francis St, Boston, MA 02115 USA. EM amalhotra1@partners.org RI Eckert, Danny/A-6145-2012; Saboisky, Julian/P-5782-2014 OI Eckert, Danny/0000-0003-3503-2363; Saboisky, Julian/0000-0002-9450-6023 NR 28 TC 4 Z9 4 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD FEB PY 2010 VL 65 IS 2 BP 95 EP 96 DI 10.1136/thx.2009.127860 PG 2 WC Respiratory System SC Respiratory System GA 553WS UT WOS:000274398100002 PM 20147587 ER PT J AU Park, H Karajanagi, S Wolak, K Aanestad, J Daheron, L Kobler, JB Lopez-Guerra, G Heaton, JT Langer, RS Zeitels, SM AF Park, Hyoungshin Karajanagi, Sandeep Wolak, Kathryn Aanestad, Jon Daheron, Laurence Kobler, James B. Lopez-Guerra, Gerardo Heaton, James T. Langer, Robert S. Zeitels, Steven M. TI Three-Dimensional Hydrogel Model Using Adipose-Derived Stem Cells for Vocal Fold Augmentation SO TISSUE ENGINEERING PART A LA English DT Article ID HYALURONIC-ACID; STROMAL CELLS; VASCULAR CONSTRUCTS; LENTIVIRUS VECTOR; COLLAGEN; FIBRIN; INJECTION; BIOMATERIALS; MICE; DIFFERENTIATION AB Adipose-derived stem cells (ASCs) may provide a clinical option for rebuilding damaged superficial lamina propria of the vocal fold. We investigated the effects of five hydrogels (hyaluronic acid [HA], collagen, fibrin, and cogels of fibrin-collagen and fibrin-HA) on the differentiation of ASCs, with the long-term goal of establishing the conditions necessary for controlling the differentiation of ASC into the functional equivalent of superficial lamina propria fibroblasts. Human ASCs were isolated and characterized by fluorescence-activated cell sorting and real-time polymerase chain reaction. According to fluorescence-activated cell sorting and gene analysis, over 90% of isolated ASCs expressed adult stem cell surface markers and expressed adult stem cell genes. Scaffold-specific gene expression and morphology were assessed by culturing the ASCs in three-dimensional hydrogels. Twofold higher amounts of total DNA were detected in fibrin and cogel cultures than in collagen and HA cultures. Elastin expression was significantly higher in cells grown in fibrin-based gels than in cells grown in other gels. Cells grown in the cogels showed elongated morphology, expressed decorin marker, and exhibited glycosaminoglycan synthesis, which indicate ASC differentiation. Our data suggest that it may be possible to control the differentiation of ASCs using scaffolds appropriate for vocal fold tissue engineering applications. In particular, cogels of HA or collagen with fibrin enhanced proliferation, differentiation, and elastin expression. C1 [Park, Hyoungshin; Wolak, Kathryn; Aanestad, Jon; Kobler, James B.; Lopez-Guerra, Gerardo; Heaton, James T.; Zeitels, Steven M.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Dept Surg, Boston, MA 02114 USA. [Karajanagi, Sandeep; Langer, Robert S.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Daheron, Laurence] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Zeitels, SM (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Dept Surg, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM zeitels.steven@mgh.harvard.edu OI Lopez-Guerra, Gerardo/0000-0003-0305-4680 FU Institute of Laryngology and Voice Restoration; Eugene B. Casey Foundation FX This research was supported in part by the Institute of Laryngology and Voice Restoration and the Eugene B. Casey Foundation. The authors thank William G. Austen, M. D., Division of Plastic Surgery, Massachusetts General Hospital, for his assistance with this investigation. The authors also thank Drs. Victoria Herrera and Yoshihiko Kumai for their critical discussion. NR 38 TC 25 Z9 26 U1 0 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD FEB PY 2010 VL 16 IS 2 BP 535 EP 543 DI 10.1089/ten.tea.2009.0029 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 552XT UT WOS:000274329000018 PM 19728785 ER PT J AU Tennis, MA Vanscoyk, M Keith, RL Winn, RA AF Tennis, Meredith A. Vanscoyk, Michelle Keith, Robert L. Winn, Robert A. TI The role of prostacyclin in lung cancer SO TRANSLATIONAL RESEARCH LA English DT Article ID VASCULAR SMOOTH-MUSCLE; ACTIVATED RECEPTOR-GAMMA; CELL-LINES; GENE-EXPRESSION; CARCINOMA-CELLS; MURINE MODEL; PROSTAGLANDIN; SYNTHASE; ANALOGS; GROWTH AB Prostanoids are bioactive lipids that interact with 7-membrane-spanning G-protein-coupled receptors on target cells to impart their biologic effects.(1) They include prostaglandins, prostacyclin, and thromboxane. Prostanoids are widely distributed; mediate several diverse biologic effects like platelet aggregation and smooth-muscle contraction; and are known to be involved in allergies, acquired immunity, and cancer metastasis.(2) Prostanoids have also been associated with breast and endometrial cancer promotion, and with the inhibition of melanoma. The role of prostanoids in the development of lung disease has been poorly understood. In particular, prostacyclin possesses significant anti-inflammatory and antimetastatic properties and is the main product of cyclooxygenase-2 activity in the lung. In fact, the balance of the various members of the prostanoids family, specifically the prosoglandins PGE(2) and prostacyclin (PGI(2)), seems to play an increasingly important role in the development of lung cancer. Gaining a better understanding of prostanoids and their associated pathways is critical to the future development of molecular-based and pharmaceutical treatments of lung disease. (Translational Research 2010;155:57-61) C1 [Winn, Robert A.] Univ Colorado Denver, Hlth Sci Ctr, Dept Med, Div Pulm & Crit Care Med, Aurora, CO 80045 USA. Denver VA Med Ctr, Dept Med, Div Pulm Sci & Crit Care Med, Denver, CO USA. RP Winn, RA (reprint author), Univ Colorado Denver, Hlth Sci Ctr, Dept Med, Div Pulm & Crit Care Med, 12700 E 19th Ave, Aurora, CO 80045 USA. EM robert.winn@ucdenver.edu NR 53 TC 6 Z9 7 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 J9 TRANSL RES JI Transl. Res. PD FEB PY 2010 VL 155 IS 2 BP 57 EP 61 DI 10.1016/j.trsl.2009.06.010 PG 5 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 593GH UT WOS:000277440500002 PM 20129485 ER PT J AU Tomas, E Habener, JF AF Tomas, Eva Habener, Joel F. TI Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID MEDIATED GLUCOSE-UPTAKE; NEUTRAL ENDOPEPTIDASE-24.11; GLP-1 RECEPTOR; DIABETES-MELLITUS; GENE-THERAPY; RAT-HEART; LIVER; MITOCHONDRIA; AGONIST; AMIDE AB GLP-1 (9-36)amide is the cleavage product of GLP-1 (7-36) amide, formed by the action of diaminopeptidyl peptidase-4 (Dpp4), and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (936)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. In this paper, we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes. C1 [Tomas, Eva; Habener, Joel F.] Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. RP Habener, JF (reprint author), Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. EM jhabener@partners.org FU Merck Company; USPHS [DK030834] FX We thank Violeta Stanojevic for thoughtful comments on the manuscript. Supported in part by an Investigator Initiated Studies Program grant from Merck & Company and by USPHS DK030834 to JFH. NR 60 TC 61 Z9 67 U1 0 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD FEB PY 2010 VL 21 IS 2 BP 59 EP 67 DI 10.1016/j.tem.2009.11.007 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 563TJ UT WOS:000275156800001 PM 20018525 ER PT J AU Gupta, M de Leval, L Selig, M Oliva, E Nielsen, GP AF Gupta, Mamta de Leval, Laurence Selig, Martin Oliva, Esther Nielsen, G. Petur TI Uterine Tumors Resembling Ovarian Sex Cord Tumors: An Ultrastructural Analysis of 13 Cases SO ULTRASTRUCTURAL PATHOLOGY LA English DT Article DE electron microscopy; immunohistochemistry; ovary; sex cord tumors; uterus ID ENDOMETRIAL STROMAL SARCOMA; GRANULOSA-CELL TUMORS; INHIBIN EXPRESSION; DIFFERENTIATION; NEOPLASMS; PHENOTYPE; MARKERS; AREAS AB Uterine tumors resembling ovarian sex cord tumors (UTROSCT) are tumors of unclear histogenesis. The authors analyzed the ultrastructural features of 13 UTROSCT and correlated the findings with their immunohistochemical profile. Features included cells with frequent organoid, nested or cord-like arrangement (8), lumen formation (2; one of which showed surface microvilli), nuclei with irregular indentations (8), intermediate filaments (13), prominent paranuclear aggregates (5), cell junctions (9), desmosome-like junctions (2), tonofilaments (2), basal lamina (1), and cytoplasmic lipid droplets (7; prominent in 3). No dense bodies, subplasmalemmal densities or pinocytotic vesicles were seen. Ultrastructural epithelial differentiation was present in 2 tumors (positive for keratin or epithelial membrane antigen). Prominent lipid droplets correlated with sex cord markers positivity in 2 tumors. Ultrastructural features of smooth muscle differentiation were lacking and abundant paranuclear filaments did not correlate with myoid markers. UTROSCT are polyphenotypic neoplasms ultrastructurally with focal epithelial and variable sex cord-like differentiation. These findings suggest that UTROSCT may result from divergent differentiation in endometrial stromal tumors or represent a distinct group of uterine tumors with sex cord-like differentiation that are closer in histogenesis to ovarian sex cord stromal tumors. 60% diameter) was determined by peak systolic velocity (PSV) > 300 cm/s and renal aortic ratio (RAR) > 4.0. Renal function (creatinine) and blood pressure were measured at baseline and follow-up. SESs were implanted in 16 patients (22 renal arteries) during the study period. The study cohort was predominantly female (75%) with a mean age of 68 +/- 12 years. RA-ISR was treated with SESs with a mean diameter of 3.5 mm and mean length of 17.9 +/- 3.8 mm. The mean post-dilation balloon diameter was 4.8 +/- 0.6. The baseline renal artery PSV was 445 +/- 131 cm/s with a mean RAR of 5.0 +/- 1.6. Follow-up information was available in 21 renal arteries. During a median follow-up of 12 months (range: 9-15 months), 15 renal arteries (71.4%) developed recurrence of ISR by ultrasonographic criteria. Univariate analysis revealed that female sex was an independent predictor of recurrence of ISR after SES implantation (p < 0.05). In conclusion, placement of a SES for the treatment of ISR in renal arteries is associated with high initial technical success but significant restenosis on duplex ultrasonography at follow-up. C1 [Kiernan, Thomas J.; Yan, Bryan P.; Eisenberg, Jonathan D.; Ruggiero, Nicholas J.; Gupta, Vishal; Drachman, Douglas; Schainfeld, Robert M.; Jaff, Michael R.; Rosenfield, Kenneth; Garasic, Joseph] Massachusetts Gen Hosp, Dept Intervent Cardiol & Vasc Med, Boston, MA 02114 USA. RP Kiernan, TJ (reprint author), Massachusetts Gen Hosp, Dept Intervent Cardiol & Vasc Med, Boston, MA 02114 USA. EM tom_kiernan@hotmail.com RI Yan, Bryan/P-5928-2015 NR 14 TC 6 Z9 7 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD FEB PY 2010 VL 15 IS 1 BP 3 EP 7 DI 10.1177/1358863X09106897 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 545WX UT WOS:000273768800001 PM 19793778 ER PT J AU Wilkie, D Berry, D Cain, K Huang, HY Mekwa, J Lewis, F Gallucci, B Lin, YC Chen, ACC Ko, NY AF Wilkie, Diana Berry, Donna Cain, Kevin Huang, Hsiu-Ying Mekwa, Julia Lewis, Frances Gallucci, Betty Lin, Yu-Chuan Chen, Angela Chia-Chen Ko, Nai-Ying TI Effects of Coaching Patients With Lung Cancer to Report Cancer Pain SO WESTERN JOURNAL OF NURSING RESEARCH LA English DT Article DE lung cancer; pain; coaching; self-monitoring; self-reporting; patient-centered communications ID LOW-BACK-PAIN; BREAST-CANCER; COPING STRATEGIES; MANAGEMENT; INTERVENTION; EDUCATION; TRIAL; COMMUNICATION; QUESTIONNAIRE; OUTPATIENTS AB The authors have examined the effects of coaching sensory self-monitoring and reporting on pain-related variables in patients with lung cancer. Randomly assigned to coached or not-coached groups, 2 15 patients have their interactions with their providers audiotaped and complete study measures pre- and postintervention. Of the 151 patients who complete the 4-week study, those coached are more likely than those not coached to give their providers unsolicited sensory pain information and to mention it before their providers ask for it. The mean number of pain parameters discussed during the audiotaped clinic visit is statistically larger at study end for the coached group. Scores for analgesic adequacy, all pain indices except one, anxiety, depression, and catastrophizing coping are not significantly different. Although coaching increases the amount of pain data communicated to providers by patients with lung cancer, the magnitude is small and does not lead to improved adequacy of analgesics prescribed for each patient's pain level. C1 [Wilkie, Diana] Univ Illinois, Chicago, IL USA. [Berry, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cain, Kevin; Lewis, Frances; Gallucci, Betty] Univ Washington, Seattle, WA 98195 USA. [Huang, Hsiu-Ying] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Mekwa, Julia] Univ Zululand, ZA-3886 Kwa Dlangezwa, South Africa. [Lin, Yu-Chuan] Tzu Chi Univ, Hualien, Taiwan. [Chen, Angela Chia-Chen] Arizona State Univ, Tempe, AZ USA. [Ko, Nai-Ying] Natl Cheng Kung Univ, Tainan 70101, Taiwan. RP Wilkie, D (reprint author), 845 S Damen, Chicago, IL 60612 USA. EM dwilkie@uic.edu FU National Institutes of Health, National Cancer Institute [R29 CA62477, 2R01 CA62477, 2 R01 CA081918]; University of Washington [2-S07RR05758]; University of Washington Graduate School Research Fund [10-3647] FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: This research was made possible by Grants R29 CA62477 (data collection), 2R01 CA62477 (data analysis and publication preparation), and 2 R01 CA081918 (publication revision) from the National Institutes of Health, National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. The sample included five participants from a pilot study funded by the University of Washington, School of Nursing Biomedical Research Support Grant (2-S07RR05758) and the University of Washington Graduate School Research Fund (10-3647). NR 55 TC 26 Z9 27 U1 2 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0193-9459 J9 WESTERN J NURS RES JI West. J. Nurs. Res. PD FEB PY 2010 VL 32 IS 1 BP 23 EP 46 DI 10.1177/0193945909348009 PG 24 WC Nursing SC Nursing GA 553YF UT WOS:000274402000003 PM 20164474 ER PT J AU Figueiredo, JL Siegel, C Nahrendorf, M Weissleder, R AF Figueiredo, Jose-Luiz Siegel, Cory Nahrendorf, Matthias Weissleder, Ralph TI Intraoperative Near-Infrared Fluorescent Cholangiography (NIRFC) in Mouse Models of Bile Duct Injury SO WORLD JOURNAL OF SURGERY LA English DT Article ID LAPAROSCOPIC CHOLECYSTECTOMY; BILIARY RECONSTRUCTION; INDOCYANINE GREEN; MANAGEMENT; SYSTEM; VISUALIZATION; TOMOGRAPHY; THICKNESS; SURGEONS; LEAKS AB Accidental injury to the common bile duct is a rare but serious complication of laparoscopic cholecystectomy. Accurate visualization of the biliary ducts may prevent injury or allow its early detection. Conventional X-ray cholangiography is often used and can mitigate the severity of injury when correctly interpreted. However, it may be useful to have an imaging method that could provide real-time extrahepatic bile duct visualization without changing the field of view from the laparoscope. The purpose of the present study was to test a new near-infrared (NIR) fluorescent agent that is rapidly excreted via the biliary route in preclinical models to evaluate intraoperative real-time near infrared fluorescent cholangiography (NIRFC). To investigate probe function and excretion, a lipophilic near-infrared fluorescent agent with hepatobiliary excretion was injected intravenously into one group of C57/BL6 control mice and four groups of C57/BL6 mice under the following experimentally induced conditions: (1) chronic biliary obstruction, (2) acute biliary obstruction (3) bile duct perforation, and (4) choledocholithiasis, respectively. The biliary system was imaged intravitally for 1 h with near-infrared fluorescence (NIRF) with an intraoperative small animal imaging system (excitation 649 nm, emission 675 nm). The extrahepatic ducts and extraluminal bile were clearly visible due to the robust fluorescence of the excreted fluorochrome. Twenty-five minutes after intravenous injection, the target-to-background ratio peaked at 6.40 +/- A 0.83 but signal was clearly visible for similar to 60 min. The agent facilitated rapid identification of biliary obstruction and bile duct perforation. Implanted beads simulating choledocholithiasis were promptly identifiable within the common bile duct lumen. Near-infrared fluorescent agents with hepatobiliary excretion may be used intraoperatively to visualize extrahepatic biliary anatomy and physiology. Used in conjunction with laparoscopic imaging technologies, the use of this technique should enhance hepatobiliary surgery. C1 [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Figueiredo, Jose-Luiz; Siegel, Cory; Nahrendorf, Matthias; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. [Figueiredo, Jose-Luiz; Siegel, Cory; Nahrendorf, Matthias; Weissleder, Ralph] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, CPZN 5206,185 Cambridge St, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu FU NCI NIH HHS [P50 CA086355, P50 CA086355-08]; NIBIB NIH HHS [R01 EB006432-04, R01 EB006432] NR 41 TC 25 Z9 26 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD FEB PY 2010 VL 34 IS 2 BP 336 EP 343 DI 10.1007/s00268-009-0332-8 PG 8 WC Surgery SC Surgery GA 542DI UT WOS:000273471200022 PM 20033407 ER PT J AU Gerton, BK Theeler, B Samii, A AF Gerton, Brooke K. Theeler, Brett Samii, Ali TI Backpack Treatment for Camptocormia SO MOVEMENT DISORDERS LA English DT Letter ID PARKINSONS-DISEASE; PATHOGENESIS C1 [Gerton, Brooke K.; Samii, Ali] Vet Affairs Puget Sound Hlth Care Syst, Parkinsons Dis Res Educ Ctr, Dept Neurol, Seattle, WA USA. [Gerton, Brooke K.; Samii, Ali] Vet Affairs Puget Sound Hlth Care Syst, Ctr Clin, Seattle, WA USA. [Gerton, Brooke K.; Samii, Ali] Univ Washington, Seattle, WA 98195 USA. [Theeler, Brett] Madigan Army Med Ctr, Dept Med, Neurol Serv, Tacoma, WA 98431 USA. RP Gerton, BK (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Parkinsons Dis Res Educ Ctr, Dept Neurol, Seattle, WA USA. EM bgerton@u.washington.edu NR 6 TC 18 Z9 18 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN 30 PY 2010 VL 25 IS 2 BP 247 EP 248 DI 10.1002/mds.22909 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 586TY UT WOS:000276937600018 PM 20077473 ER PT J AU Lin, HZ Liu, DP Zhou, XH AF Lin, Huazhen Liu, Danping Zhou, Xiao-Hua TI A correlated random-effects model for normal longitudinal data with nonignorable missingness SO STATISTICS IN MEDICINE LA English DT Article DE nonignorable missing; correlated random effects; Laplace approximation; longitudinal data ID DROP-OUT; INFORMATIVE DROPOUT; DATA SUBJECT; BINARY DATA; NONRESPONSE; REGRESSION; TIME; INFERENCE; OUTCOMES; COUNT AB The missing data problem is common in longitudinal or hierarchical structure studies. In this paper, we propose a correlated random-effects model to fit normal longitudinal or cluster data when the missingness mechanism is nonignorable. Computational challenges arise in the model fitting due to intractable numerical integrations. We obtain the estimates of the parameters based on an accurate approximation of the log likelihood, which has higher-order accuracy but with less computational burden than the existing approximation. We apply the proposed method to a real data set arising from an autism study. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Liu, Danping; Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lin, Huazhen] Sichuan Univ, Sch Math, Chengdu 610064, Sichuan, Peoples R China. [Zhou, Xiao-Hua] VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Seattle, WA 98108 USA. RP Zhou, XH (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM azhou@u.washington.edu RI Liu, Danping/D-2544-2013 FU National Natural Science Foundation of China [10771148]; AHRQ [R01HS013105]; U.S. Department of Veterans Affairs, Veterans Affairs Health Administration, HSRD [ECI-03-206]; National Science Foundation of China [30728019] FX Contract/grant sponsor: National Natural Science Foundation of China; contract/grant number: 10771148; Contract/grant sponsor: AHRQ contract/grant number: R01HS013105; Contract/grant sponsor: U.S. Department of Veterans Affairs, Veterans Affairs Health Administration, HSR&D, contract/grant number. ECI-03-206; Contract/grant sponsor: National Science Foundation of China; contract/grant number: 30728019 NR 23 TC 4 Z9 4 U1 0 U2 8 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 30 PY 2010 VL 29 IS 2 BP 236 EP 247 DI 10.1002/sim.3760 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 544OD UT WOS:000273666600007 PM 19941316 ER PT J AU Pipkin, ME Sacks, JA Cruz-Guilloty, F Lichtenheld, MG Bevan, MJ Rao, A AF Pipkin, Matthew E. Sacks, Jilian A. Cruz-Guilloty, Fernando Lichtenheld, Mathias G. Bevan, Michael J. Rao, Anjana TI Interleukin-2 and Inflammation Induce Distinct Transcriptional Programs that Promote the Differentiation of Effector Cytolytic T Cells SO IMMUNITY LA English DT Article ID HISTONE ACETYLATION; MEMORY DEVELOPMENT; CLONAL EXPANSION; VIRAL-INFECTION; CYTOKINE GENES; CD8(+) MEMORY; CUTTING EDGE; BET; EXPRESSION; PERFORIN AB Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression of memory CTL markers Bcl6 and IL-7R alpha. Binding of Eomes and STAT5 to Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2R alpha and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7R alpha repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2R alpha-deficient effector CD8(+) T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1(+) and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development. C1 [Pipkin, Matthew E.; Cruz-Guilloty, Fernando; Rao, Anjana] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Pipkin, Matthew E.; Cruz-Guilloty, Fernando; Rao, Anjana] Immune Dis Inst, Boston, MA 02115 USA. [Sacks, Jilian A.; Bevan, Michael J.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Sacks, Jilian A.; Bevan, Michael J.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Lichtenheld, Mathias G.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Dev Ctr AIDS Res,Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM arao@cbr.med.harvard.edu FU NIH [AI44432, AI707088, AI19335]; University of Miami Developmental Center for AIDS Research [5P30AI073961]; National Cancer Institute [F32CA126247]; Ford Foundation Predoctoral Fellowship FX We thank Dr. S. Reiner for generously providing the Eomes-VP16 retroviral construct. This work was funded by NIH grants AI44432 and AI707088 A.R.) and AI19335 (to M.J.B.); University of Miami Developmental Center for AIDS Research 5P30AI073961 (to M.G.L.); and the National Cancer Institute F32CA126247 (to M.E.P). F.C.G. was a predoctoral fellow of the Ryan Foundation and was supported by a Ford Foundation Predoctoral Fellowship. NR 50 TC 298 Z9 303 U1 2 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JAN 29 PY 2010 VL 32 IS 1 BP 79 EP 90 DI 10.1016/j.immuni.2009.11.012 PG 12 WC Immunology SC Immunology GA 550HW UT WOS:000274119900013 PM 20096607 ER PT J AU Kalia, V Sarkar, S Subramaniam, S Haining, WN Smith, KA Ahmed, R AF Kalia, Vandana Sarkar, Surojit Subramaniam, Shruti Haining, W. Nicholas Smith, Kendall A. Ahmed, Rafi TI Prolonged Interleukin-2R alpha Expression on Virus-Specific CD8(+) T Cells Favors Terminal-Effector Differentiation In Vivo SO IMMUNITY LA English DT Article ID IMMUNOLOGICAL MEMORY; CLONAL EXPANSION; VIRAL-INFECTION; GENE-EXPRESSION; FLOW-CYTOMETRY; IL-2 RECEPTOR; BLIMP-1; PROLIFERATION; LYMPHOCYTES; ACTIVATION AB CD25, the high-affinity interleukin-2 (IL-2) receptor alpha chain, is rapidly upregulated by antigen-specific CD8(+) T cells after T cell receptor stimulation. Here, we demonstrate that during an acute viral infection, CD25 expression is quite dynamic-after initial upregulation, a subset of virus-specific T cells sustains CD25 expression longer than the rest. At this time when there is distinct heterogeneity in CD25 expression, examination of the in vivo fate of effector cells revealed that CD25(lo) cells, which are relatively less sensitive to IL-2, preferentially upregulate CD127 and CD62L and give rise to functional long-lived memory cells. In contrast, CD25(hi) cells perceiving prolonged IL-2 signals proliferate more rapidly, are prone to apoptosis, exhibit a more pronounced effector phenotype, and appear to be terminally differentiated. Consistent with this, sustained IL-2 receptor signaling during expansion drove terminal-effector differentiation. These data support the hypothesis that prolonged IL-2 signals during priming promote terminal-effector differentiation. C1 [Kalia, Vandana; Sarkar, Surojit; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Subramaniam, Shruti] Loma Linda Univ, Loma Linda, CA 92350 USA. [Haining, W. Nicholas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Childrens Hosp, Boston, MA 02115 USA. [Smith, Kendall A.] Cornell Univ, New York, NY 14853 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu FU NIH [AI30048]; Bill and Melinda Gates Foundation [CAVD 38645]; Elizabeth Glaser Pediatric AIDS Foundation FX The authors wish to acknowledge support from NIH Grant AI30048 (RA), Bill and Melinda Gates Foundation Grant CAVD 38645 (R.A.), and Elizabeth Glaser Pediatric AIDS Foundation Scholar awards (S.S. and V.K.). We wish to thank B.T. Konieczny, R. Karaffa and M. Hulsey for their excellent technical assistance. NR 45 TC 247 Z9 248 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JAN 29 PY 2010 VL 32 IS 1 BP 91 EP 103 DI 10.1016/j.immuni.2009.11.010 PG 13 WC Immunology SC Immunology GA 550HW UT WOS:000274119900014 PM 20096608 ER PT J AU Fujikawa, DG Zhao, S Ke, XR Shinmei, SS Allen, SG AF Fujikawa, Denson G. Zhao, Shuangping Ke, Xingrao Shinmei, Steve S. Allen, Suni G. TI Mild as well as severe insults produce necrotic, not apoptotic, cells: Evidence from 60-min seizures SO NEUROSCIENCE LETTERS LA English DT Article DE Apoptosis; Caspase-3; Excitotoxicity; Necrosis; Programmed cell death; Status epilepticus ID INTERNUCLEOSOMAL DNA CLEAVAGE; INDUCED STATUS EPILEPTICUS; ACID-INDUCED SEIZURES; NEURONAL DAMAGE; KAINIC ACID; TEMPORAL EVOLUTION; CEREBRAL-CORTEX; BRAIN-DAMAGE; RAT-BRAIN; NECROSIS AB We tested the hypothesis that mild insults produce apoptotic, and severe insults necrotic, cells by subjecting adult Wistar rats to 60-min instead of 3-h generalized seizures. Rats' brains were evaluated 6 and 24 h later for evidence of neuronal necrosis by light and electron microscopy, the presence of TUNEL staining and active caspase-3 immunoreactivity, and for evidence of DNA laddering 24 h after seizures. Apoptotic neurons from the retrosplenial cortex of postnatal day 8 rat pups served as positive controls. Six and 24 h after seizures, 16 and 15 brain regions respectively out of 24 showed significant numbers of acidophilic neurons by hematoxylin and eosin stain. Three brain regions had significant numbers of TUNEL-positive neurons 24 h after seizures. No neurons showed active caspase-3 immunoreactivity. Acidophilic neurons were necrotic by electron-microscopic examination. Ultrastructurally, they were shrunken and electron-dense, with shrunken, pyknotic nuclei and swollen mitochondria with disrupted cristae. Nuclei did not contain the irregular chromatin clumps found after 3-h seizures. None of the six brain regions studied ultrastructurally that show DNA laddering 24 h after 3-h seizures showed DNA laddering 24 h after 60-min seizures, probably because there were too few damaged neurons, although the lack of chromatin clumping might have been a contributing factor. Following seizures, a mild as well as a severe insult produces caspase-3-negative necrotic neurons. These results do not support the hypothesis that mild insults produce apoptotic, and severe insults, necrotic, cells. Published by Elsevier Ireland Ltd. C1 [Fujikawa, Denson G.; Zhao, Shuangping; Allen, Suni G.] VA Greater Los Angeles Healthcare Syst, Expt Neurol Lab, North Hills, CA 91343 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, Dept Neurol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, Brain Res Inst, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Ke, Xingrao] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Shinmei, Steve S.] Univ Calif Davis, Adm Univ Extens, Davis, CA 95616 USA. RP Fujikawa, DG (reprint author), VA Greater Los Angeles Healthcare Syst, Expt Neurol Lab, Mail Code 151B4,16111 Plummer St, North Hills, CA 91343 USA. EM dfujikaw@ucla.edu FU Office of Research and Development, Department of Veterans Affairs FX This study was funded by the Office of Research and Development, Department of Veterans Affairs. Dr. Jeffrey A. Gornbein, a UCLA biomathematician, provided expert assistance in the statistical analysis of data. NR 24 TC 9 Z9 11 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 29 PY 2010 VL 469 IS 3 BP 333 EP 337 DI 10.1016/j.neulet.2009.12.022 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 558DX UT WOS:000274722100011 PM 20026247 ER PT J AU Naeger, DM Martin, JN Sinclair, E Hunt, PW Bangsberg, DR Hecht, F Hsue, P McCune, JM Deeks, SG AF Naeger, David M. Martin, Jeffrey N. Sinclair, Elizabeth Hunt, Peter W. Bangsberg, David R. Hecht, Frederick Hsue, Priscilla McCune, Joseph M. Deeks, Steven G. TI Cytomegalovirus-Specific T Cells Persist at Very High Levels during Long-Term Antiretroviral Treatment of HIV Disease SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; LYMPHOCYTE SUBPOPULATIONS; HIGH-FREQUENCIES; AIDS PATIENTS; RNA LEVELS; INFECTION; CD4(+); IMMUNE; LOAD; IMMUNOSENESCENCE AB Background: In healthy, HIV seronegative, CMV seropositive adults, a large proportion of T cells are CMV-specific. High-level CMV-specific T cell responses are associated with accelerated immunologic aging ("immunosenesence") in the elderly population. The impact of untreated and treated HIV infection on the frequency of these cells remains undefined. Methodology/Principal Findings: We measured the proportion of CD4+ and CD8+ T cells responding to CMV pp65 and IE proteins was measured using flow cytometry in 685 unique HIV seronegative and seropositive individuals. The proportion of CMV-specific CD8+ T cells was consistently higher in the HIV-seropositive subjects compared to the HIV-seronegative subjects. This HIV effect was observed even in patients who lacked measurable immunodeficiency. Among the HIV-seropositive subjects, CMV-specific CD8+ T cell responses were proportionately lower during recent infection, higher during chronic untreated infection and higher still during long-term antiretroviral treated infection. The CD8+ T cell response to just two CMV proteins (pp65 and IE) was approximately 6% during long-term therapy, which was over twice that seen in HIV-seronegative persons. CMV-specific CD4+ T cell responses followed the same trends, but the magnitude of the effect was smaller. Conclusions/Significance: Long-term successfully treated HIV infected patients have remarkably high levels of CMV-specific effector cells. These levels are similar to that observed in the elderly, but occur at much younger ages. Future studies should focus on defining the potential role of the CMV-specific inflammatory response in non-AIDS morbidity and mortality, including immunosenescence. C1 [Naeger, David M.; Martin, Jeffrey N.; Sinclair, Elizabeth; Hunt, Peter W.; Hecht, Frederick; Hsue, Priscilla; McCune, Joseph M.; Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Initiat Global Hlth, Boston, MA USA. RP Naeger, DM (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM sdeeks@php.ucsf.edu FU National Institutes of Health [AI41531, AI052745, AI069994, DPI OD00329]; University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research [P30 MH59037]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]; Center for AIDS Prevention Studies [P30 MH62246]; Doris Duke Charitable Foundation; American Foundation for AIDS Research [106710-40-RGRL] FX Funding: This research was supported by a grants from the National Institutes of Health (AI41531, AI052745, AI069994)), University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research, P30 MH59037; the UCSF Clinical and Translational Research Institute Clinical Research Center (UL1 RR024131); the Center for AIDS Prevention Studies (P30 MH62246); The Doris Duke Charitable Foundation and the American Foundation for AIDS Research (106710-40-RGRL). JMM is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and the NIH Director's Pioneer Award Program, part of the NIH Roadmap for Medical Research, through grant number DPI OD00329. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 85 Z9 85 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 29 PY 2010 VL 5 IS 1 AR e8886 DI 10.1371/journal.pone.0008886 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 550PA UT WOS:000274139100003 PM 20126452 ER PT J AU Tan, YHC Krishnaswamy, S Nandi, S Kanteti, R Vora, S Onel, K Hasina, R Lo, FY El-Hashani, E Cervantes, G Robinson, M Kales, SC Lipkowitz, S Karrison, T Sattler, M Vokes, EE Wang, YC Salgia, R AF Tan, Yi-Hung Carol Krishnaswamy, Soundararajan Nandi, Suvobroto Kanteti, Rajani Vora, Sapana Onel, Kenan Hasina, Rifat Lo, Fang-Yi El-Hashani, Essam Cervantes, Gustavo Robinson, Matthew Kales, Stephen C. Lipkowitz, Stanley Karrison, Theodore Sattler, Martin Vokes, Everett E. Wang, Yi-Ching Salgia, Ravi TI CBL Is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine Kinases SO PLOS ONE LA English DT Article ID GROWTH-FACTOR RECEPTOR; ACQUIRED UNIPARENTAL DISOMY; C-CBL; UBIQUITIN LIGASE; BINDING-SITE; OF-FUNCTION; PROTEIN; DOMAIN; AMPLIFICATION; PHOSPHORYLATION AB Background: Non-small cell lung cancer (NSCLC) is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET), and functionality in NSCLC. Methods and Findings: Using archival formalin-fixed paraffin embedded (FFPE) extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH) for the c-CBL locus (22%, n = 8/37) and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively) transfected in NSCLC cell lines, there was increased cell viability and cell motility. Conclusions: Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis. C1 [Tan, Yi-Hung Carol; Lo, Fang-Yi] Natl Taiwan Normal Univ, Dept Life Sci, Taipei, Taiwan. [Krishnaswamy, Soundararajan; Nandi, Suvobroto; Kanteti, Rajani; Hasina, Rifat; El-Hashani, Essam; Cervantes, Gustavo; Robinson, Matthew; Vokes, Everett E.; Salgia, Ravi] Univ Chicago, Pritzker Sch Med, Med Ctr, Canc Res Ctr,Dept Med, Chicago, IL 60637 USA. [Vora, Sapana; Onel, Kenan] Univ Chicago, Pritzker Sch Med, Med Ctr, Canc Res Ctr,Dept Pediat, Chicago, IL 60637 USA. [Kales, Stephen C.; Lipkowitz, Stanley] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Karrison, Theodore] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. [Sattler, Martin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sattler, Martin] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Yi-Ching] Natl Cheng Kung Univ, Coll Med, Dept Pharmacol, Tainan 70101, Taiwan. RP Tan, YHC (reprint author), Natl Taiwan Normal Univ, Dept Life Sci, Taipei, Taiwan. EM rsalgia@medicine.bsd.uchicago.edu FU National Institutes of Health (NIH)/National Cancer Institute (NCI) [5RO1CA125541-03, 3RO1CA125541-03S109, 5RO1CA129501-02, 3RO1CA129501-02S109, 1R21CA140003-01]; MARF; V-Foundation; National Science Council, Taiwan [NSC96-2628-B-006-048-MY3] FX Funding: Supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) Grants: 5RO1CA125541-03, 3RO1CA125541-03S109, 5RO1CA129501-02, 3RO1CA129501-02S109, 1R21CA140003-01, MARF, V-Foundation, Cancer Research Foundation and American Respiratory Health Association of America (RS) and grant NSC96-2628-B-006-048-MY3 from the National Science Council, Taiwan. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funding agenices had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 50 Z9 51 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 29 PY 2010 VL 5 IS 1 AR e8972 DI 10.1371/journal.pone.0008972 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 550PA UT WOS:000274139100020 PM 20126411 ER PT J AU Boilard, E Nigrovic, PA Larabee, K Watts, GFM Coblyn, JS Weinblatt, ME Massarotti, EM Remold-O'Donnell, E Farndale, RW Ware, J Lee, DM AF Boilard, Eric Nigrovic, Peter A. Larabee, Katherine Watts, Gerald F. M. Coblyn, Jonathan S. Weinblatt, Michael E. Massarotti, Elena M. Remold-O'Donnell, Eileen Farndale, Richard W. Ware, Jerry Lee, David M. TI Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production SO SCIENCE LA English DT Article ID RHEUMATOID-ARTHRITIS; GLYCOPROTEIN-VI; ACTIVATION; DISEASE; COMPLEXES; MECHANISM; RECEPTOR; PLASMA; CHAIN AB In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles-submicrometer vesicles elaborated by activated platelets-in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases. C1 [Boilard, Eric; Nigrovic, Peter A.; Larabee, Katherine; Watts, Gerald F. M.; Coblyn, Jonathan S.; Weinblatt, Michael E.; Massarotti, Elena M.; Lee, David M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Nigrovic, Peter A.] Childrens Hosp Boston, Div Immunol, Boston, MA 02115 USA. [Remold-O'Donnell, Eileen] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Farndale, Richard W.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. [Ware, Jerry] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. RP Lee, DM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. EM dlee@rics.bwh.harvard.edu FU NIH [P01 AI065858, K08AR051321, HL091269]; Arthritis Foundation; Cogan Family Foundation; British Heart Foundation and Medical Research Council, UK; National Heart, Lung, and Blood Institute [HL50545] FX Financial support for this work was provided by NIH grant P01 AI065858, an Arthritis Foundation Investigator Award, and the Cogan Family Foundation (D. M. L.); an Arthritis Foundation Postdoctoral Fellowship Award (E. B.); NIH grants K08AR051321 (P. A. N.) and HL091269 (E. R.-O.); the British Heart Foundation and Medical Research Council, UK (R. W. F.); and National Heart, Lung, and Blood Institute grant HL50545 (J. W.). D. M. L., E. B., and J. W. have filed a provisional patent application for glycoprotein VI as a target for treatment for inflammatory arthritis. NR 31 TC 388 Z9 413 U1 8 U2 69 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 JAN 29 PY 2010 VL 327 IS 5965 BP 580 EP 583 DI 10.1126/science.1181928 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 549CT UT WOS:000274020500038 PM 20110505 ER PT J AU Ecker, AS Berens, P Keliris, GA Bethge, M Logothetis, NK Tolias, AS AF Ecker, Alexander S. Berens, Philipp Keliris, Georgios A. Bethge, Matthias Logothetis, Nikos K. Tolias, Andreas S. TI Decorrelated Neuronal Firing in Cortical Microcircuits SO SCIENCE LA English DT Article ID PRIMARY VISUAL-CORTEX; AREA MT; NOISE CORRELATIONS; INFORMATION; VARIABILITY; DISCHARGE; ACCURACY; MACAQUE; CONNECTIVITY; SYNAPSES AB Correlated trial-to-trial variability in the activity of cortical neurons is thought to reflect the functional connectivity of the circuit. Many cortical areas are organized into functional columns, in which neurons are believed to be densely connected and to share common input. Numerous studies report a high degree of correlated variability between nearby cells. We developed chronically implanted multitetrode arrays offering unprecedented recording quality to reexamine this question in the primary visual cortex of awake macaques. We found that even nearby neurons with similar orientation tuning show virtually no correlated variability. Our findings suggest a refinement of current models of cortical microcircuit architecture and function: Either adjacent neurons share only a few percent of their inputs or, alternatively, their activity is actively decorrelated. C1 [Ecker, Alexander S.; Berens, Philipp; Tolias, Andreas S.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Ecker, Alexander S.; Berens, Philipp; Keliris, Georgios A.; Bethge, Matthias; Logothetis, Nikos K.] Max Planck Inst Biol Cybernet, D-72076 Tubingen, Germany. [Ecker, Alexander S.; Berens, Philipp; Bethge, Matthias] Univ Tubingen, Inst Theoret Phys, D-72076 Tubingen, Germany. [Ecker, Alexander S.; Berens, Philipp; Bethge, Matthias] Univ Tubingen, Ctr Integrat Neurosci, D-72076 Tubingen, Germany. [Logothetis, Nikos K.] Univ Manchester, Div Imaging Sci & Biomed Engn, Manchester M1 7HL, Lancs, England. [Tolias, Andreas S.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Tolias, Andreas S.] Rice Univ, Dept Computat & Appl Math, Houston, TX 77005 USA. RP Tolias, AS (reprint author), Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. EM atolias@cns.bcm.edu RI Ecker, Alexander/A-5184-2010; Berens, Philipp/A-5653-2009; Bethge, Matthias/B-1554-2008; Keliris, Georgios A/B-6692-2008; OI Ecker, Alexander/0000-0003-2392-5105; Keliris, Georgios A/0000-0001-6732-1261; Berens, Philipp/0000-0002-0199-4727 FU National Eye Institute, NIH [R01 EY018847]; Max Planck Society; U.S. Department of Defense [W81XWH-08-2-0147]; Department of Veterans Affairs; Arnold and Mabel Beckman Foundation; German Federal Ministry of Education and Research (BMBF) [FKZ:01GQ0601] FX We thank M. Subramanian, A. Hoenselaar, T. J. Williford, and D. Murray for help with experiments; R. J. Cotton for his contribution in setting up recording equipment; and the Siapas laboratory at Caltech for providing the recording software. We thank R. J. Cotton, P. Dayan, S. Deneve, K. D. Harris, E. V. Lubenov, W. J. Ma, J. H. Macke, A. Renart, J. de la Rocha, A. G. Siapas, and S. M. Smirnakis for comments on the manuscript and discussions. This work was supported by the National Eye Institute, NIH (R01 EY018847), the Max Planck Society, the U.S. Department of Defense (W81XWH-08-2-0147), a VA Merit Award from the Department of Veterans Affairs, and an Arnold and Mabel Beckman Foundation Young Investigator Award to A. S. T., and by the German Federal Ministry of Education and Research (BMBF) through the Bernstein award to M. B. (FKZ:01GQ0601). NR 31 TC 279 Z9 283 U1 1 U2 24 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 JAN 29 PY 2010 VL 327 IS 5965 BP 584 EP 587 DI 10.1126/science.1179867 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 549CT UT WOS:000274020500039 PM 20110506 ER PT J AU Kirsch, DG Santiago, PM di Tomaso, E Sullivan, JM Hou, WS Dayton, T Jeffords, LB Sodha, P Mercer, KL Cohen, R Takeuchi, O Korsmeyer, SJ Bronson, RT Kim, CF Haigis, KM Jain, RK Jacks, T AF Kirsch, David G. Santiago, Philip M. di Tomaso, Emmanuelle Sullivan, Julie M. Hou, Wu-Shiun Dayton, Talya Jeffords, Laura B. Sodha, Pooja Mercer, Kim L. Cohen, Rhianna Takeuchi, Osamu Korsmeyer, Stanley J. Bronson, Roderick T. Kim, Carla F. Haigis, Kevin M. Jain, Rakesh K. Jacks, Tyler TI p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis SO SCIENCE LA English DT Article ID BONE-MARROW; CELL-DEATH; ENDOTHELIAL APOPTOSIS; GAMMA-IRRADIATION; DNA-DAMAGE; IN-VIVO; RADIOSENSITIVITY; PUMA; PROLIFERATION; RADIOTHERAPY AB Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells affected by radiation to cause the GI syndrome are derived from the epithelium or endothelium and whether the target cells die by apoptosis or other mechanisms are controversial issues. Studying mouse models, we found that selective deletion of the proapoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after sub-total-body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not from endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by the death of GI epithelial cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis. C1 [Kirsch, David G.; Santiago, Philip M.; Hou, Wu-Shiun; Dayton, Talya; Sodha, Pooja; Mercer, Kim L.; Cohen, Rhianna; Kim, Carla F.; Haigis, Kevin M.; Jacks, Tyler] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Kirsch, David G.; di Tomaso, Emmanuelle; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Kirsch, David G.; di Tomaso, Emmanuelle; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kirsch, David G.; Sullivan, Julie M.; Jeffords, Laura B.] Duke Univ, Med Ctr, Dept Radiat Oncol & Pharmacol, Durham, NC 27708 USA. [Kirsch, David G.; Sullivan, Julie M.; Jeffords, Laura B.] Duke Univ, Med Ctr, Dept Canc Biol, Durham, NC 27708 USA. [Takeuchi, Osamu; Korsmeyer, Stanley J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bronson, Roderick T.] Tufts Univ, Sch Med & Vet Med, North Grafton, MA 01536 USA. [Jacks, Tyler] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Jacks, T (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM tjacks@mit.edu RI Takeuchi, Osamu/D-6007-2011 FU Howard Hughes Medical Institute; National Cancer Institute [P30-CA14051, KO8 CA 114176, P01 CA80124]; Dana Farber Cancer Center for Medical Countermeasures Against Radiation [U19-AI06775]; National Institute of Allergy and Infectious Diseases [RC1-AI078521]; American Society of Clinical Oncology FX We thank M. Serrano for the super-p53 mice; A. Berns for the p53FL mice; P. Crawford and J. Gordon for advice; E. Travis for providing a model jig; J. Down, C. Pope, and K. Doppke for performing dosimetry measurements; and K. Held for critically reading the manuscript. This work is funded by the Howard Hughes Medical Institute (T. J.), partially funded by Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute (NCI) (T. J.), NCI grant KO8 CA 114176 (D. G. K.), the pilot project from the Dana Farber Cancer Center for Medical Countermeasures Against Radiation U19-AI06775 (D. G. K.), grant RC1-AI078521 from the National Institute of Allergy and Infectious Diseases (D. G. K.), an American Society of Clinical Oncology Young Investigator Award (D. G. K.), and NCI grant P01 CA80124 (R. K. J.). T. J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. NR 33 TC 98 Z9 104 U1 1 U2 13 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 JAN 29 PY 2010 VL 327 IS 5965 BP 593 EP 596 DI 10.1126/science.1166202 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 549CT UT WOS:000274020500042 PM 20019247 ER PT J AU Chauhan, D Singh, AV Ciccarelli, B Richardson, PG Palladino, MA Anderson, KC AF Chauhan, Dharminder Singh, Ajita V. Ciccarelli, Bryan Richardson, Paul G. Palladino, Michael A. Anderson, Kenneth C. TI Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma SO BLOOD LA English DT Article ID MARROW STROMAL CELLS; BONE-MARROW; THERAPEUTIC APPLICATIONS; THALIDOMIDE ANALOGS; DRUG-RESISTANCE; BORTEZOMIB; APOPTOSIS; SURVIVAL; ACTIVATION; CASPASE-12 AB Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 is distinct from bortezomib (Velcade) and, importantly, triggers apoptosis in multiple myeloma (MM) cells resistant to bortezomib. Here we demonstrate that combining NPI-0052 and lenalidomide (Revlimid) induces synergistic anti-MM activity in vitro using MM-cell lines or patient MM cells. NPI-0052 plus lenalidomide-induced apoptosis is associated with (1) activation of caspase-8, caspase-9, caspase-12, caspase-3, and poly(ADP) ribose polymerase; (2) activation of BH-3 protein BIM; (3) translocation of BIM to endoplasmic reticulum; (4) inhibition of migration of MM cells and angiogenesis; and (5) suppression of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities. Importantly, blockade of BIM using siRNA significantly abrogates NPI-0052 plus lenalidomide-induced apoptosis. Furthermore, studies using biochemical inhibitors of caspase-8 versus caspase-9 demonstrate that NPI-0052 plus lenalidomide-triggered apoptosis is primarily dependent on caspase-8 signaling. In animal tumor model studies, low-dose combination of NPI-0052 and lenalidomide is well tolerated, significantly inhibits tumor growth, and prolongs survival. Taken together, our study provides the preclinical rationale for clinical protocols evaluating lenalidomide together with NPI-0052 to improve patient outcome in MM. (Blood. 2010;115:834-845) C1 [Chauhan, Dharminder; Singh, Ajita V.; Ciccarelli, Bryan; Richardson, Paul G.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Chauhan, Dharminder; Singh, Ajita V.; Ciccarelli, Bryan; Richardson, Paul G.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Myeloma Ctr, Boston, MA 02115 USA. [Palladino, Michael A.] Nereus Pharmaceut, San Diego, CA USA. RP Anderson, KC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,LeBow Inst Myeloma Therapeut, Mayer Bldg Rm 561,44 Binney St, Boston, MA 02115 USA. EM Dharminder_Chauhan@dfci.harvard.edu; Kenneth_Anderson@dfci.harvard.edu FU National Institutes of Health [SPORE-P50100707, PO1-CA078378, RO1CA050947] FX This work was supported by the National Institutes of Health (grants SPORE-P50100707, PO1-CA078378, and RO1CA050947). NR 46 TC 66 Z9 68 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 28 PY 2010 VL 115 IS 4 BP 834 EP 845 DI 10.1182/blood-2009-03-213009 PG 12 WC Hematology SC Hematology GA 549XA UT WOS:000274086600015 PM 19965674 ER PT J AU Andrews, S Burgess, SJ Skaalrud, D Kelly, JX Peyton, DH AF Andrews, Simeon Burgess, Steven J. Skaalrud, Deborah Kelly, Jane Xu Peyton, David H. TI Reversal Agent and Linker Variants of Reversed Chloroquines: Activities against Plasmodium falciparum SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BETA-HEMATIN INHIBITION; DRUG-RESISTANCE; MALARIA; ANTIMALARIAL; COMBINATIONS; TRANSPORTER AB We have shown that "reversed chloroquine molecules" constructed from chloroquine-like and resistance "reversal-agent"-like cores can be powerful drugs against malaria (J. Med. Chem. 2006, 49, 5623-5625). Several reversed chloroquines are now presented that probe parameters governing the activities against chloroquine-resistant and chloroquine-sensitive malaria strains. The design is tolerant to linker and reversal agent changes, but it piperazinyl group adjacent to the quinoline, at least for the group Of Compounds studied here, may be detrimental. C1 [Andrews, Simeon; Burgess, Steven J.; Skaalrud, Deborah; Kelly, Jane Xu; Peyton, David H.] Portland State Univ, Dept Chem, Portland, OR 97207 USA. [Burgess, Steven J.; Kelly, Jane Xu] DesignMedix Inc, Portland, OR 97201 USA. [Kelly, Jane Xu] Portland VA Med Ctr, Portland, OR 97239 USA. RP Peyton, DH (reprint author), Portland State Univ, Dept Chem, POB 751, Portland, OR 97207 USA. EM peytond@pdx.edu FU Medical Research Foundation of Oregon [0530]; National Institutes of Health [AI067837, AI072923]; Murdock Charitable Trust FX The authors thank the following for supporting this research: the Medical Research Foundation of Oregon (Grant 0530), the National Institutes of Health (Grants AI067837 and AI072923) to DHP, and a grant from the Murdock Charitable Trust for the NMR instruments. NR 19 TC 54 Z9 54 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 28 PY 2010 VL 53 IS 2 BP 916 EP 919 DI 10.1021/jm900972u PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 544PX UT WOS:000273672100037 PM 20088608 ER PT J AU Mayack, SR Shadrach, JL Kim, FS Wagers, AJ AF Mayack, Shane R. Shadrach, Jennifer L. Kim, Francis S. Wagers, Amy J. TI Systemic signals regulate ageing and rejuvenation of blood stem cell niches (Retracted article. See vol. 467, pg. 872, 2010) SO NATURE LA English DT Article; Retracted Publication ID HEMATOPOIETIC-STEM; IGF-I; PROGENITOR CELLS; SKELETAL-MUSCLE; GROWTH; OSTEOBLASTS; PATHWAYS; BONE; IDENTIFICATION; REGENERATION AB Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function. C1 [Mayack, Shane R.; Shadrach, Jennifer L.; Kim, Francis S.; Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst,Joslin Diabet Ctr, Boston, MA 02115 USA. RP Wagers, AJ (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst,Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02115 USA. EM amy.wagers@joslin.harvard.edu FU Burroughs-Welcome Fund; WM Keck Foundation; Glenn Foundation; National Institutes of Health (NIH) [1 DP2 OD004345-01, T32DK07260-29]; Iacocca Foundation; Joslin Diabetes Center DERC [P30DK036836] FX This work was supported in part by funding from the Burroughs-Welcome Fund, WM Keck Foundation, Glenn Foundation, and National Institutes of Health (NIH) 1 DP2 OD004345-01 (to A. J. W.), by fellowships from the NIH (T32DK07260-29) and the Iacocca Foundation (to S. R. M.), and by the Joslin Diabetes Center DERC (P30DK036836). We thank J. LaVecchio and G. Buruzula for expert cell sorting, C. J. Luckey for anti-IGF-1 antibody, and L. Zon, R. Lee, D. Rossi, L. P. Kane, S. Lowe and C. Dall'Osso for helpful advice and critical reading of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 37 TC 80 Z9 87 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 28 PY 2010 VL 463 IS 7280 BP 495 EP U109 DI 10.1038/nature08749 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548QK UT WOS:000273981100041 PM 20110993 ER PT J AU Zhang, JM Adrian, FJ Jahnke, W Cowan-Jacob, SW Li, AG Iacob, RE Sim, T Powers, J Dierks, C Sun, FX Guo, GR Ding, Q Okram, B Choi, Y Wojciechowski, A Deng, XM Liu, GX Fendrich, G Strauss, A Vajpai, N Grzesiek, S Tuntland, T Liu, Y Bursulaya, B Azam, M Manley, PW Engen, JR Daley, GQ Warmuth, M Gray, NS AF Zhang, Jianming Adrian, Francisco J. Jahnke, Wolfgang Cowan-Jacob, Sandra W. Li, Allen G. Iacob, Roxana E. Sim, Taebo Powers, John Dierks, Christine Sun, Fangxian Guo, Gui-Rong Ding, Qiang Okram, Barun Choi, Yongmun Wojciechowski, Amy Deng, Xianming Liu, Guoxun Fendrich, Gabriele Strauss, Andre Vajpai, Navratna Grzesiek, Stephan Tuntland, Tove Liu, Yi Bursulaya, Badry Azam, Mohammad Manley, Paul W. Engen, John R. Daley, George Q. Warmuth, Markus Gray, Nathanael S. TI Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors SO NATURE LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CELL LUNG-CANCER; KINASE-INHIBITOR; C-ABL; TYROSINE KINASE; LYMPHOBLASTIC-LEUKEMIA; IMATINIB RESISTANCE; SELECTIVE INHIBITOR; MUTATIONS; DYNAMICS AB In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone. C1 [Adrian, Francisco J.; Li, Allen G.; Dierks, Christine; Sun, Fangxian; Guo, Gui-Rong; Ding, Qiang; Liu, Guoxun; Tuntland, Tove; Liu, Yi; Bursulaya, Badry] Novartis Res Fdn, Dept Chem, Genom Inst, San Diego, CA 92121 USA. [Zhang, Jianming; Sim, Taebo; Choi, Yongmun; Wojciechowski, Amy; Deng, Xianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhang, Jianming; Sim, Taebo; Powers, John; Choi, Yongmun; Wojciechowski, Amy; Deng, Xianming; Azam, Mohammad; Daley, George Q.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Jahnke, Wolfgang; Cowan-Jacob, Sandra W.; Fendrich, Gabriele; Strauss, Andre; Manley, Paul W.] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland. [Iacob, Roxana E.; Engen, John R.] Northwestern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Iacob, Roxana E.; Engen, John R.] Northwestern Univ, Barnett Inst Chem & Biol Anal, Boston, MA 02115 USA. [Sim, Taebo] Korea Inst Sci & Technol, Life Sci Res Div, Seoul 136791, South Korea. [Powers, John; Azam, Mohammad; Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Powers, John; Azam, Mohammad; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Powers, John; Azam, Mohammad; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Okram, Barun] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Okram, Barun] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Vajpai, Navratna; Grzesiek, Stephan] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland. [Warmuth, Markus] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA. RP Adrian, FJ (reprint author), Novartis Res Fdn, Dept Chem, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA. EM fadrian@gnf.org; markus.warmuth@novartis.com; nathanael_gray@dfci.harvard.edu RI Dierks, Christine/L-4358-2013 FU NCI NIH HHS [R01 CA130876, R01 CA130876-03] NR 41 TC 263 Z9 271 U1 8 U2 78 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 28 PY 2010 VL 463 IS 7280 BP 501 EP U116 DI 10.1038/nature08675 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548QK UT WOS:000273981100042 PM 20072125 ER PT J AU Krishnamoorthy, KS Eichler, FS Goyal, NA Small, JE Snuderl, M AF Krishnamoorthy, Kalpathy S. Eichler, Florian S. Goyal, Namita A. Small, Juan E. Snuderl, Matija TI A Boy with Developmental Delay and Irritability Infantile Krabbe disease (globoid-cell leukodystrophy) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CEREBRAL-PALSY; TERM INFANTS; DEMYELINATIVE NEUROPATHIES; PERIPHERAL NEUROPATHY; OPTIC-NERVE; CLASSIFICATION; ENLARGEMENT; CHILDREN; MRI C1 [Krishnamoorthy, Kalpathy S.] Massachusetts Gen Hosp, Div Pediat Neurol, Boston, MA 02114 USA. [Eichler, Florian S.; Goyal, Namita A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Small, Juan E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Snuderl, Matija] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Krishnamoorthy, Kalpathy S.] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. [Eichler, Florian S.; Goyal, Namita A.] Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02138 USA. [Small, Juan E.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Snuderl, Matija] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Krishnamoorthy, KS (reprint author), Massachusetts Gen Hosp, Div Pediat Neurol, Boston, MA 02114 USA. NR 27 TC 4 Z9 4 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 28 PY 2010 VL 362 IS 4 BP 346 EP 356 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 548OT UT WOS:000273975000012 PM 20107221 ER PT J AU Wu, CL Jordan, KW Ratai, EM Sheng, JH Adkins, CB DeFeo, EM Jenkins, BG Ying, L McDougal, WS Cheng, LL AF Wu, Chin-Lee Jordan, Kate W. Ratai, Eva M. Sheng, Jinhua Adkins, Christen B. DeFeo, Elita M. Jenkins, Bruce G. Ying, Leslie McDougal, W. Scott Cheng, Leo L. TI Metabolomic Imaging for Human Prostate Cancer Detection SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; MR SPECTROSCOPY; BREAST-CANCER; 3 T; RESOLUTION; PROFILES; TISSUE; MORTALITY; BIOPSIES; SEQUENCE AB As current radiological approaches cannot accurately localize prostate cancer in vivo, biopsies are conducted at random within prostates for patients at risk for prostate cancer, leading to high false-negative rates. Metabolomic imaging can map cancer-specific biomolecular profile values onto anatomical structures to direct biopsy. In this preliminary study, we evaluated five whole prostates removed during prostatectomy from biopsy-proven cancer patients on a 7-tesla human whole-body magnetic resonance scanner. Localized, multi-cross-sectional, multivoxel magnetic resonance spectra were used to construct a malignancy index based on prostate cancer metabolomic profiles obtained from previous intact tissue analyses with a 14-tesla spectrometer. This calculated malignancy index is linearly correlated with lesion size and demonstrates a 93 to 97% overall accuracy for detecting the presence of prostate cancer lesions, suggesting the potential clinical utility of this approach. C1 [Wu, Chin-Lee; Jordan, Kate W.; Adkins, Christen B.; DeFeo, Elita M.; Cheng, Leo L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Wu, Chin-Lee; McDougal, W. Scott] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. [Ratai, Eva M.; Jenkins, Bruce G.; Cheng, Leo L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Sheng, Jinhua; Ying, Leslie] Univ Wisconsin, Dept Elect Engn & Comp Sci, Milwaukee, WI 53201 USA. RP Cheng, LL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. EM cheng@nmr.mgh.harvard.edu OI Jordan, Kate/0000-0002-3089-2543 FU A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital; Claire and John Bertucci Prostate Cancer Research Fund; [CA115746]; [CA095624] FX CA115746 (L.L.C.); CA095624 (L.L.C.); A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital; and Claire and John Bertucci Prostate Cancer Research Fund. NR 34 TC 5 Z9 7 U1 0 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JAN 27 PY 2010 VL 2 IS 16 AR 16ra8 DI 10.1126/scitranslmed.3000513 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 590YO UT WOS:000277264600004 PM 20371475 ER PT J AU Di Salvo, TG Acker, MA Dec, GW Byrne, JG AF Di Salvo, Thomas G. Acker, Michael A. Dec, G. William Byrne, John G. TI Mitral Valve Surgery in Advanced Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE mitral regurgitation; heart failure; cardiac surgery ID CARDIAC RESYNCHRONIZATION THERAPY; LEFT-VENTRICULAR FUNCTION; ACORN CLINICAL-TRIAL; COLLEGE-OF-CARDIOLOGY; LONG-TERM SURVIVAL; DILATED CARDIOMYOPATHY; SYSTOLIC DYSFUNCTION; AFTERLOAD REDUCTION; SURGICAL-TREATMENT; SUPPORT DEVICE AB The appropriateness and timing of mitral valve surgery in patients with advanced heart failure and severe mitral regurgitation remains controversial. Recent surgical results provide evidence for beneficial effects on left ventricular remodeling and functional capacity. Given the absence of randomized trials comparing the outcomes of mitral valve surgery to medical therapy, however, clinical decision making regarding surgery for these fragile patients poses a dilemma to thoughtful clinicians. This paper reviews the pathophysiology of mitral regurgitation in heart failure and proposes an integrated approach to management. (J Am Coll Cardiol 2010; 55: 271-82) (C) 2010 by the American College of Cardiology Foundation C1 [Di Salvo, Thomas G.; Byrne, John G.] Vanderbilt Univ, Nashville, TN USA. [Acker, Michael A.] Univ Penn, Philadelphia, PA 19104 USA. [Dec, G. William] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Di Salvo, TG (reprint author), Vanderbilt Heart & Vasc Inst, 1215 21st Ave,MCE 5th Floor,Suite 5037, Nashville, TN 37232 USA. EM thomas.g.disalvo@vanderbilt.edu NR 87 TC 42 Z9 43 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 26 PY 2010 VL 55 IS 4 BP 271 EP 282 DI 10.1016/j.jacc.2009.08.059 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 546HP UT WOS:000273802200001 PM 20117430 ER PT J AU Ix, JH Katz, R Peralta, CA de Boer, IH Allison, MA Bluemke, DA Siscovick, DS Lima, JAC Criqui, MH AF Ix, Joachim H. Katz, Ronit Peralta, Carmen A. de Boer, Ian H. Allison, Matthew A. Bluemke, David A. Siscovick, David S. Lima, Joao A. C. Criqui, Michael H. TI A High Ankle Brachial Index Is Associated With Greater Left Ventricular Mass MESA (Multi-Ethnic Study of Atherosclerosis) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; heart failure; left ventricular mass; medial arterial calcification; vascular stiffness ID PERIPHERAL ARTERIAL-DISEASE; CARDIOVASCULAR HEALTH; RISK-FACTORS; CALCIFICATION; PRESSURES; PREVALENCE; MORTALITY; EVENTS; ADULTS AB Objectives This study sought to determine the association of high ankle brachial index (ABI) measurements with left ventricular (LV) mass, and to compare its strength with that of low ABI with LV mass. Background Arterial stiffness leads to LV mass through nonatherosclerotic pathways in mice. In humans, a high ABI indicates stiff peripheral arteries and is associated with cardiovascular disease (CVD) events. Whether high ABI is associated with LV mass in humans and whether this might reflect consequences of arterial stiffness, atherosclerosis, or both is unknown. Methods Among 4,972 MESA (Multi-Ethnic Study of Atherosclerosis) participants without clinical CVD, we used linear regression to evaluate the association of low (<0.90) and high (>1.40 or incompressible) ABI with LV mass by cardiac magnetic resonance imaging (MRI). Intermediate ABIs served as the reference category. To determine the effect of subclinical atherosclerosis, models were adjusted for common and internal carotid intima media thickness (cIMT) and natural log-transformed coronary artery calcification. Results Compared with subjects with intermediate ABI, LV mass was higher with either low (2.70 g/m(2) higher, 95% confidence interval: 0.65 to 4.75) or high ABI (6.84 g/m2 higher, 95% confidence interval: 3.2 to 10.47) after adjustment for traditional CVD risk factors, kidney function, and C-reactive protein. However, further adjustment for cIMT and CAC substantially attenuated the association of low ABI with LV mass index (1.24 g/m(2) higher, 95% confidence interval: -0.84 to 3.33), whereas the association of high ABI was minimally altered (6.01 g/m(2) higher, 95% confidence interval: 2.36 to 9.67). Conclusions High ABI is associated with greater LV mass; an association that is not attenuated with adjustment for subclinical atherosclerosis in nonperipheral arterial beds. High ABI might lead to greater LV mass through nonatherosclerotic pathways. (J Am Coll Cardiol 2010; 55: 342-9) (C) 2010 by the American College of Cardiology Foundation C1 [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, San Diego VA Healthcare Syst, San Diego, CA 92161 USA. [Ix, Joachim H.; Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Div Prevent Med, Dept Family & Prevent, San Diego, CA 92161 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Katz, Ronit] Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [de Boer, Ian H.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Peralta, Carmen A.] Univ Calif San Diego, Div Nephrol, Dept Med, San Diego, CA 92161 USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Bluemke, David A.] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. RP Ix, JH (reprint author), Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, San Diego VA Healthcare Syst, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu OI Bluemke, David/0000-0002-8323-8086; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute (NHLBI) [R21HL091217, N01-HC-95159, N01-HC-95169]; American Heart Association Fellow to Faculty Transition Award FX From the *Division of Nephrology and Hypertension, Department of Medicine, and the dagger Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California San Diego, San Diego, California; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, California; Collaborative Health Studies Coordinating Center, Department of Biostatistics, ||Division of Nephrology, Department of Medicine, and the Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington; #Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California; **San Francisco Veterans Affairs Medical Center, San Francisco, California; dagger dagger Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Maryland; and the Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. This study was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R21HL091217 (to Dr. Ix), an American Heart Association Fellow to Faculty Transition Award, and contracts N01-HC-95159 through N01-HC-95169 from the NHLBI. Michael R. Jaff, MD, served as Guest Editor for this article. NR 28 TC 40 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 26 PY 2010 VL 55 IS 4 BP 342 EP 349 DI 10.1016/j.jacc.2009.11.010 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 546HP UT WOS:000273802200011 PM 20117440 ER PT J AU Huang, Y Pastor, WA Shen, YH Tahiliani, M Liu, DR Rao, A AF Huang, Yun Pastor, William A. Shen, Yinghua Tahiliani, Mamta Liu, David R. Rao, Anjana TI The Behaviour of 5-Hydroxymethylcytosine in Bisulfite Sequencing SO PLOS ONE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; DNA METHYLATION; TET2 MUTATIONS; CYTOSINE METHYLATION; MAMMALIAN DEVELOPMENT; MLL RECOMBINOME; EUKARYOTIC DNA; THYMINE GLYCOL; CPG SEQUENCES; CANCER AB Background: We recently showed that enzymes of the TET family convert 5-mC to 5-hydroxymethylcytosine (5-hmC) in DNA. 5-hmC is present at high levels in embryonic stem cells and Purkinje neurons. The methylation status of cytosines is typically assessed by reaction with sodium bisulfite followed by PCR amplification. Reaction with sodium bisulfite promotes cytosine deamination, whereas 5-methylcytosine (5-mC) reacts poorly with bisulfite and is resistant to deamination. Since 5-hmC reacts with bisulfite to yield cytosine 5-methylenesulfonate (CMS), we asked how DNA containing 5-hmC behaves in bisulfite sequencing. Methodology/Principal Findings: We used synthetic oligonucleotides with different distributions of cytosine as templates for generation of DNAs containing C, 5-mC and 5-hmC. The resulting DNAs were subjected in parallel to bisulfite treatment, followed by exposure to conditions promoting cytosine deamination. The extent of conversion of 5-hmC to CMS was estimated to be 99.7%. Sequencing of PCR products showed that neither 5-mC nor 5-hmC undergo C-to-T transitions after bisulfite treatment, confirming that these two modified cytosine species are indistinguishable by the bisulfite technique. DNA in which CMS constituted a large fraction of all bases (28/201) was much less efficiently amplified than DNA in which those bases were 5-mC or uracil (the latter produced by cytosine deamination). Using a series of primer extension experiments, we traced the inefficient amplification of CMS-containing DNA to stalling of Taq polymerase at sites of CMS modification, especially when two CMS bases were either adjacent to one another or separated by 1-2 nucleotides. Conclusions: We have confirmed that the widely used bisulfite sequencing technique does not distinguish between 5-mC and 5-hmC. Moreover, we show that CMS, the product of bisulfite conversion of 5-hmC, tends to stall DNA polymerases during PCR, suggesting that densely hydroxymethylated regions of DNA may be underrepresented in quantitative methylation analyses. C1 [Huang, Yun; Pastor, William A.; Tahiliani, Mamta; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Huang, Yun; Pastor, William A.; Tahiliani, Mamta; Rao, Anjana] Immune Dis Inst, Boston, MA USA. [Shen, Yinghua; Liu, David R.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Shen, Yinghua; Liu, David R.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. RP Huang, Y (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM arao@idi.harvard.edu RI Duello, Theresa/P-5752-2015; OI Huang, Yun/0000-0001-5950-9168 FU National Institutes of Health (NIH) [R01 AI044432, RC1 DA028422]; Juvenile Diabetes Research Foundation; Howard Hughes Medical Institute; NIH/National Institute of General Medical Sciences (NIGMS) [R01 GM065865]; National Science Foundation and Department of Defense; GlaxoSmithKline-Immune Disease Institute Alliance FX This work was supported by National Institutes of Health (NIH) grants R01 AI044432 and RC1 DA028422 and a Scholar Award from the Juvenile Diabetes Research Foundation to A. R., Howard Hughes Medical Institute and NIH/National Institute of General Medical Sciences (NIGMS) (R01 GM065865) funding to D. R. L., and National Science Foundation and Department of Defense graduate fellowships to W. A. P. Y.H. is the recipient of a fellowship from the GlaxoSmithKline-Immune Disease Institute Alliance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 346 Z9 353 U1 11 U2 57 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2010 VL 5 IS 1 AR e8888 DI 10.1371/journal.pone.0008888 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 547NO UT WOS:000273896500011 PM 20126651 ER PT J AU Scherer, EM Leaman, DP Zwick, MB McMichael, AJ Burton, DR AF Scherer, Erin M. Leaman, Daniel P. Zwick, Michael B. McMichael, Andrew J. Burton, Dennis R. TI Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 4E10; gp41; HIV; neutralizing antibody; tryptophan ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROXIMAL EXTERNAL REGION; NEUTRALIZING MONOCLONAL-ANTIBODY; GP41 ECTODOMAIN; EPITOPE RECOGNITION; TYPE-1 GLYCOPROTEIN; LIPID-COMPOSITION; HIV-ANTIBODIES; VACCINE DESIGN; IN-VITRO AB The broadly neutralizing anti-HIV antibody 4E10 recognizes an epitope very close to the virus membrane on the glycoprotein gp41. It was previously shown that epitope recognition improves in a membrane context and that 4E10 binds directly, albeit weakly, to lipids. Furthermore, a crystal structure of Fab 4E10 complexed to an epitope peptide revealed that the centrally placed, protruding H3 loop of the antibody heavy chain does not form peptide contacts. To investigate the hypothesis that the H3 loop apex might interact with the viral membrane, two Trp residues in this region were substituted separately or in combination with either Ala or Asp by site-directed mutagenesis. The resultant IgG variants exhibited similar affinities for an epitope peptide as WT 4E10 but lower apparent affinities for both viral membrane mimetic liposomes and Env(-) virus. Variants also exhibited lower apparent affinities for Env(+) virions and failed to significantly neutralize a number of 4E10-sensitive viruses. For the extremely sensitive HXB2 virus, variants did neutralize, but at 37- to >250-fold lower titers than WT 4E10, with Asp substitutions exerting a greater effect on neutralization potency than Ala substitutions. Because reductions in lipid binding reflect trends in neutralization potency, we conclude that Trp residues in the antibody H3 loop enable membrane proximal epitope recognition through favorable lipid interactions. The requirement for lipophilic residues such as Trp adjacent to the antigen binding site may explain difficulties in eliciting 4E10-like neutralizing antibody responses by immunization and helps define a unique motif for antibody recognition of membrane proximal antigens. C1 [Leaman, Daniel P.; Zwick, Michael B.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Scherer, Erin M.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Leaman, Daniel P.; Zwick, Michael B.; Burton, Dennis R.] Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [McMichael, Andrew J.] John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [Burton, Dennis R.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM burton@scripps.edu FU National Institutes of Health [AI33292, AI069993, T32 AI007606]; International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium FX We thank Jillian Sola and Niccole Schultz for assistance with antibody expression and purification. This work was funded in part through National Institutes of Health Grants AI33292 (to D. R. B.) AI069993 (to M. B. Z.), and T32 AI007606 (to M. B. Z.) and the International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium. NR 50 TC 74 Z9 74 U1 3 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 26 PY 2010 VL 107 IS 4 BP 1529 EP 1534 DI 10.1073/pnas.0909680107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600055 PM 20080706 ER PT J AU Hung, KE Maricevich, MA Richard, LG Chen, WY Richardson, MP Kunin, A Bronson, RT Mahmood, U Kucherlapati, R AF Hung, Kenneth E. Maricevich, Marco A. Richard, Larissa Georgeon Chen, Wei Y. Richardson, Michael P. Kunin, Alexandra Bronson, Roderick T. Mahmood, Umar Kucherlapati, Raju TI Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE colon cancer; mouse model; adenovirus; colonoscopy; mammalian target of rapamycin ID ONCOGENIC K-RAS; BETA-CATENIN; CANCER; APC; MICE; PROGRESSION; LUNG; COLONOSCOPY; CELL; TUMORIGENESIS AB Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS. C1 [Hung, Kenneth E.; Chen, Wei Y.; Richardson, Michael P.] Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA. [Maricevich, Marco A.; Kunin, Alexandra; Mahmood, Umar] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Richard, Larissa Georgeon; Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Richard, Larissa Georgeon; Kucherlapati, Raju] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bronson, Roderick T.] Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. RP Hung, KE (reprint author), 750 Washington St,Box 233, Boston, MA 02111 USA. EM khung@tuftsmedicalcenter.org OI Wong, Alexandra/0000-0002-8587-2494 FU American Gastroenterological Association; National Institute of Diabetes and Digestive and Kidney Diseases [5K08DK078033]; National Institute of Biomedical Imaging and Bioengineering [5R01EB001872]; National Cancer Institute [5U01CA084301, 5P50CA127003] FX We thank Eric Martin and Alain Charest for critical review of the manuscript. The work reported here is supported by grants from the American Gastroenterological Association (Research Scholar Award) and from the National Institute of Diabetes and Digestive and Kidney Diseases, Grant 5K08DK078033 (to K. H.); from the National Institute of Biomedical Imaging and Bioengineering, Grant 5R01EB001872 (to U. M.); and from the National Cancer Institute, Grant 5U01CA084301 (to R. K.) and Grant 5P50CA127003 (to U. M. and R. K.). NR 33 TC 89 Z9 91 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 26 PY 2010 VL 107 IS 4 BP 1565 EP 1570 DI 10.1073/pnas.0908682107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600061 PM 20080688 ER PT J AU Shaham, O Slate, NG Goldberger, O Xu, QW Ramanathan, A Souza, AL Clish, CB Sims, KB Mootha, VK AF Shaham, Oded Slate, Nancy G. Goldberger, Olga Xu, Qiuwei Ramanathan, Arvind Souza, Amanda L. Clish, Clary B. Sims, Katherine B. Mootha, Vamsi K. TI A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE biochemical genetics; biomarker; metabolomics; mitochondria ID MAGNETIC-RESONANCE SPECTROSCOPY; DISORDERS; CREATINE; CHILDREN; CLASSIFICATION; BIOSYNTHESIS; PREVALENCE; CRITERIA; MUTANTS AB Mutations in either the mitochondrial or nuclear genomes can give rise to respiratory chain disease (RCD), a large class of devastating metabolic disorders. Their clinical management is challenging, in part because we lack facile and accurate biomarkers to aid in diagnosis and in the monitoring of disease progression. Here we introduce a sequential strategy that combines biochemical analysis of spent media from cell culture with analysis of patient plasma to identify disease biomarkers. First, we applied global metabolic profiling to spotlight 32 metabolites whose uptake or secretion kinetics were altered by chemical inhibition of the respiratory chain in cultured muscle. These metabolites span a wide range of pathways and include lactate and alanine, which are used clinically as biomarkers of RCD. We next measured the cell culture-defined metabolites in human plasma to discover that creatine is reproducibly elevated in two independent cohorts of RCD patients, exceeding lactate and alanine in magnitude of elevation and statistical significance. In cell culture extracellular creatine was inversely related to the intracellular phosphocreatine: creatine ratio suggesting that the elevation of plasma creatine in RCD patients signals a low energetic state of tissues using the phosphocreatine shuttle. Our study identifies plasma creatine as a potential biomarker of human mitochondrial dysfunction that could be clinically useful. More generally, we illustrate how spent media from cellular models of disease may provide a window into the biochemical derangements in human plasma, an approach that could, in principle, be extended to a range of complex diseases. C1 [Shaham, Oded; Slate, Nancy G.; Goldberger, Olga; Sims, Katherine B.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Shaham, Oded; Ramanathan, Arvind; Souza, Amanda L.; Clish, Clary B.; Mootha, Vamsi K.] MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. [Shaham, Oded; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Sims, Katherine B.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Xu, Qiuwei] Merck Res Labs, West Point, PA 19486 USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM vamsi@hms.harvard.edu FU National Human Genome Research Institute; Eli and Dorothy Berman Fund; Howard Hughes Medical Institute; Clinical Research Center at the Massachusetts Institute of Technology [RR-01066]; National Center for Research Resources; National Institutes of Health; Broad Institute Scientific Planning and Allocation of Resources Committee [R01DK081457] FX We thank R. Wei and E. Yang for assistance with MS; H. Vu and W. Schaefer for assistance with NMR spectroscopy; and V. Gohil, M. Jain, T. Kitami, R. Nilsson, S. Vafai, and R. Haller for valuable discussions and comments on the manuscript. O. S. was supported by a training grant for bioinformatics and integrative genomics from the National Human Genome Research Institute and a fellowship from the Eli and Dorothy Berman Fund. V. K. M. was supported by an Early Career Physician-Scientist Award from the Howard Hughes Medical Institute. Clinical studies were conducted in part at the Clinical Research Center at the Massachusetts Institute of Technology funded by Grant RR-01066 from the National Center for Research Resources, National Institutes of Health. This work was supported by a grant from the Broad Institute Scientific Planning and Allocation of Resources Committee and by Grant R01DK081457 from the National Institutes of Health to V. K. M. NR 28 TC 57 Z9 59 U1 0 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 JAN 26 PY 2010 VL 107 IS 4 BP 1571 EP 1575 DI 10.1073/pnas.0906039107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600062 PM 20080599 ER PT J AU Kamruzzaman, M Udden, SMN Cameron, DE Calderwood, SB Nair, GB Mekalanos, JJ Faruque, SM AF Kamruzzaman, M. Udden, S. M. Nashir Cameron, D. Ewen Calderwood, Stephen B. Nair, G. Balakrish Mekalanos, John J. Faruque, Shah M. TI Quorum-regulated biofilms enhance the development of conditionally viable, environmental Vibrio cholerae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE biofilm formation; conditionally viable environmental cells (CVEC); quorum sensing; transmissibility of cholera ID SALMONELLA-TYPHIMURIUM; ESCHERICHIA-COLI; HOST; COLONIZATION; EPIDEMIOLOGY; INFECTIVITY; BANGLADESH; RESISTANCE; MOTILITY; TOXIN AB The factors that enhance the waterborne spread of bacterial epidemics and sustain the pathogens in nature are unclear. The epidemic diarrheal disease cholera caused by Vibrio cholerae spreads through water contaminated with the pathogen. However, the bacteria exist in water mostly as clumps of cells, which resist cultivation by standard techniques but revive into fully virulent form in the intestinal milieu. These conditionally viable environmental cells (CVEC), alternatively called viable but nonculturable cells, presumably play a crucial role in cholera epidemiology. However, the precise mechanism causing the transition of V. cholerae to the CVEC form and this form's significance in the biology of the pathogen are unknown. Here we show that this process involves biofilm formation that is dependent on quorum sensing, a regulatory response that is controlled by cell density. V. cholerae strains carrying mutations in genes required for quorum sensing and biofilm formation displayed altered CVEC formation in environmental water following intestinal infections. Analysis of naturally occurring V. cholerae CVEC showed that organisms that adopt this quiescent physiological state typically exist as clumps of cells that comprise a single clone closely related to isolates causing the most recent local cholera epidemic. These results support a model of cholera transmission in which in vivo-formed biofilms convert to CVEC upon the introduction of cholera stools into environmental water. Our data further suggest that a temporary loss of quorum sensing due to dilution of extracellular autoinducers confers a selective advantage to communities of V. cholerae by blocking quorum-mediated regulatory responses that would break down biofilms and thus interfere with CVEC formation. C1 [Kamruzzaman, M.; Udden, S. M. Nashir; Nair, G. Balakrish; Faruque, Shah M.] Int Ctr Diarrhoeal Dis Res, Mol Genet Lab, Dhaka 1212, Bangladesh. [Cameron, D. Ewen; Mekalanos, John J.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Calderwood, Stephen B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Nair, G. Balakrish] Natl Inst Cholera & Enter Dis, Kolkata 700010, India. RP Nair, GB (reprint author), Int Ctr Diarrhoeal Dis Res, Mol Genet Lab, Dhaka 1212, Bangladesh. EM gbnair_2000@yahoo.com; john_mekalanos@hms.harvard.edu; faruque@icddrb.org FU National Institutes of Health [2R01-GM068851-5, AI070963-01A1, U01-AI058935] FX This research was funded in part by National Institutes of Health grants 2R01-GM068851-5, AI070963-01A1, and U01-AI058935 under different sub-agreements between the Harvard Medical School, Massachusetts General Hospital, and the International Centre for Diarrheal Disease Research in Bangladesh. The International Centre for Diarrheal Disease Research in Bangladesh is supported by countries and agencies that share its concern for the health problems of developing countries. NR 34 TC 31 Z9 34 U1 1 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 JAN 26 PY 2010 VL 107 IS 4 BP 1588 EP 1593 DI 10.1073/pnas.0913404107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600065 PM 20080633 ER PT J AU Cannon, CP Harrington, RA James, S Ardissino, D Becker, RC Emanuelsson, H Husted, S Katus, H Keltai, M Khurmi, NS Kontny, F Lewis, BS Steg, PG Storey, RF Wojdyla, D Wallentin, L AF Cannon, Christopher P. Harrington, Robert A. James, Stefan Ardissino, Diego Becker, Richard C. Emanuelsson, Hakan Husted, Steen Katus, Hugo Keltai, Matyas Khurmi, Nardev S. Kontny, Frederic Lewis, Basil S. Steg, Philippe Gabriel Storey, Robert F. Wojdyla, Daniel Wallentin, Lars CA PLATO Investigators TI Comparison of ticagrelor with clopidogrel in patients with planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study SO LANCET LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; ST-SEGMENT ELEVATION; P2Y(12) RECEPTOR ANTAGONIST; COLLABORATIVE METAANALYSIS; PLATELET-AGGREGATION; CLINICAL-TRIALS; UNSTABLE ANGINA; TASK-FORCE; PCI-CURE; INTERVENTION AB Background Variation in and irreversibility of platelet inhibition with clopiclogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopiclogrel in such patients. Methods At randomisation, an invasive strategy was planned for 13408 (72.0%) of 18624 patients hospitalised for acute coronary syndromes (with or without ST elevation). in a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872. Findings 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopiclogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopiclogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785). Interpretation Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned. C1 [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Harrington, Robert A.; Becker, Richard C.; Wojdyla, Daniel] Duke Clin Res Inst, Durham, NC USA. [James, Stefan; Wallentin, Lars] Uppsala Clin Res Ctr, Uppsala, Sweden. [James, Stefan; Wallentin, Lars] Dept Med Sci, Uppsala, Sweden. [Ardissino, Diego] Azienda Osped Univ Parma, Parma, Italy. [Emanuelsson, Hakan] AstraZeneca, Molndal, Sweden. [Khurmi, Nardev S.] AstraZeneca, Wilmington, DE USA. [Husted, Steen] Arhus Univ Hosp, Aarhus, Denmark. [Katus, Hugo] Univ Klinikum Heidelberg, Heidelberg, Germany. [Keltai, Matyas] Hungarian Inst Cardiol, Budapest, Hungary. [Kontny, Frederic] Volvat Med Ctr, Oslo, Norway. [Lewis, Basil S.] Lady Davis Carmel Med Ctr, Haifa, Israel. [Steg, Philippe Gabriel] APHP, INSERM, U698, Paris, France. [Steg, Philippe Gabriel] Univ Paris, F-75252 Paris, France. [Storey, Robert F.] Univ Sheffield, Sheffield, S Yorkshire, England. RP Cannon, CP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM cpcannon@partners.org RI Katus, Hugo/P-1712-2016 FU Accumetrics; AstraZeneca; Bristol-Myers Squibb; Sanofi-Aventis; GlaxoSmithlKline; Merck; Intekrin Therapeutics; Novartis; Takeda; Pfizer; Eli Lilly; Boehringer-Irigelheiin FX CPC has received research or grant support from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithlKline, Merck, Intekrin Therapeutics, Novartis, and Takeda; and owns equity in ALItomedics Medical Systems. RAH has received consulting fees from Bristol-Myers Squibb, Sanorfi-Aventis, Portola Pharmaceuticals, Schering-Plough, arid AstraZeneca; lecture fees from Schering-Plough, Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly; and grant support from Millennium Phannaceuticals, Schering-Plough, Tlie Medicines Company, Portola Pharmaceuticals, AstraZeneca, and Bristol-Myers Squibb. SJ has received research grants arid advisory board fees from AstraZeneca; and honoraria from AstraZeneca, Bristol-Myers Squibb, Schering-Plough, and Eli Lilly. DA has received research grants from AstraZeneca, Eli Lilly, Pfizer, and Boston Scientific; speaker's bureau payments and honoraria from GIaxoSmithKline, Boehringer-Irigelheiin, Sanofi-Aventis, Pfizer, Eli Lilly, AstraZeneca. Schering-Plough, Daiichi Sankyo, Merck, arid Boston Scientific: and advisory board fees from Sanofi-Aventis, Pfizer, Eli Lillv AstraZeneca, Schering-Plough, Daiichi Sarikyo, and Mechionic. RCB has received consulting fees from Regado Biosciences, AstraZeneca, Eli Lilly, and Bristol-Myers Squibb; and grant support from Momenta Pharmaceuticals, The Medicines Company, and Bristol-Myers Squibb. H E has been an employee ofand owned equity in AstraZeneca. SH has received consulting fees from AstraZeneca, Sanofi-Aventis, and Eli Lilly; and lecture fees from AstraZeneca, Sanofi-Avenfis, and Bristol-Myers Squibb. H K has received consulting arid lecture fees from AstraZeneca, Bayer Healthcare, Abbott, Roche, and Menarim. MK has received consulting and lecture fees from AstraZeneca. NSK has been an employee ofAstraZeneca. FK has received advisory board fees from AstraZeneca and Boehringer-Ingelheim; consulting fees from AstraZeneca, Boeh ringer-I ngelheim, and Sanofi-Aventis; grant support froul Merck Sharp and Dohme, and Perseus Proteomics; and lecture fees from AstraZerieca, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly, Pfizer, and Sanofi-Aventis. BSL has received consulting fees froni Bristol-Myers Squibb and Sanofi-Aventis; and grant support from AstraZeneca. PGS has received research grants from Sanofi-Aventis arid Servier; lecture fees from AstraZeneca, Boehringer-Ingelheirn ' Bristol-Myers Squibb, GlaxoSmith Kline, Menarim, Mechronic, Nyconied, Pierre Fabre, Sanofi-Averitis, Servier, and The Medicines Company; consulting or advisory board fees from Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Endotis, GlaxoSmith Kline, Medtronic, Merck Sharp and Dohme, Nycomed, Sanofi-Aventis, Servier, and The Medicines Company; and has been a stockholder ofAterovax. RFS has received consulting fees from AstraZeneca. Eli Lilly, Daiichi Sankyo, Teva, and Schering-Plough; lecture fees from Eli Lilly, Daiichi Sankyo, arid AstraZeneca; and grant support from AstraZeneca, Eli Lilly, Daiichi Sankyo, arid Schering-Plough. DW declares that he has no conflicts of interest. LW has received consulting fees from Regado Biosciences and Athera Biotechnologies; lecture fees from Boehringer-Ingelheim, AstraZeneca, and Eli Lilly; and grant support from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmitliKline, and Schering-Plough. NR 35 TC 291 Z9 318 U1 2 U2 34 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 JAN 23 PY 2010 VL 375 IS 9711 BP 283 EP 293 DI 10.1016/S0140-6736(09)62191-7 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 549QS UT WOS:000274069300029 PM 20079528 ER PT J AU Kwong, LN Chin, L AF Kwong, Lawrence N. Chin, Lynda TI The Brothers RAF SO CELL LA English DT Editorial Material ID BRAF; CRAF; MUTATIONS; MELANOMA; INHIBITION; RESISTANCE; MECHANISM; PATHWAYS; CANCER; CELLS C1 [Kwong, Lawrence N.; Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chin, Lynda] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Chin, L (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu NR 9 TC 11 Z9 11 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 22 PY 2010 VL 140 IS 2 BP 180 EP 182 DI 10.1016/j.cell.2010.01.013 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 546QX UT WOS:000273826500009 PM 20141832 ER PT J AU Zhong, L D'Urso, A Toiber, D Sebastian, C Henry, RE Vadysirisack, DD Guimaraes, A Marinelli, B Wikstrom, JD Nir, T Clish, CB Vaitheesvaran, B Iliopoulos, O Kurland, I Dor, Y Weissleder, R Shirihai, OS Ellisen, LW Espinosa, JM Mostoslavsky, R AF Zhong, Lei D'Urso, Agustina Toiber, Debra Sebastian, Carlos Henry, Ryan E. Vadysirisack, Douangsone D. Guimaraes, Alexander Marinelli, Brett Wikstrom, Jakob D. Nir, Tomer Clish, Clary B. Vaitheesvaran, Bhavapriya Iliopoulos, Othon Kurland, Irwin Dor, Yuval Weissleder, Ralph Shirihai, Orian S. Ellisen, Leif W. Espinosa, Joaquin M. Mostoslavsky, Raul TI The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1 alpha SO CELL LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; CALORIE RESTRICTION; MITOCHONDRIAL-FUNCTION; GENOMIC INSTABILITY; GENE-EXPRESSION; LIFE-SPAN; HIF-1-ALPHA; CELLS; HIF-1; ACETYLATION AB SIRT6 is a member of a highly conserved family of NAD(+)-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcription factor Hif1 alpha, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1 alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity. C1 [Zhong, Lei; D'Urso, Agustina; Toiber, Debra; Sebastian, Carlos; Vadysirisack, Douangsone D.; Iliopoulos, Othon; Ellisen, Leif W.; Mostoslavsky, Raul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Henry, Ryan E.; Espinosa, Joaquin M.] Univ Colorado, Dept Mol Cellular & Dev Biol, Howard Hughes Med Inst, Boulder, CO 80309 USA. [Guimaraes, Alexander; Marinelli, Brett; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Iliopoulos, Othon] Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, Boston, MA 02114 USA. [Wikstrom, Jakob D.; Shirihai, Orian S.] Boston Univ, Sch Med, Dept Mol Med, Boston, MA 02118 USA. [Nir, Tomer; Dor, Yuval] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel. [Clish, Clary B.] Broad Inst MIT & Harvard, Ctr Prote, Cambridge, MA 02142 USA. [Vaitheesvaran, Bhavapriya; Kurland, Irwin] Albert Einstein Coll Med, Michael F Price Ctr, Bronx, NY 10461 USA. [Wikstrom, Jakob D.] Stockholm Univ, Arrhenius Labs F3, Wenner Gren Inst, SE-10691 Stockholm, Sweden. RP Mostoslavsky, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM rmostoslavsky@mgh.harvard.edu RI Dor, Yuval/C-2405-2011; OI Wikstrom, Jakob/0000-0002-4287-1774 FU V Foundation; Sidney Kimmel Cancer Research Foundation; AFAR; The Massachusetts Life Sciences Center; Joslin Diabetes Center; Metabolic Physiology Core [P30 DK57521]; Brain Power for Israel Fund; NIH [RO1 CA117907]; Howard Hughes Medical Institute FX This work was supported by the V Foundation (R.M.), the Sidney Kimmel Cancer Research Foundation (R.M.), a New Investigator Grant from AFAR (R.M.), A New Investigator Award from The Massachusetts Life Sciences Center (R.M.), a P&F Award from the Joslin Diabetes Center (R.M.), and Grant P30 DK57521 from the Metabolic Physiology Core (BADERC). D. T. is supported by a fellowship from the Brain Power for Israel Fund. Y.D. is supported by JDRF. J.M.E. is supported by NIH-RO1 CA117907 and the Howard Hughes Medical Institute. We thank Magali Silberman, Daniel Holoch, Pere Puigserver, John Dominy, Matthew Vander Heiden, Mike Zimmer, David Lombard, Bjoern Schwer, Fred Alt, Katrin Chua, and members of the Bardeesy, Hochedlinger, Hock, and Ramaswamy labs for reagents and helpful discussions. We thank Kelly Shay, Laura Prickett-Rice, and Kate Folz-Donahue for technical assistance. We are also thankful to Nabeel Bardeesy and Hanno Hock for critically reading the manuscript and Jose Polo for assistance with the ChIP assays. NR 50 TC 367 Z9 386 U1 8 U2 52 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 22 PY 2010 VL 140 IS 2 BP 280 EP 293 DI 10.1016/j.cell.2009.12.041 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 546QX UT WOS:000273826500018 PM 20141841 ER PT J AU Giedraitis, V Glaser, A Sarajarvi, T Brundin, R Gunnarsson, MD Schjeide, BM Tanzi, RE Helisalmi, S Pirttila, T Kilander, L Lannfelt, L Soininen, H Bertram, L Ingelsson, M Hiltunen, M AF Giedraitis, Vilmantas Glaser, Anna Sarajarvi, Timo Brundin, RoseMarie Gunnarsson, Malin Degerman Schjeide, Brit-Maren Tanzi, Rudolph E. Helisalmi, Seppo Pirttila, Tuula Kilander, Lena Lannfelt, Lars Soininen, Hilkka Bertram, Lars Ingelsson, Martin Hiltunen, Mikko TI CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid SO NEUROSCIENCE LETTERS LA English DT Article DE CALHM1; Calcium homeostasis modulator-1; Amyloid-beta; Alzheimer's disease; Cerebrospinal fluid; Biomarker; Total tau; Phospho-tau; Genotyping SNP ID ALZHEIMERS-DISEASE RISK; CLINICAL-DIAGNOSIS; APOLIPOPROTEIN-E; APOE; ASSOCIATION; GENOTYPE; ALLELE AB Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Hiltunen, Mikko] Univ Kuopio, Dept Neurol, FIN-70211 Kuopio, Finland. [Giedraitis, Vilmantas; Glaser, Anna; Brundin, RoseMarie; Gunnarsson, Malin Degerman; Kilander, Lena; Lannfelt, Lars; Ingelsson, Martin] Uppsala Univ, Dept Publ Hlth Geriatr, Rudbeck Lab, Uppsala, Sweden. [Sarajarvi, Timo; Helisalmi, Seppo; Pirttila, Tuula; Soininen, Hilkka; Hiltunen, Mikko] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. [Schjeide, Brit-Maren; Bertram, Lars] Max Planck Inst Mol Genet, Dept Vertebrate Genom, Neuropsychiat Genet Grp, Berlin, Germany. [Schjeide, Brit-Maren; Tanzi, Rudolph E.; Bertram, Lars] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MIND,Genet & Aging Res Unit,Dept Neurol, Charlestown, MA USA. RP Hiltunen, M (reprint author), Univ Kuopio, Dept Neurol, POB 1627, FIN-70211 Kuopio, Finland. EM mhiltune@uku.fi RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X FU Swedish Research Council; Swedish Brain Foundation; Swedish Alzheimer Foundation; Helsinki University Hospital; Kuopio University Hospital [5772708]; Nordic Centre of Excellence of Neurodegeneration; University of Kuopio Graduate School of Molecular Medicine; Cure Alzheimer's Fund FX Financial support for this project was provided by the Swedish Research Council, the Swedish Brain Foundation, the Swedish Alzheimer Foundation, the EVO Research Fund of Helsinki University Hospital, the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, The Nordic Centre of Excellence of Neurodegeneration, the University of Kuopio Graduate School of Molecular Medicine and the Cure Alzheimer's Fund. NR 13 TC 9 Z9 9 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 22 PY 2010 VL 469 IS 2 BP 265 EP 267 DI 10.1016/j.neulet.2009.12.011 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 555KD UT WOS:000274508700019 PM 20005921 ER PT J AU Roccaro, AM Sacco, A Husu, EN Pitsillides, C Vesole, S Azab, AK Azab, F Melhem, M Ngo, HT Quang, P Maiso, P Runnels, J Liang, MC Wong, KK Lin, C Ghobrial, IM AF Roccaro, Aldo M. Sacco, Antonio Husu, Emanuel N. Pitsillides, Costas Vesole, Steven Azab, Abdel Kareem Azab, Feda Melhem, Molly Ngo, Hai T. Quang, Phong Maiso, Patricia Runnels, Judith Liang, Mei-Chih Wong, Kwok-Kin Lin, Charles Ghobrial, Irene M. TI Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; MULTIPLE-MYELOMA; SIGNALING PATHWAYS; BINDING PARTNER; KINASE PATHWAY; CANCER; PTEN; AKT; EXPRESSION; RAPAMYCIN AB We have previously shown clinical activity of a mammalian target of rapamycin (mTOR) complex 1 inhibitor in Waldenstrom macroglobulinemia (WM). However, 50% of patients did not respond to therapy. We therefore examined mechanisms of activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR in WM, and mechanisms of overcoming resistance to therapy. We first demonstrated that primary WM cells show constitutive activation of the PI3K/Akt pathway, supported by decreased expression of phosphate and tensin homolog tumor suppressor gene (PTEN) at the gene and protein levels, together with constitutive activation of Akt and mTOR. We illustrated that dual targeting of the PI3K/mTOR pathway by the novel inhibitor NVP-BEZ235 showed higher cytotoxicity on WM cells compared with inhibition of the PI3K or mTOR pathways alone. In addition, NVP-BEZ235 inhibited both rictor and raptor, thus abrogating the rictor-induced Akt phosphorylation. NVP-BEZ235 also induced significant cytotoxicity in WM cells in a caspase-dependent and -independent manner, through targeting the Forkhead box transcription factors. In addition, NVP-BEZ235 targeted WM cells in the context of bone marrow microenvironment, leading to significant inhibition of migration, adhesion in vitro, and homing in vivo. These studies therefore show that dual targeting of the PI3K/mTOR pathway is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR signaling cascade, such as WM. (Blood. 2010; 115: 559-569) C1 [Roccaro, Aldo M.; Sacco, Antonio; Husu, Emanuel N.; Vesole, Steven; Azab, Abdel Kareem; Azab, Feda; Melhem, Molly; Ngo, Hai T.; Quang, Phong; Maiso, Patricia; Liang, Mei-Chih; Wong, Kwok-Kin; Ghobrial, Irene M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pitsillides, Costas; Runnels, Judith; Lin, Charles] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. RP Ghobrial, IM (reprint author), 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; Maiso, Patricia/0000-0003-3745-1924; Roccaro, Aldo/0000-0002-1872-5128; wong, kwok kin/0000-0001-6323-235X FU International Waldenstrom's Macroglobulinemia Foundation [R21 1R21CA126119-01]; Michelle and Steven Kirsch laboratory for Waldenstrom's; Waldenstrom's FX This work was supported in part by R21 1R21CA126119-01 and the International Waldenstrom's Macroglobulinemia Foundation. This work was also supported by the Michelle and Steven Kirsch laboratory for Waldenstrom's and the Heje fellowship for Waldenstrom's. NR 36 TC 59 Z9 61 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 21 PY 2010 VL 115 IS 3 BP 559 EP 569 DI 10.1182/blood-2009-07-235747 PG 11 WC Hematology SC Hematology GA 546OR UT WOS:000273820600017 PM 19965685 ER PT J AU Vardiman, J Thiele, J Arber, DA Brunning, R Borowitz, MJ Porwit, A Harris, NL Le Beau, MM Hellstrom-Lindberg, E Tefferi, A Bloomfield, CD AF Vardiman, James Thiele, Juergen Arber, Daniel A. Brunning, Richard Borowitz, Michael J. Porwit, Anna Harris, Nancy Lee Le Beau, Michelle M. Hellstrom-Lindberg, Eva Tefferi, Ayalew Bloomfield, Clara D. TI Factors considered in the 2008 WHO classification of myeloid neoplasms and acute leukemias Response SO BLOOD LA English DT Letter ID INDEPENDENT PROGNOSTIC RELEVANCE; AML C1 [Vardiman, James] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Thiele, Juergen] Univ Cologne, Cologne, Germany. [Arber, Daniel A.] Stanford Univ, Stanford, CA 94305 USA. [Brunning, Richard] Univ Minnesota, Minneapolis, MN USA. [Borowitz, Michael J.] Johns Hopkins Univ, Baltimore, MD USA. [Porwit, Anna; Hellstrom-Lindberg, Eva] Karolinska Univ Hosp, Stockholm, Sweden. [Harris, Nancy Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Harris, Nancy Lee] Harvard Univ, Sch Med, Boston, MA USA. [Tefferi, Ayalew] Mayo Clin, Rochester, MN USA. [Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Vardiman, J (reprint author), Univ Chicago, Med Ctr, 5841 S Maryland Ave,Mailcode 0008, Chicago, IL 60637 USA. EM james.vardiman@uchospitals.edu NR 4 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 21 PY 2010 VL 115 IS 3 BP 749 EP 750 DI 10.1182/blood-2009-11-250399 PG 4 WC Hematology SC Hematology GA 546OR UT WOS:000273820600042 ER PT J AU Bienvenu, F Jirawatnotai, S Elias, JE Meyer, CA Mizeracka, K Marson, A Frampton, GM Cole, MF Odom, DT Odajima, J Geng, Y Zagozdzon, A Jecrois, M Young, RA Liu, XS Cepko, CL Gygi, SP Sicinski, P AF Bienvenu, Frederic Jirawatnotai, Siwanon Elias, Joshua E. Meyer, Clifford A. Mizeracka, Karolina Marson, Alexander Frampton, Garrett M. Cole, Megan F. Odom, Duncan T. Odajima, Junko Geng, Yan Zagozdzon, Agnieszka Jecrois, Marie Young, Richard A. Liu, X. Shirley Cepko, Constance L. Gygi, Steven P. Sicinski, Piotr TI Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen SO NATURE LA English DT Article ID KINASE-INDEPENDENT MECHANISM; CELL-CYCLE; ESTROGEN-RECEPTOR; MOUSE RETINA; BREAST; TRANSFORMATION; RECRUITMENT; EXPRESSION; REPRESSES; CANCER AB Cyclin D1 belongs to the core cell cycle machinery, and it is frequently overexpressed in human cancers(1,2). The full repertoire of cyclin D1 functions in normal development and oncogenesis is unclear at present. Here we developed Flag-and haemagglutinin-tagged cyclin D1 knock-in mouse strains that allowed a high-throughput mass spectrometry approach to search for cyclin D1-binding proteins in different mouse organs. In addition to cell cycle partners, we observed several proteins involved in transcription. Genome-wide location analyses (chromatin immunoprecipitation coupled to DNA microarray; ChIP-chip) showed that during mouse development cyclin D1 occupies promoters of abundantly expressed genes. In particular, we found that in developing mouse retinas-an organ that critically requires cyclin D1 function(3,4)-cyclin D1 binds the upstream regulatory region of the Notch1 gene, where it serves to recruit CREB binding protein (CBP) histone acetyltransferase. Genetic ablation of cyclin D1 resulted in decreased CBP recruitment, decreased histone acetylation of the Notch1 promoter region, and led to decreased levels of the Notch1 transcript and protein in cyclin D1-null (Ccnd1(-/-)) retinas. Transduction of an activated allele of Notch1 into Ccnd1(-/-) retinas increased proliferation of retinal progenitor cells, indicating that upregulation of Notch1 signalling alleviates the phenotype of cyclin D1-deficiency. These studies show that in addition to its well-established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development. Our approach, which we term 'genetic-proteomic', can be used to study the in vivo function of essentially any protein. C1 [Bienvenu, Frederic; Jirawatnotai, Siwanon; Odajima, Junko; Geng, Yan; Zagozdzon, Agnieszka; Jecrois, Marie; Sicinski, Piotr] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bienvenu, Frederic; Jirawatnotai, Siwanon; Odajima, Junko; Geng, Yan; Zagozdzon, Agnieszka; Jecrois, Marie; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Elias, Joshua E.; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Meyer, Clifford A.; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Meyer, Clifford A.; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mizeracka, Karolina; Cepko, Constance L.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Jirawatnotai, Siwanon] Mahidol Univ, Inst Mol Biosci, Salaya 73170, Nakhon Prathom, Thailand. [Marson, Alexander; Frampton, Garrett M.; Cole, Megan F.; Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Marson, Alexander; Frampton, Garrett M.; Cole, Megan F.; Young, Richard A.] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Odom, Duncan T.] Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England. RP Sicinski, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM Peter_Sicinski@dfci.harvard.edu RI Young, Richard/F-6495-2012; OI Young, Richard/0000-0001-8855-8647; Odom, Duncan/0000-0001-6201-5599 FU Cancer Research UK; European Research Council; EMBO Young Investigator Award; [R01 CA108420]; [P01 CA080111]; [P01 CA109901]; [HG3456]; [R01 EYO9676]; [HG004069] FX We thank T. Liu, Y. Ndassa-Colday, J. Marto, R. Bronson, B. Smith, E. Jacobsen, M. Brown and members of the Brown laboratory for help at different stages of the project, M. Ewen for p-Babe-puro-Cyclin D1 and cyclin D1(K112E) plasmids, G. Seigel for R28 cells, T. Volkert, J. Love and E. Fox for help with arrays, P. White and O. Smirnova for help with BCBC arrays. This work was supported by grants R01 CA108420, P01 CA080111 and P01 CA109901 (to P. S.), HG3456 (to S. P. G.), R01 EYO9676 (to C. L. C.), HG004069 (to X. S. L.), Cancer Research UK, European Research Council Starting Grant, and an EMBO Young Investigator Award (all to D. T. O.). P. S. is a Leukemia and Lymphoma Society Scholar. NR 30 TC 131 Z9 135 U1 1 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 JAN 21 PY 2010 VL 463 IS 7279 BP 374 EP 378 DI 10.1038/nature08684 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 545PM UT WOS:000273748100048 PM 20090754 ER PT J AU Smits, P Bolton, AD Funari, V Hong, M Boyden, ED Lu, L Manning, DK Dwyer, ND Moran, JL Prysak, M Merriman, B Nelson, SF Bonafe, L Superti-Furga, A Ikegawa, S Krakow, D Cohn, DH Kirchhausen, T Warman, ML Beier, DR AF Smits, Patrick Bolton, Andrew D. Funari, Vincent Hong, Minh Boyden, Eric D. Lu, Lei Manning, Danielle K. Dwyer, Noelle D. Moran, Jennifer L. Prysak, Mary Merriman, Barry Nelson, Stanley F. Bonafe, Luisa Superti-Furga, Andrea Ikegawa, Shiro Krakow, Deborah Cohn, Daniel H. Kirchhausen, Tom Warman, Matthew L. Beier, David R. TI Lethal Skeletal Dysplasia in Mice and Humans Lacking the Golgin GMAP-210 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID THYROID-HORMONE RECEPTOR; RIBBON FORMATION; ER STRESS; PROTEIN; APPARATUS; MOUSE; MECHANISMS; MUTATIONS; PHENOTYPE; CARTILAGE AB BACKGROUND Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease. METHODS We screened mutagenized mice and observed a neonatal lethal skeletal dysplasia with an autosomal recessive pattern of inheritance. Through genetic mapping and positional cloning, we identified the causative mutation. RESULTS Affected mice had a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210); the affected mice lacked this protein. Golgi architecture was disturbed in multiple tissues, including cartilage. Skeletal development was severely impaired, with chondrocytes showing swelling and stress in the endoplasmic reticulum, abnormal cellular differentiation, and increased cell death. Golgi-mediated glycosylation events were altered in fibroblasts and chondrocytes lacking GMAP-210, and these chondrocytes had intracellular accumulation of perlecan, an extracellular matrix protein, but not of type II collagen or aggrecan, two other extracellular matrix proteins. The similarities between the skeletal and cellular phenotypes in these mice and those in patients with achondrogenesis type 1A, a neonatal lethal form of skeletal dysplasia in humans, suggested that achondrogenesis type 1A may be caused by GMAP-210 deficiency. Sequence analysis revealed loss-of-function mutations in the 10 unrelated patients with achondrogenesis type 1A whom we studied. CONCLUSIONS GMAP-210 is required for the efficient glycosylation and cellular transport of multiple proteins. The identification of a mutation affecting GMAP-210 in mice, and then in humans, as the cause of a lethal skeletal dysplasia underscores the value of screening for abnormal phenotypes in model organisms and identifying the causative mutations. C1 [Smits, Patrick; Hong, Minh; Boyden, Eric D.; Warman, Matthew L.] Childrens Hosp, Dept Orthoped Surg, Orthoped Res Labs, Boston, MA 02115 USA. [Warman, Matthew L.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Lu, Lei; Kirchhausen, Tom] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Bolton, Andrew D.; Manning, Danielle K.; Dwyer, Noelle D.; Moran, Jennifer L.; Prysak, Mary; Beier, David R.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Lu, Lei; Kirchhausen, Tom] Brigham & Womens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Lu, Lei; Kirchhausen, Tom] Brigham & Womens Hosp, Dept Cell Biol, Boston, MA 02115 USA. [Warman, Matthew L.] Brigham & Womens Hosp, Dept Genet, Boston, MA 02115 USA. [Funari, Vincent; Krakow, Deborah; Cohn, Daniel H.] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Funari, Vincent; Merriman, Barry; Nelson, Stanley F.; Krakow, Deborah; Cohn, Daniel H.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90048 USA. [Bonafe, Luisa] Univ Lausanne, CHU Vaudois, Div Mol Pediat, Lausanne, Switzerland. [Superti-Furga, Andrea] Univ Freiburg, Dept Pediat, D-7800 Freiburg, Germany. [Ikegawa, Shiro] RIKEN, Ctr Genom Med, Tokyo, Japan. RP Warman, ML (reprint author), Childrens Hosp, Dept Orthoped Surg, Orthoped Res Labs, Enders 907-2,320 Longwood Ave, Boston, MA 02115 USA. EM matthew.warman@childrens.harvard.edu RI Nelson, Stanley/D-4771-2009; superti-furga, andrea/E-9162-2015; Lu, Lei/A-2225-2011; Ikegawa, Shiro/N-6895-2015; OI superti-furga, andrea/0000-0002-3543-7531; Lu, Lei/0000-0002-8192-1471; Ikegawa, Shiro/0000-0003-0316-2147; Moran, Jennifer/0000-0002-5664-4716 FU National Institutes of Health [HD36404, UO1 HD43430, GM075252, A1063430, AR050180]; Swiss National Research Foundation [320000-116506]; Arthritis Foundation FX Supported by grants from the National Institutes of Health (HD36404 and UO1 HD43430, to Dr. Beier; GM075252 and A1063430, to Dr. Kirchhausen; and AR050180, to Dr. Warman) and the Swiss National Research Foundation (320000-116506, to Dr. Bonafe) and by an Arthritis Foundation Investigator Award to Dr. Smits. NR 40 TC 48 Z9 52 U1 1 U2 7 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 JAN 21 PY 2010 VL 362 IS 3 BP 206 EP 216 DI 10.1056/NEJMoa0900158 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400007 PM 20089971 ER PT J AU Pober, BR AF Pober, Barbara R. TI MEDICAL PROGRESS Williams-Beuren Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID SUPRAVALVULAR AORTIC-STENOSIS; AUTOSOMAL-DOMINANT INHERITANCE; VITAMIN-D; IDIOPATHIC HYPERCALCEMIA; MENTAL-RETARDATION; SUDDEN-DEATH; CHILDREN; ADULTS; DELETION; ANOMALIES C1 Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA. RP Pober, BR (reprint author), Massachusetts Gen Hosp, Ctr Human Genet, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM pober.barbara@mgh.harvard.edu FU Williams Syndrome Association for development of the Williams Syndrome Patient and Clinical Research Registry FX Supported in part by a grant from the Williams Syndrome Association for development of the Williams Syndrome Patient and Clinical Research Registry (see the Supplementary Appendix). No other potential conflict of interest relevant to this article was reported. NR 95 TC 219 Z9 224 U1 5 U2 23 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 21 PY 2010 VL 362 IS 3 BP 239 EP 252 DI 10.1056/NEJMra0903074 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400010 PM 20089974 ER PT J AU Isselbacher, EM Kligerman, SJ Lam, KM Hurtado, RM AF Isselbacher, Eric M. Kligerman, Seth J. Lam, Kaitlyn M. Hurtado, Rocio M. TI A Man with Abdominal and Flank Pain Chronic infection with Trypanosoma cruzi (Chagas' disease) and cardiomyopathy, apical left ventricular aneurysm, and thromboembolic disease with renal infarctions SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEART-DISEASE; HYPERTROPHIC CARDIOMYOPATHY; ECHOCARDIOGRAPHY C1 [Isselbacher, Eric M.; Lam, Kaitlyn M.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hurtado, Rocio M.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Kligerman, Seth J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kligerman, Seth J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Isselbacher, Eric M.; Lam, Kaitlyn M.; Hurtado, Rocio M.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Kligerman, Seth J.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. RP Isselbacher, EM (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NR 26 TC 1 Z9 1 U1 1 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 JAN 21 PY 2010 VL 362 IS 3 BP 254 EP 262 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400013 PM 20089976 ER PT J AU Clay, R Camann, W AF Clay, Rayna Camann, William TI Case 33-2009: A Woman with Fever after Cesarean Section SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID PROPHYLAXIS; DELIVERY C1 [Clay, Rayna; Camann, William] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Clay, R (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM wcamann@partners.org NR 6 TC 2 Z9 2 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 JAN 21 PY 2010 VL 362 IS 3 BP 273 EP 273 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400025 PM 20089983 ER PT J AU del Carmen, MG de Moya, MA AF del Carmen, Marcela G. de Moya, Marc A. TI Case 33-2009: A Woman with Fever after Cesarean Section REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [del Carmen, Marcela G.; de Moya, Marc A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 6 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 JAN 21 PY 2010 VL 362 IS 3 BP 273 EP 274 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400026 ER PT J AU Chen, LL Ulmer, S Deisboeck, TS AF Chen, L. Leon Ulmer, Stephan Deisboeck, Thomas S. TI An agent-based model identifies MRI regions of probable tumor invasion in a patient with glioblastoma SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID FUNCTIONAL DIFFUSION MAP; BRAIN-TUMORS; MALIGNANT GLIOMAS; CELL-MIGRATION; BIOMARKER; GROWTH; BEVACIZUMAB; RESECTION; ONCOLOGY AB We present an application of a previously developed agent-based glioma model (Chen et al 2009 Biosystems 95 234-42) for predicting spatio-temporal tumor progression using a patient-specific MRI lattice derived from apparent diffusion coefficient (ADC) data. Agents representing collections of migrating glioma cells are initialized based upon voxels at the outer border of the tumor identified on T1-weighted (Gd+) MRI at an initial time point. These simulated migratory cells exhibit a specific biologically inspired spatial search paradigm, representing a weighting of the differential contribution from haptotactic permission and biomechanical resistance on the migration decision process. ADC data from 9 months after the initial tumor resection were used to select the best search paradigm for the simulation, which was initiated using data from 6 months after the initial operation. Using this search paradigm, 100 simulations were performed to derive a probabilistic map of tumor invasion locations. The simulation was able to successfully predict a recurrence in the dorsal/posterior aspect long before it was depicted on T1-weighted MRI, 18 months after the initial operation. C1 [Chen, L. Leon; Deisboeck, Thomas S.] Massachusetts Gen Hosp, Complex Biosyst Modeling Lab, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Charlestown, MA USA. [Ulmer, Stephan] Univ Hosp Schleswig Holstein, Inst Neuroradiol, Kiel, Germany. RP Deisboeck, TS (reprint author), Massachusetts Gen Hosp, Complex Biosyst Modeling Lab, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Charlestown, MA USA. EM DEISBOEC@helix.mgh.harvard.edu FU NIH [CA 113004]; Harvard-MIT (HST) Athinoula A Martinos Center for Biomedical Imaging and the Department of Radiology at Massachusetts General Hospital FX This work has been supported in part by NIH grant CA 113004 and by the Harvard-MIT (HST) Athinoula A Martinos Center for Biomedical Imaging and the Department of Radiology at Massachusetts General Hospital. NR 30 TC 3 Z9 3 U1 0 U2 4 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 JAN 21 PY 2010 VL 55 IS 2 BP 329 EP 338 DI 10.1088/0031-9155/55/2/001 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 535IG UT WOS:000272960400001 PM 20019405 ER PT J AU Chan, TCY Tsitsiklis, JN Bortfeld, T AF Chan, Timothy C. Y. Tsitsiklis, John N. Bortfeld, Thomas TI Optimal margin and edge-enhanced intensity maps in the presence of motion and uncertainty SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MODULATED RADIATION-THERAPY; X-RAY-BEAM; DOSE DISTRIBUTIONS; IMRT OPTIMIZATION; RADIOTHERAPY; PROBABILITY; ORGAN; REDUCTION; PROFILES AB In radiation therapy, intensity maps involving margins have long been used to counteract the effects of dose blurring arising from motion. More recently, intensity maps with increased intensity near the edge of the tumour (edge enhancements) have been studied to evaluate their ability to offset similar effects that affect tumour coverage. In this paper, we present a mathematical methodology to derive margin and edge-enhanced intensity maps that aim to provide tumour coverage while delivering minimum total dose. We show that if the tumour is at most about twice as large as the standard deviation of the blurring distribution, the optimal intensity map is a pure scaling increase of the static intensity map without any margins or edge enhancements. Otherwise, if the tumour size is roughly twice (or more) the standard deviation of motion, then margins and edge enhancements are preferred, and we present formulae to calculate the exact dimensions of these intensity maps. Furthermore, we extend our analysis to include scenarios where the parameters of the motion distribution are not known with certainty, but rather can take any value in some range. In these cases, we derive a similar threshold to determine the structure of an optimal margin intensity map. C1 [Chan, Timothy C. Y.] Univ Toronto, Toronto, ON M5S 3G8, Canada. [Tsitsiklis, John N.] MIT, Informat & Decis Syst Lab, Cambridge, MA 02139 USA. [Bortfeld, Thomas] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Bortfeld, Thomas] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Chan, TCY (reprint author), Univ Toronto, Toronto, ON M5S 3G8, Canada. EM tcychan@mie.utoronto.ca; jnt@mit.edu; tbortfeld@partners.org FU NCI NIH HHS [R01-CA118200, R01-CA103904] NR 30 TC 8 Z9 8 U1 0 U2 0 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 JAN 21 PY 2010 VL 55 IS 2 BP 515 EP 533 DI 10.1088/0031-9155/55/2/012 PG 19 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 535IG UT WOS:000272960400012 PM 20023327 ER PT J AU Nakamura, K Sasajima, J Mizukami, Y Sugiyama, Y Yamazaki, M Fujii, R Kawamoto, T Koizumi, K Sato, K Fujiya, M Sasaki, K Tanno, S Okumura, T Shimizu, N Kawabe, J Karasaki, H Kono, T Ii, M Bardeesy, N Chung, DC Kohgo, Y AF Nakamura, Kazumasa Sasajima, Junpei Mizukami, Yusuke Sugiyama, Yoshiaki Yamazaki, Madoka Fujii, Rie Kawamoto, Toru Koizumi, Kazuya Sato, Kazuya Fujiya, Mikihiro Sasaki, Katsunori Tanno, Satoshi Okumura, Toshikatsu Shimizu, Norihiko Kawabe, Jun-ichi Karasaki, Hidenori Kono, Toru Ii, Masaaki Bardeesy, Nabeel Chung, Daniel C. Kohgo, Yutaka TI Hedgehog Promotes Neovascularization in Pancreatic Cancers by Regulating Ang-1 and IGF-1 Expression in Bone-Marrow Derived Pro-Angiogenic Cells SO PLOS ONE LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; MESENCHYMAL STEM-CELLS; SONIC HEDGEHOG; BRANCHING MORPHOGENESIS; GENE-THERAPY; FACTOR-I; GROWTH; TUMOR; DIFFERENTIATION; LUNG AB Background: The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells. Methodology/Principal Findings: Cyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. BM transplants, co-culture systems of tumor cells and BM-derived pro-angiogenic cells (BMPCs) were employed to assess the role of tumor-derived Hh in regulating the BM compartment and the contribution of BM-derived cells to angiogenesis in PDAC. Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. Host-derived Ang-1 and IGF-1 mRNA levels were downregulated by cyclopamine in the tumor xenografts. In vitro co-culture and matrigel plug assays demonstrated that PDAC cell-derived Shh induced Ang-1 and IGF-1 production in BMPCs, resulting in their enhanced migration and capillary morphogenesis activity. Conclusions/Significance: We identified the BMPCs as alternative stromal targets of Hh-ligand in PDAC suggesting that the tumor vasculature is an attractive therapeutic target of Hh blockade. Our data is consistent with the emerging concept that BM-derived cells make important contributions to epithelial tumorigenesis. C1 [Nakamura, Kazumasa; Sasajima, Junpei; Mizukami, Yusuke; Sugiyama, Yoshiaki; Yamazaki, Madoka; Fujii, Rie; Kawamoto, Toru; Koizumi, Kazuya; Sato, Kazuya; Fujiya, Mikihiro; Sasaki, Katsunori; Tanno, Satoshi; Kohgo, Yutaka] Asahikawa Med Coll, Div Gastroenterol & Hematol Oncol, Dept Med, Asahikawa, Hokkaido 078, Japan. [Tanno, Satoshi; Okumura, Toshikatsu] Asahikawa Med Coll, Dept Gen Med, Asahikawa, Hokkaido 078, Japan. [Shimizu, Norihiko] Asahikawa Med Coll, Dept Anim Facil, Asahikawa, Hokkaido 078, Japan. [Kawabe, Jun-ichi] Asahikawa Med Coll, Dept Cardiovasc Regenerat & Innovat, Asahikawa, Hokkaido 078, Japan. [Karasaki, Hidenori; Kono, Toru] Asahikawa Med Coll, Div Gastroenterol & Gen Surg, Dept Surg, Asahikawa, Hokkaido 078, Japan. [Ii, Masaaki] Inst Biomed Res & Innovat, Grp Vasc Regenerat Res, Kobe, Hyogo, Japan. [Bardeesy, Nabeel; Chung, Daniel C.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Bardeesy, Nabeel; Chung, Daniel C.] Harvard Univ, Sch Med, Boston, MA USA. [Chung, Daniel C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Nakamura, K (reprint author), Asahikawa Med Coll, Div Gastroenterol & Hematol Oncol, Dept Med, Asahikawa, Hokkaido 078, Japan. EM mizu@asahikawa-med.ac.jp FU New Energy and Industrial Technology Development Organization of Japan [07A05010a] FX This work was supported by a grant to Y. M. from the New Energy and Industrial Technology Development Organization of Japan (07A05010a). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 44 Z9 48 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 21 PY 2010 VL 5 IS 1 AR e8824 DI 10.1371/journal.pone.0008824 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546AJ UT WOS:000273779100016 PM 20098680 ER PT J AU Gaziano, JM AF Gaziano, J. Michael TI Fifth Phase of the Epidemiologic Transition The Age of Obesity and Inactivity SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CARDIOVASCULAR-DISEASE; UNITED-STATES; OVERWEIGHT; SMOKING; MORTALITY; TRENDS; CHINA C1 [Gaziano, J. Michael] VA Boston Healthcare Syst, MAVERIC, Boston, MA 02130 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Cardiol, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02115 USA. RP Gaziano, JM (reprint author), VA Boston Healthcare Syst, Massachusetts Vet Res & Informat Ctr 151MAV, 150 S Huntington Ave, Boston, MA 02130 USA. EM jmgaziano@partners.org NR 14 TC 44 Z9 46 U1 0 U2 7 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 JAN 20 PY 2010 VL 303 IS 3 BP 275 EP 276 DI 10.1001/jama.2009.2025 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 544WM UT WOS:000273690600027 PM 20071469 ER PT J AU Clough-Gorr, KM Stuck, AE Thwin, SS Silliman, RA AF Clough-Gorr, Kerri M. Stuck, Andreas E. Thwin, Soe Soe Silliman, Rebecca A. TI Older Breast Cancer Survivors: Geriatric Assessment Domains Are Associated With Poor Tolerance of Treatment Adverse Effects and Predict Mortality Over 7 Years of Follow-Up SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; FUNCTIONAL ASSESSMENT; ADJUVANT TAMOXIFEN; CONTROLLED-TRIALS; SOCIAL SUPPORT; AGE; CHEMOTHERAPY; ONCOLOGY; WOMEN; CARE AB Purpose To evaluate geriatric assessment (GA) domains in relation to clinically important outcomes in older breast cancer survivors. Methods Six hundred sixty women diagnosed with primary breast cancer in four US geographic regions (Los Angeles, CA; Minnesota; North Carolina; and Rhode Island) were selected with disease stage I to IIIA, age >= 65 years at date of diagnosis, and permission from attending physician to contact. Data were collected over 7 years of follow-up from consenting patients' medical records, telephone interviews, physician questionnaires, and the National Death Index. Outcomes included self-reported treatment tolerance and all-cause mortality. Four GA domains were described by six individual measures, as follows: sociodemographic by adequate finances; clinical by Charlson comorbidity index (CCI) and body mass index; function by number of physical function limitations; and psychosocial by the five-item Mental Health Index (MHI5) and Medical Outcomes Study Social Support Survey (MOS-SSS). Associations were evaluated using t tests, chi(2) tests, and regression analyses. Results In multivariable regression including age and stage, three measures from two domains (clinical and psychosocial) were associated with poor treatment tolerance; these were CCI >= 1 (odds ratio [OR] = 2.49; 95% CI, 1.18 to 5.25), MHI5 score less than 80 (OR = 2.36; 95% CI, 1.15 to 4.86), and MOS-SSS score less than 80 (OR = 3.32; 95% CI, 1.44 to 7.66). Four measures representing all four GA domains predicted mortality; these were inadequate finances (hazard ratio [HR] = 1.89; 95% CI, 1.24 to 2.88; CCI >= 1 (HR = 1.38; 95% CI, 1.01 to 1.88), functional limitation (HR = 1.40; 95% CI, 1.01 to 1.93), and MHI5 score less than 80 (HR = 1.34; 95% CI, 1.01 to 1.85). In addition, the proportion of women with these outcomes incrementally increased as the number of GA deficits increased. Conclusion This study provides longitudinal evidence that GA domains are associated with poor treatment tolerance and predict mortality at 7 years of follow-up, independent of age and stage of disease. C1 [Clough-Gorr, Kerri M.] Boston Univ, Med Ctr, Sch Med, Sect Geriatr, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. US Dept Vet Affairs, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. Univ Bern, ISPM, CH-3012 Bern, Switzerland. Univ Hosp Bern, Inselspital, Dept Geriatr, CH-3010 Bern, Switzerland. RP Clough-Gorr, KM (reprint author), Boston Univ, Med Ctr, Sch Med, Sect Geriatr, 88 E Newton St,Robinson 2, Boston, MA 02118 USA. EM kmclough@bu.edu FU National Cancer Institute, Bethesda, MD [CA106979, CA/AG 70818, CA84506] FX Supported by Grants No. CA106979, CA/AG 70818, and CA84506 from the National Cancer Institute, Bethesda, MD. NR 67 TC 46 Z9 47 U1 1 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 JAN 20 PY 2010 VL 28 IS 3 BP 380 EP 386 DI 10.1200/JCO.2009.23.5440 PG 7 WC Oncology SC Oncology GA 544MY UT WOS:000273662700005 PM 20008637 ER PT J AU Balboni, TA Paulk, ME Balboni, MJ Phelps, AC Loggers, ET Wright, AA Block, SD Lewis, EF Peteet, JR Prigerson, HG AF Balboni, Tracy Anne Paulk, Mary Elizabeth Balboni, Michael J. Phelps, Andrea C. Loggers, Elizabeth Trice Wright, Alexi A. Block, Susan D. Lewis, Eldrin F. Peteet, John R. Prigerson, Holly Gwen TI Provision of Spiritual Care to Patients With Advanced Cancer: Associations With Medical Care and Quality of Life Near Death SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TREATMENT PREFERENCES; TERMINALLY-ILL; ETHNIC-DIFFERENCES; PALLIATIVE CARE; BREAST-CANCER; END; NEEDS; HOPE; ACKNOWLEDGMENT; ACCEPTABILITY AB Purpose To determine whether spiritual care from the medical team impacts medical care received and quality of life (QoL) at the end of life (EoL) and to examine these relationships according to patient religious coping. Patients and Methods Prospective, multisite study of patients with advanced cancer from September 2002 through August 2008. We interviewed 343 patients at baseline and observed them (median, 116 days) until death. Spiritual care was defined by patient-rated support of spiritual needs by the medical team and receipt of pastoral care services. The Brief Religious Coping Scale (RCOPE) assessed positive religious coping. EoL outcomes included patient QoL and receipt of hospice and any aggressive care (eg, resuscitation). Analyses were adjusted for potential confounders and repeated according to median-split religious coping. Results Patients whose spiritual needs were largely or completely supported by the medical team received more hospice care in comparison with those not supported (adjusted odds ratio [AOR] = 3.53; 95% CI, 1.53 to 8.12, P = .003). High religious coping patients whose spiritual needs were largely or completely supported were more likely to receive hospice (AOR = 4.93; 95% CI, 1.64 to 14.80; P = .004) and less likely to receive aggressive care (AOR = 0.18; 95% CI, 0.04 to 0.79; P = .02) in comparison with those not supported. Spiritual support from the medical team and pastoral care visits were associated with higher QOL scores near death (20.0 [95% CI, 18.9 to 21.1] v 17.3 [95% CI, 15.9 to 18.8], P = .007; and 20.4 [95% CI, 19.2 to 21.1] v 17.7 [95% CI, 16.5 to 18.9], P = .003, respectively). Conclusion Support of terminally ill patients' spiritual needs by the medical team is associated with greater hospice utilization and, among high religious copers, less aggressive care at EoL. Spiritual care is associated with better patient QoL near death. C1 [Balboni, Tracy Anne] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 01225 USA. Dana Farber Canc Inst, Dept Psychooncol & Palliat Care, Boston, MA 01225 USA. Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 01225 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 01225 USA. Boston Univ, Dept Pract Theol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Internal Med, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Ctr Palliat Care, Dept Med,Med Sch,Cardiovasc Div, Boston, MA 02115 USA. Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. RP Balboni, TA (reprint author), Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Smith 275,44 Binney St, Boston, MA 01225 USA. EM tbalboni@lroc.harvard.edu FU National Institute of Mental Health [MH63892]; National Cancer Institute [CA 106370]; Fetzer Foundation; American Society of Clinical Oncology FX Supported in part by the following grants to H. G. P.: Grant No. MH63892 from the National Institute of Mental Health, Grant No. CA 106370 from the National Cancer Institute, and a Fetzer Foundation grant. This research was also supported in part by an American Society of Clinical Oncology Young Investigator Award to T. A. B. NR 37 TC 121 Z9 123 U1 4 U2 15 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2010 VL 28 IS 3 BP 445 EP 452 DI 10.1200/JCO.2009.24.8005 PG 8 WC Oncology SC Oncology GA 544MY UT WOS:000273662700015 PM 20008625 ER PT J AU Santillan, AA Messina, JL Marzban, SS Crespo, G Sondak, VK Zager, JS AF Santillan, Alfredo A. Messina, Jane L. Marzban, Suroosh S. Crespo, Gema Sondak, Vernon K. Zager, Jonathan S. TI Pathology Review of Thin Melanoma and Melanoma in Situ in a Multidisciplinary Melanoma Clinic: Impact on Treatment Decisions SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID AMERICAN-JOINT-COMMITTEE; PRIMARY CUTANEOUS MELANOMA; MANDATORY 2ND OPINION; LYMPH-NODE POSITIVITY; MALIGNANT-MELANOMA; STAGING SYSTEM; MITOTIC RATE; INTEROBSERVER VARIABILITY; BRESLOW DEPTH; CLARK LEVEL AB Purpose Patients with thin melanoma (<= 1.0 mm) and melanoma in situ (MIS) represent the majority of newly diagnosed melanoma. We estimated the impact of expert review of outside pathology material on the staging and thus treatment decisions affecting patients referred to a multidisciplinary clinic with early-stage melanoma. Patients and Methods We studied patients with a diagnosis of thin melanoma or MIS referred to H. Lee Moffitt Cancer Center from 2006 to 2009. After comparing the referring laboratory and in-house dermatopathologic interpretations, we calculated any differences in diagnosis and tumor staging and the potential impact of differences in diagnosis and staging on prognosis and surgical treatment using the National Comprehensive Cancer Network clinical guidelines. Results The overall pathologic discordance rate in diagnosis was 4% (15 of 420 patients; 95% CI, 2% to 6%). The overall change in tumor staging rate was 24% (97 of 405 patients; 95% CI, 20% to 28%). Pathology review led to changes in surgical excision margins in 12% of patients (52 of 420 patients; 95% CI, 9% to 16%) and in the decision about whether to perform a sentinel lymph node biopsy in 16% of patients (67 of 420 patients; 95% CI, 13% to 20%). Key pathologic factors, particularly mitotic rate, were frequently missing from outside pathology reports. Conclusion Our data suggest that review of thin melanoma or MIS by an expert dermatopathologist results in frequent, clinically meaningful alterations in diagnosis, staging, prognosis, and surgical treatment. Referral of these patients to a multidisciplinary melanoma clinic is appropriate, and management of such patients should include review of the biopsy whenever feasible. C1 Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, Sect Surg Oncol, San Antonio, TX USA. Audie L Murphy Vet Affairs Hosp, Sect Surg Oncol, San Antonio, TX USA. Univ S Florida, Coll Med, Dept Oncol Sci, Tampa, FL USA. Univ S Florida, Coll Med, Dept Dermatol, Tampa, FL USA. Univ S Florida, Coll Med, Dept Surg, Tampa, FL 33612 USA. RP Zager, JS (reprint author), 12902 Magnolia Dr,SRB4-24012, Tampa, FL 33602 USA. EM jonathan.zager@moffitt.org NR 29 TC 26 Z9 26 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 JAN 20 PY 2010 VL 28 IS 3 BP 481 EP 486 DI 10.1200/JCO.2009.24.7734 PG 6 WC Oncology SC Oncology GA 544MY UT WOS:000273662700020 PM 20008627 ER PT J AU Wong, SL Mangu, PB Choti, MA Crocenzi, TS Dodd, GD Dorfman, GS Eng, C Fong, YM Giusti, AF Lu, D Marsland, TA Michelson, R Poston, GJ Schrag, D Seidenfeld, J Benson, A AF Wong, Sandra L. Mangu, Pamela B. Choti, Michael A. Crocenzi, Todd S. Dodd, Gerald D., III Dorfman, Gary S. Eng, Cathy Fong, Yuman Giusti, Andrew F. Lu, David Marsland, Thomas A. Michelson, Rob Poston, Graeme J. Schrag, Deborah Seidenfeld, Jerome Benson, Al B., III TI American Society of Clinical Oncology 2009 Clinical Evidence Review on Radiofrequency Ablation of Hepatic Metastases From Colorectal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID LONG-TERM SURVIVAL; POSITRON-EMISSION-TOMOGRAPHY; UNRESECTABLE LIVER-TUMORS; THERMAL ABLATION; RISK-FACTORS; SURGICAL-TREATMENT; HEPATOBILIARY MALIGNANCY; PERCUTANEOUS ABLATION; CARCINOMA METASTASES; DIAPHRAGMATIC INJURY AB Purpose To review the evidence about the efficacy and utility of radiofrequency ablation (RFA) for hepatic metastases from colorectal cancer (CRHM). Methods The American Society of Clinical Oncology (ASCO) convened a panel to conduct and analyze a comprehensive systematic review of the RFA literature from Medline and the Cochrane Collaboration Library. Results Because data were considered insufficient to form the basis of a practice guideline, ASCO has instead published a clinical evidence review. The evidence is from single-arm, retrospective, and prospective trials. No randomized controlled trials have been included. The following three clinical issues were considered by the panel: the efficacy of surgical hepatic resection versus RFA for resectable tumors; the utility of RFA for unresectable tumors; and RFA approaches (open, laparoscopic, or percutaneous). Evidence suggests that hepatic resection improves overall survival (OS), particularly for patients with resectable tumors without extrahepatic disease. Careful patient and tumor selection is discussed at length in the literature. RFA investigators report a wide variability in the 5-year survival rate (14% to 55%) and local tumor recurrence rate (3.6% to 60%). The reported mortality rate was low (0% to 2%), and the major complications rate was commonly reported to be between 6% and 9%. RFA is currently performed with all three approaches. Conclusion There is a compelling need for more research to determine the efficacy and utility of RFA to increase local recurrence-free, progression-free, and disease-free survival as well as OS for patients with CRHM. Clinical trials have established that hepatic resection can improve OS for patients with resectable CRHM. C1 [Wong, Sandra L.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Colorectal Canc Coalit, Alexandria, VA USA. Johns Hopkins Univ, Baltimore, MD USA. Oregon Clin, Portland, OR USA. Univ Colorado, Sch Med, Denver, CO USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Mem Sloan Kettering Canc Ctr, Weill Cornell Med Coll, New York, NY 10021 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Orange Pk Canc Ctr, Orange Pk, FL USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Northwestern Univ, Chicago, IL 60611 USA. Aintree Univ Hosp NHS Fdn Trust, Liverpool L9 7AL, Merseyside, England. RP Wong, SL (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 147 TC 173 Z9 194 U1 5 U2 15 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2010 VL 28 IS 3 BP 493 EP 508 DI 10.1200/JCO.2009.23.4450 PG 16 WC Oncology SC Oncology GA 544MY UT WOS:000273662700022 PM 19841322 ER PT J AU Allen, PM Liu, WH Chauhan, VP Lee, J Ting, AY Fukumura, D Jain, RK Bawendi, MG AF Allen, Peter M. Liu, Wenhao Chauhan, Vikash P. Lee, Jungmin Ting, Alice Y. Fukumura, Dai Jain, Rakesh K. Bawendi, Moungi G. TI InAs(ZnCdS) Quantum Dots Optimized for Biological Imaging in the Near-Infrared SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CORE-SHELL NANOCRYSTALS; IN-VIVO; BIOTIN LIGASE; LIVING CELLS; SIZE SERIES; MONOVALENT; PROTEINS AB We present the synthesis of InAs quantum dots (QDs) with a ZnCdS shell with bright and stable emission in the near-infrared (NIR, 700-900 nm) region for biological imaging applications, We demonstrate how NIR QDs can image tumor vasculature in vivo at significantly deeper penetration depths and with higher contrast than visible emitting CdSe(CdS) QDs. Targeted cellular labeling is also presented and may enable multiplexed and low auto fluorescence cellular imaging. C1 [Allen, Peter M.; Liu, Wenhao; Lee, Jungmin; Ting, Alice Y.; Bawendi, Moungi G.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chauhan, Vikash P.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Chauhan, Vikash P.; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bawendi, MG (reprint author), MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mgb@mit.edu RI Chauhan, Vikash/H-8172-2013 OI Chauhan, Vikash/0000-0001-9126-2302 FU US NCI [R01-CA85140, R01-CA115767, R01-CA126642, P01-CA80124]; MIT-Harvard NIH CCNE [1U54-CA119349]; US ARO through the ISN [W911NF-07-D-0004]; NSF-MRSEC [DMR-0117795] FX This work was supported by the US NCI grants R01-CA85140, R01-CA115767 (R.K.J.), R01-CA126642 (R.K.J. and M.G.B.) and P01-CA80124 (R.K.J. and D.F.), by the MIT-Harvard NIH CCNE (1U54-CA119349) (M.G.B.), by the US ARO through the ISN (W911NF-07-D-0004) (M.G.B.), and the NSF-MRSEC program (DMR-0117795). We thank D. Liu and P. Zou for providing cells and plasmids. NR 15 TC 106 Z9 107 U1 8 U2 77 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 JAN 20 PY 2010 VL 132 IS 2 BP 470 EP + DI 10.1021/ja908250r PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 562VY UT WOS:000275084600021 PM 20025222 ER PT J AU Liu, WH Greytak, AB Lee, J Wong, CR Park, J Marshall, LF Jiang, W Curtin, PN Ting, AY Nocera, DG Fukumura, D Jain, RK Bawendi, MG AF Liu, Wenhao Greytak, Andrew B. Lee, Jungmin Wong, Cliff R. Park, Jongnam Marshall, Lisa F. Jiang, Wen Curtin, Peter N. Ting, Alice Y. Nocera, Daniel G. Fukumura, Dai Jain, Rakesh K. Bawendi, Moungi G. TI Compact Biocompatible Quantum Dots via RAFT-Mediated Synthesis of Imidazole-Based Random Copolymer Ligand SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SEMICONDUCTOR NANOCRYSTALS; MONOVALENT STREPTAVIDIN; SURFACE MODIFICATION; BIOTIN LIGASE; LIVING CELLS; SIZE SERIES; LIVE CELLS; CDSE; LUMINESCENT; RECEPTORS AB We present a new class of polymeric ligands for quantum dot (OD) water solubilization to yield biocompatible and derivatizable QDs with compact size (similar to 10-12 nm diameter), high quantum yields (>50%), excellent stability across a large pH range (pH 5-10.5), and low nonspecific binding. To address the fundamental problem of thiol instability in traditional ligand exchange systems, the polymers here employ a stable multidentate imidazole binding motif to the OD surface. The polymers are synthesized via reversible addition-fragmentation chain transfer-mediated polymerization to produce molecular weight controlled monodisperse random copolymers from three types of monomers that feature imidazole groups for CID binding, polyethylene glycol (PEG) groups for water solubilization, and either primary amines or biotin groups for derivatization. The polymer architecture can be tuned by the monomer ratios to yield aqueous QDs with targeted surface functionalities. By incorporating amino-PEG monomers, we demonstrate covalent conjugation of a dye to form a highly efficient QD-dye energy transfer pair as well as covalent conjugation to streptavidin for high-affinity single molecule imaging of biotinylated receptors on live cells with minimal nonspecific binding. The small size and low serum binding of these polymer-coated QDs also allow us to demonstrate their utility for in vivo imaging of the tumor microenvironment in live mice. C1 [Liu, Wenhao; Greytak, Andrew B.; Lee, Jungmin; Wong, Cliff R.; Park, Jongnam; Marshall, Lisa F.; Curtin, Peter N.; Ting, Alice Y.; Nocera, Daniel G.; Bawendi, Moungi G.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Jiang, Wen; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Jiang, Wen; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bawendi, MG (reprint author), MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mgb@mit.edu RI Park, Jongnam/F-5085-2010; OI Park, Jongnam/0000-0002-0954-0172; Greytak, Andrew/0000-0001-8978-6457; Jiang, Wen/0000-0001-9154-633X FU U.S. National Cancer Institute [R01-CA126642, R01-CA085140, R01-CA115767, P01-CA080124, R01-CA096915]; MIT-Harvard NIH Center for Cancer Nanotechnology Excellence [1U54-CA119349]; MIT DCIF [CHE-980806, DBI-9729592]; ISN [W911NF-07-D-0004]; NSF-MRSEC [DMR-0117795]; Army Research Office [W911NF-06-1-0101]; National Science Foundation; Life Sciences Research Foundation FX This research was supported by the U.S. National Cancer Institute Grants Nos. R01-CA126642 (R.K.J., M.G.B., and D.G.N.), R01-CA085140, R01-CA115767 (R.K.J.), P01-CA080124 (R.K.J. and D.F.), R01-CA096915 (D.F.); by the MIT-Harvard NIH Center for Cancer Nanotechnology Excellence (1U54-CA119349) (M.G.B.); by the MIT DCIF (CHE-980806, DBI-9729592); by the ISN (W911NF-07-D-0004) (M.G.B. and D.G.N.); by the NSF-MRSEC program (DMR-0117795) via the use of its shared user facilities; and by the Army Research Office (W911NF-06-1-0101) (D.G.N). W.L. was supported by a National Science Foundation Graduate Research Fellowship. A.B.G. was a Novartis fellow of the Life Sciences Research Foundation. We would like to thank Dan Liu and Peng Zou for valuable assistance with cells, plasmids, and cell culture protocols. NR 52 TC 143 Z9 145 U1 8 U2 98 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 JAN 20 PY 2010 VL 132 IS 2 BP 472 EP 483 DI 10.1021/ja908137d PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 562VY UT WOS:000275084600022 PM 20025223 ER PT J AU Wolpin, BM Kraft, P Fuchs, CS AF Wolpin, Brian M. Kraft, Peter Fuchs, Charles S. TI Re: ABO Blood Group and the Risk of Pancreatic Cancer Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID EXPRESSION; CARCINOMA C1 [Wolpin, Brian M.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Channing Lab,Med Sch, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 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 NR 4 TC 0 Z9 0 U1 0 U2 4 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 JAN 20 PY 2010 VL 102 IS 2 BP 137 EP 137 DI 10.1093/jnci/djp449 PG 1 WC Oncology SC Oncology GA 549YO UT WOS:000274091200016 ER PT J AU Ma, CHE Bampton, ETW Evans, MJ Taylor, JSH AF Ma, C. H. E. Bampton, E. T. W. Evans, M. J. Taylor, J. S. H. TI SYNERGISTIC EFFECTS OF OSTEONECTIN AND BRAIN-DERIVED NEUROTROPHIC FACTOR ON AXOTOMIZED RETINAL GANGLION CELLS NEURITE OUTGROWTH VIA THE MITOGEN-ACTIVATED PROTEIN KINASE-EXTRACELLULAR SIGNAL-REGULATED KINASE1/2 PATHWAYS SO NEUROSCIENCE LA English DT Article DE MAPK-ERK1/2; neurite outgrowth; osteonectin; PI-3K-Akt; retinal ganglion cell; Schwann cell ID NERVE GROWTH-FACTOR; ENDOTHELIAL-CELLS; TYROSINE PHOSPHORYLATION; NEURONAL SURVIVAL; GENE-EXPRESSION; SCHWANN-CELLS; AXON GROWTH; MATRICELLULAR PROTEIN; MATRIX GLYCOPROTEIN; CELLULAR-SURVIVAL AB Our previous study identified osteonectin (ON) in a screen of factors made by Schwann cells (SCs) which promoted peripheral and central neurons survival and neuritogenesis, however, the mechanisms of ON promoting effects are largely unknown. In the present study, we investigated the effects of ON-deficient SC-conditioned medium (SCCM) and molecular mechanisms of ON, in regulating retinal ganglion cells (RGCs) survival and neurite outgrowth. Neonatal rat RGCs and SCs were purified by immunopanning technique. RGC survival and neuritogenesis reduced significantly when treated with either ON-null mice SCCM or ON-immunodepleted (IP) SCCM (P<0.05). In contrast to wild type SCCM, in the presence of a tyrosine kinase receptor (Trk) inhibitor (K252a), ON-null mice SCCM-induced neuritogenesis were further reduced by 24%. The Trk-mediated signaling pathways became more sensitive to K252a inhibition in the absence of ON. We also showed the synergistic effects of ON and brain-derived neurotrophic factor (BDNF) in promoting RGCs growth and the involvement of ON in two major neurotrophin-mediated signaling pathways, PI-3K-Akt and MAPK-Erk1/2. ON alone activated Akt phosphorylation and increased survival. Blockage of TrkB signalling pathway by TrkB-Fc chimera (BDNF scavenger) or K252a in ON-treated cultures reduced Akt-P level significantly. This suggests that ON induces BDNF synthesis and secretion from RGCs. The enhancement of neuritogenesis and Erk1/2 phosphorylation by ON in BDNF-treated cultures further demonstrate the signaling pathways responsible for the synergistic effect of ON on BDNF-induced neurite outgrowth. To the best of our knowledge, this is the first report showing the synergistic effects of ON on classical neurotrophins which participate in the same signalling pathways in regulating RGC neurite outgrowth. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Ma, C. H. E.; Bampton, E. T. W.; Taylor, J. S. H.] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Evans, M. J.] Cardiff Univ, Sch Biosci, Cardiff CF10 3US, S Glam, Wales. RP Ma, CHE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 149 Bldg,13th St,Room 4309, Charlestown, MA 02129 USA. EM chi.ma@mgh.harvard.edu OI MA, Chi Him Eddie/0000-0003-2054-0445 FU Hong Kong Croucher Foundation (CHEM) FX We thank the Hong Kong Croucher Foundation (CHEM) for financial support. Dr. Chi Me is a recipient of the Hong Kong Croucher Foundation Scholarship. NR 91 TC 12 Z9 14 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JAN 20 PY 2010 VL 165 IS 2 BP 463 EP 474 DI 10.1016/j.neuroscience.2009.10.026 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 545IC UT WOS:000273724700017 PM 19837135 ER PT J AU Forsberg, EC Passegue, E Prohaska, SS Wagers, AJ Koeva, M Stuart, JM Weissman, IL AF Forsberg, E. Camilla Passegue, Emmanuelle Prohaska, Susan S. Wagers, Amy J. Koeva, Martina Stuart, Joshua M. Weissman, Irving L. TI Molecular Signatures of Quiescent, Mobilized and Leukemia-Initiating Hematopoietic Stem Cells SO PLOS ONE LA English DT Article ID COLONY-STIMULATING FACTOR; ACUTE MYELOID-LEUKEMIA; MURINE BONE-MARROW; SELF-RENEWAL; GENE-EXPRESSION; MYELOPROLIFERATIVE DISORDER; TRANSCRIPTION FACTOR; PROGENITOR CELLS; NF-Y; DIFFERENTIATION AB Hematopoietic stem cells (HSC) are rare, multipotent cells capable of generating all specialized cells of the blood system. Appropriate regulation of HSC quiescence is thought to be crucial to maintain their lifelong function; however, the molecular pathways controlling stem cell quiescence remain poorly characterized. Likewise, the molecular events driving leukemogenesis remain elusive. In this study, we compare the gene expression profiles of steady-state bone marrow HSC to non-self-renewing multipotent progenitors; to HSC treated with mobilizing drugs that expand the HSC pool and induce egress from the marrow; and to leukemic HSC in a mouse model of chronic myelogenous leukemia. By intersecting the resulting lists of differentially regulated genes we identify a subset of molecules that are downregulated in all three circumstances, and thus may be particularly important for the maintenance and function of normal, quiescent HSC. These results identify potential key regulators of HSC and give insights into the clinically important processes of HSC mobilization for transplantation and leukemic development from cancer stem cells. C1 [Forsberg, E. Camilla; Koeva, Martina; Stuart, Joshua M.] Univ Calif Santa Cruz, Dept Biomol Engn, Inst Biol Stem Cells, Santa Cruz, CA 95064 USA. [Passegue, Emmanuelle] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. [Prohaska, Susan S.; Weissman, Irving L.] Stanford Univ, Sch Med, Dept Pathol, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Prohaska, Susan S.; Weissman, Irving L.] Stanford Univ, Sch Med, Dept Dev Biol, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Wagers, Amy J.] Harvard Univ, Harvard Stem Cell Inst, Joslin Diabet Ctr, Cambridge, MA 02138 USA. [Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Forsberg, EC (reprint author), Univ Calif Santa Cruz, Dept Biomol Engn, Inst Biol Stem Cells, Santa Cruz, CA 95064 USA. EM cforsber@ucsc.edu FU California Institute for Regenerative Medicine; American Society of Hematology (ASH); Burroughs Wellcome Fund; National Institutes of Health (NIH) [1RO1HL092471-01, 1RO1HL088582-01, R01CA086017, R01HL058770, R01CA086065, P01DK053074]; California Institute for Regenerative Medicine (CIRM); Department of Biomolecular Engineering, University of California Santa Cruz; National Science Foundation's Division of Biological Infrastructure [DBI-0543197]; Alfred P. Sloan Foundation FX This work was supported by a New Faculty Award from the California Institute for Regenerative Medicine (ECF); by an American Society of Hematology (ASH) Scholar Award (EP), by grants from the Burroughs Wellcome Fund (AJW) and the National Institutes of Health (NIH) (1RO1HL092471-01 (EP) and 1RO1HL088582-01 (AJW)); a predoctoral fellowship from the California Institute for Regenerative Medicine (CIRM) stem cell training program at the Institute for Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz (MK); the National Science Foundation's Division of Biological Infrastructure DBI-0543197 (JMS) and by a fellowship from the Alfred P. Sloan Foundation (JMS); and by NIH grants R01CA086017, R01HL058770, R01CA086065, and P01DK053074 (ILW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 60 Z9 61 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2010 VL 5 IS 1 AR e8785 DI 10.1371/journal.pone.0008785 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546AI UT WOS:000273779000014 PM 20098702 ER PT J AU Nandi, A Lavine, CL Wang, PC Lipchina, I Goepfert, PA Shaw, GM Tomaras, GD Montefiori, DC Haynes, BF Easterbrook, P Robinson, JE Sodroski, JG Yang, XZ AF Nandi, Avishek Lavine, Christine L. Wang, Pengcheng Lipchina, Inna Goepfert, Paul A. Shaw, George M. Tomaras, Georgia D. Montefiori, David C. Haynes, Barton F. Easterbrook, Philippa Robinson, James E. Sodroski, Joseph G. Yang, Xinzhen CA NIAID Ctr HIV AIDS Vaccine Immunol TI Epitopes for broad and potent neutralizing antibody responses during chronic infection with human immunodeficiency virus type 1 SO VIROLOGY LA English DT Article DE HIV-1; Envelope glycoprotein; Neutralizing epitope; In vivo; Glycan; V3; CD4BS ID HUMAN MONOCLONAL-ANTIBODY; GP120 ENVELOPE GLYCOPROTEIN; CD4 BINDING-SITE; HIV-1 GP120; SENSITIVE EPITOPES; VARIABLE REGIONS; CD4-BINDING SITE; MACAQUE MONKEYS; ENV CLONES; V3 LOOP AB Neutralizing antibody (nAb) response is sporadic and has limited potency and breadth during infection with human immunodeficiency virus type 1 (HIV-1). In rare cases, broad and potent nAbs are actually induced in vivo. Identifying specific epitopes targeted by such broad and potent nAb response is valuable in guiding the design of a prophylactic vaccine aimed to induce nAb. In this study, we have defined neutralizing epitope usage in 7 out of 17 subjects with broad and potent nAbs by using targeted mutagenesis in known neutralizing epitopes of HIV-1 glycoproteins and by using in vitro depletion of serum neutralizing activity by various recombinant HIV-1 glycoproteins. Consistent with recent reports, the CD4 binding site (CD4BS) is targeted by nAbs in vivo (4 of the 7 subjects with defined neutralizing epitopes). The new finding from this study is that epitopes in the gp120 outer domain are also targeted by nAbs in vivo (5 of the 7 Subjects), The outer domain epitopes include glycan-dependent epitopes (2 Subjects), conserved nonlinear epitope in the V3 region (2 Subjects), and a CD4BS epitope composed mainly of the elements in the outer domain ( I subject). Importantly, we found indication for epitope poly-specificity, a dual usage of the V3 and CD4BS epitopes, in only one subject. This study provides a more complete profile of epitope usage for broad and potent nAb responses during HIV-1 infection. (C) 2009 Elsevier Inc. All rights reserved. C1 [Nandi, Avishek; Lavine, Christine L.; Wang, Pengcheng; Lipchina, Inna; Yang, Xinzhen] Beth Israel Deaconess Med Ctr, Dept Med, Div Viral Pathogenesis, Boston, MA 02215 USA. [Goepfert, Paul A.; Shaw, George M.] Univ Alabama, Sch Med, Dept Med, Birmingham, AL USA. [Tomaras, Georgia D.; Montefiori, David C.; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Raleigh, NC USA. [Easterbrook, Philippa] Kings Coll London, Dept HIV GUM, London WC2R 2LS, England. [Robinson, James E.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Sodroski, Joseph G.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Dept Pathol, Div Aids, Boston, MA 02215 USA. [Sodroski, Joseph G.] Harvard Univ, Sch Med, Dept Immunol & Infect Dis, Sch Publ Hlth, Boston, MA 02215 USA. RP Yang, XZ (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Viral Pathogenesis, E CLS-1011,3 Blackfan Circle, Boston, MA 02215 USA. EM xyang1@bidmc.harvard.edu RI Tomaras, Georgia/J-5041-2016 FU MAID Center for HIV/AIDS Vaccine Immunology [A1067854]; NIH [RO1 AI073133] FX We think Dr. Connie Gee for help in preparing the manuscript. We acknowledge the critical contributions of identifying and collecting samples from study subjects by the CHAVI 001 and 008 clinical working teams and the associates of Dr. Goepfert at UAB. We thank R. G. Overman for technical assistance. This work is supported by the MAID Center for HIV/AIDS Vaccine Immunology grant A1067854 and a grant from NIH to XY.-RO1 AI073133. NR 68 TC 26 Z9 26 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2010 VL 396 IS 2 BP 339 EP 348 DI 10.1016/j.virol.2009.10.044 PG 10 WC Virology SC Virology GA 542OS UT WOS:000273504600019 PM 19922969 ER PT J AU Marzocchetti, A Lima, M Tompkins, T Kavanagh, DG Gandhi, RT O'Neill, DW Bhardwaj, N Koralnik, IJ AF Marzocchetti, Angela Lima, Marco Tompkins, Troy Kavanagh, Daniel G. Gandhi, Rajesh T. O'Neill, David W. Bhardwaj, Nina Koralnik, Igor J. TI Efficient in vitro expansion of JC virus-specific CD8+ T-cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy (vol 383, pg 173, 2009) SO VIROLOGY LA English DT Correction C1 [Lima, Marco; Koralnik, Igor J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Marzocchetti, Angela; Lima, Marco; Tompkins, Troy; Koralnik, Igor J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. [Lima, Marco] Fundacao Oswaldo Cruz, Neuroinfect & HTLV Lab, Rio De Janeiro, Brazil. [Kavanagh, Daniel G.; Gandhi, Rajesh T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02215 USA. [O'Neill, David W.; Bhardwaj, Nina] NYU, Sch Med, New York, NY 10003 USA. RP Koralnik, IJ (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Neurol, E CLS-1005,330 Brookline Ave, Boston, MA 02215 USA. EM ikoralni@bidmc.harvard.edu NR 1 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 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2010 VL 396 IS 2 BP 349 EP 350 DI 10.1016/j.virol.2009.10.038 PG 2 WC Virology SC Virology GA 542OS UT WOS:000273504600020 ER PT J AU Johnson, N Bentley, J Wang, LZ Newell, DR Robson, CN Shapiro, GI Curtin, NJ AF Johnson, N. Bentley, J. Wang, L-Z Newell, D. R. Robson, C. N. Shapiro, G. I. Curtin, N. J. TI Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; CDK; NU2058; NU6102 ID ANTIESTROGEN RESISTANCE; DNA-DAMAGE; CDK2; P27(KIP1); CYCLIN-DEPENDENT-KINASE-2; PHOSPHORYLATION; CHECKPOINT; TAMOXIFEN; PROTEIN; PURINE AB BACKGROUND: Cellular proliferation, driven by cyclin-dependent kinases (CDKs) and their cyclin partners, is deregulated in cancer. Anti-estrogens, such as tamoxifen, antagonise estrogen-induced ER alpha transactivation of cyclin D1, resulting in reduced CDK4/6 activity, p27(Kip1)-mediated inhibition of CDK2 and growth arrest. We hypothesised that direct inhibition of CDK2 and CDK1 may overcome the major clinical problem of anti-estrogen resistance. METHODS: The cellular effects of CDK2/1 siRNA knockdown and purine-based CDK2/1 inhibitors, NU2058 and NU6102, were measured in anti-estrogen-sensitive and resistant breast cancer cell lines. RESULTS: CDK2 knockdown caused G1 accumulation, whereas CDK1 depletion caused G2/M slowing, and dual CDK1/2 depletion resulted in further G2/M accumulation and cell death in both anti-estrogen-sensitive and resistant cells, confirming CDK2 and CDK1 as targets for breast cancer therapy. In contrast to tamoxifen, which only affected hormone-sensitive cells, NU2058 and NU6102 reduced CDK2-mediated phosphorylation of pRb, E2F transcriptional activity and proliferation, ultimately resulting in cell death, in both anti-estrogen-sensitive and resistant cells. Both drugs caused G2/M arrest, reflective of combined CDK2/1 knockdown, with a variable degree of G1 accumulation. CONCLUSION: These studies confirm the therapeutic potential of CDK2 and CDK1 inhibitors for cancer therapy, and support their use as an alternative treatment for endocrine-resistant breast cancer. British Journal of Cancer (2010) 102, 342-350. doi:10.1038/sj.bjc.6605479 www.bjcancer.com Published online 15 December 2009 (C) 2010 Cancer Research UK C1 [Johnson, N.; Bentley, J.; Wang, L-Z; Newell, D. R.; Robson, C. N.; Curtin, N. J.] Newcastle Univ, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Johnson, N.; Shapiro, G. I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Curtin, NJ (reprint author), Newcastle Univ, No Inst Canc Res, Paul O Gorman Bldg,Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. EM n.j.curtin@ncl.ac.uk FU Cancer Research UK; Breast Cancer Campaign; NIH [R01 CA90687, P50 CA089393, P20 CA090578, KG080773] FX The research described in this paper was supported by the Cancer Research UK and the Breast Cancer Campaign. GIS is supported by NIH Grant R01 CA90687, P50 CA089393 (the DanaFarber/Harvard Cancer Center (DF/HCC) Specialized Program of Research Excellence (SPORE) in Breast Cancer) and P20 CA090578 (DF/HCC SPORE in Lung Cancer), as well as Susan G. Komen Post-Doctoral Fellowship Award KG080773 (NJ and GIS). We would also like to thank Professor Roger Griffin and colleagues in the Cancer Research UK Drug Development Programme at the Northern Institute for Cancer Research for the provision of NU2058 and NU6102, Professors Jane Endicott and Martin Noble (Oxford University) for recombinant CDK2/cyclin A3 enzyme, Dr Valerie Speirs (Leeds Univeristy) for supplying MMU2 cells and Dr Robert Clarke (Georgetown University) for LCC9 cells. NR 27 TC 18 Z9 21 U1 0 U2 3 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 JAN 19 PY 2010 VL 102 IS 2 BP 342 EP 350 DI 10.1038/sj.bjc.6605479 PG 9 WC Oncology SC Oncology GA 545JO UT WOS:000273728500014 PM 20010939 ER PT J AU Chen, J Imanaka, N Chen, J Griffin, JD AF Chen, J. Imanaka, N. Chen, J. Griffin, J. D. TI Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion SO BRITISH JOURNAL OF CANCER LA English DT Article DE Notch; hypoxia; hypoxia inducible factor (HIF); breast cancer; epithelial-to-mesenchymal transition (EMT) ID EPITHELIAL-MESENCHYMAL TRANSITION; ACUTE LYMPHOBLASTIC-LEUKEMIA; MOUSE MAMMARY EPITHELIUM; TRUNCATED INT3 GENE; TUMOR PROGRESSION; MIR-200 FAMILY; TUMORIGENESIS; METASTASIS; ACTIVATION; PHENOTYPE AB BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is associated with decreased adhesion and acquisition of metastatic potential of breast cancer cells. Epithelial-to-mesenchymal transition is mediated, in part, by two transcription repressors, Snail and Slug, that are known to be targets of the Notch signaling pathway, and JAGGED1-induced Notch activation increases EMT. However, the events that lead to increased Notch activity during EMT of breast cancer cells are unknown. METHODS: The accumulation of hypoxia inducible factors (HIFs) under hypoxia was detected by western blot analysis, and their effects on Notch signaling were measured by an in vitro Notch reporter assay. The expression of Notch target genes under hypoxia was tested by real-time PCR. The knockdown of HIF-1 alpha was mediated by retroviral delivery of shRNA. The expression of Slug and Snail under hypoxia was measured by real-time PCR. Breast cancer cell migration and invasion under hypoxia were tested with cell migration and invasion kits. RESULTS: Hypoxia increased the expression of Notch target genes such as HES1 and HEY1 in breast cancer cells, as was expression of Notch receptors and ligands. The mechanism is likely to involve the accumulation of HIF-1 alpha and HIF-2 alpha in these cells by hypoxia, which synergised with the Notch co-activator MAML1 in potentiating Notch activity. Hypoxia inducible factor-1 alpha was found to bind to HES1 promoter under hypoxia. Knockdown of HIF-1 alpha with shRNA inhibited both HES1 and HEY1 expression under hypoxia. Hypoxia increased the expression of Slug and Snail, and decreased the expression of E-cadherin, hallmarks of EMT. Notch pathway inhibition abrogated the hypoxia-mediated increase in Slug and Snail expression, as well as decreased breast cancer cell migration and invasion. CONCLUSION: Hypoxia-mediated Notch signaling may have an important role in the initiation of EMT and subsequent potential for breast cancer metastasis. British Journal of Cancer (2010) 102, 351-360. doi:10.1038/sj.bjc.6605486 www.bjcancer.com Published online 15 December 2009 (C) 2010 Cancer Research UK C1 [Chen, J.; Imanaka, N.; Chen, J.; Griffin, J. D.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM james_griffin@dfci.harvard.edu FU NIH [CA-36167] FX We thank Dr Tetsuo Sudo for the mHes1 antibody; Dr Qin Yan, Dr Yoji Minamishima and Dr William Kaelin Jr. for pcDNA3/HIF-1 alpha (P402A/P564A), pcDNA3/HIF-2 alpha (P405A/P531A) constructs and HIF-2 alpha antibody; Dr Tim Geistlinger for the advices of CHIP experiments. J D Griffin is supported by NIH grant CA-36167. NR 40 TC 128 Z9 142 U1 4 U2 40 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 JAN 19 PY 2010 VL 102 IS 2 BP 351 EP 360 DI 10.1038/sj.bjc.6605486 PG 10 WC Oncology SC Oncology GA 545JO UT WOS:000273728500015 PM 20010940 ER PT J AU Bullinger, L Armstrong, SA AF Bullinger, Lars Armstrong, Scott A. TI HELP for AML: Methylation Profiling Opens New Avenues SO CANCER CELL LA English DT Editorial Material ID MYELOID-LEUKEMIA; MAPS AB There is growing evidence that aberrant gene expression in cancer is linked to epigenetic deregulation like promoter cytosine methylation in CpG-islands. In this issue of Cancer Cell, Figueroa et al. show that genome-wide promoter DNA methylation profiling reveals unique AML subgroups and methylation patterns that are associated with clinical outcome. C1 [Bullinger, Lars; Armstrong, Scott A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bullinger, Lars] Univ Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Armstrong, Scott A.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Armstrong, Scott A.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Armstrong, SA (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM scott.armstrong@childrens.harvard.edu NR 10 TC 10 Z9 10 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 JAN 19 PY 2010 VL 17 IS 1 BP 1 EP 3 DI 10.1016/j.ccr.2009.12.033 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 554YA UT WOS:000274471300001 PM 20129241 ER PT J AU Turke, AB Zejnullahu, K Wu, YL Song, Y Dias-Santagata, D Lifshits, E Toschi, L Rogers, A Mok, T Sequist, L Lindeman, NI Murphy, C Akhavanfard, S Yeap, BY Xiao, Y Capelletti, M Iafrate, AJ Lee, C Christensen, JG Engelman, JA Janne, PA AF Turke, Alexa B. Zejnullahu, Kreshnik Wu, Yi-Long Song, Youngchul Dias-Santagata, Dora Lifshits, Eugene Toschi, Luca Rogers, Andrew Mok, Tony Sequist, Lecia Lindeman, Neal I. Murphy, Carly Akhavanfard, Sara Yeap, Beow Y. Xiao, Yun Capelletti, Marzia Iafrate, A. John Lee, Charles Christensen, James G. Engelman, Jeffrey A. Jaenne, Pasi A. TI Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC SO CANCER CELL LA English DT Article ID GROWTH-FACTOR-RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; CHRONIC MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; PROSPECTIVE PHASE-II; ACQUIRED-RESISTANCE; GEFITINIB RESISTANCE; DOMAIN MUTATIONS; T790M MUTATIONS AB MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations; of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy. C1 [Turke, Alexa B.; Song, Youngchul; Dias-Santagata, Dora; Lifshits, Eugene; Sequist, Lecia; Akhavanfard, Sara; Yeap, Beow Y.; Iafrate, A. John; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Turke, Alexa B.; Yeap, Beow Y.; Engelman, Jeffrey A.; Jaenne, Pasi A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Zejnullahu, Kreshnik; Toschi, Luca; Rogers, Andrew; Capelletti, Marzia; Jaenne, Pasi A.] Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Zejnullahu, Kreshnik; Toschi, Luca; Rogers, Andrew; Xiao, Yun; Capelletti, Marzia; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wu, Yi-Long] Guangdong Gen Hosp, Guangdong Lung Canc Inst, Guangzhou, Guangdong, Peoples R China. [Wu, Yi-Long] Guangdong Gen Hosp, Ctr Canc, Guangzhou, Guangdong, Peoples R China. [Mok, Tony] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Lindeman, Neal I.; Murphy, Carly; Xiao, Yun; Lee, Charles] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Christensen, James G.] Pfizer Global Res & Dev, Dept Res Pharmacol, La Jolla Labs, La Jolla, CA 92121 USA. [Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Engelman, JA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. EM jengelman@partners.org; pjanne@partners.org RI Wu, Yi-Long/C-3396-2008 OI Wu, Yi-Long/0000-0002-3611-0258 FU National Institutes of Health [RO1CA114465, R01CA135257, CA120060, R01CA137008, RO1CA140594]; National Cancer Institute Lung [P50CA090578]; DF/HCC Gastrointestinal Cancer [P50 CA127003]; American Association for Cancer Research; V Foundation; American Cancer Society [RSG-06-102-01-CCE]; Hazel and Samuel Bellin research fund; Ellison Foundation Scholar; Pfizer FX This study is Supported by the National Institutes of Health (grants RO1CA114465 to P.A.J. and B.Y.Y.; R01CA135257 to P.A.J., B.Y.Y.. and J.A.E.; K08 grant CA120060 to J.A.E.; R01CA137008 to J.A.E. and P.A.J., and RO1CA140594 to J.A.E). National Cancer Institute Lung (SPORE P50CA090578 to P.A.J., B.Y.Y., and J.A.E.), DF/HCC Gastrointestinal Cancer (SPORE P50 CA127003 to J.A.E.), the American Association for Cancer Research (support to J.A.E.), the V Foundation (support to J.A.E.), American Cancer Society (grant RSG-06-102-01-CCE to P.A.J., B.Y.Y., and J.A.E.), Hazel and Samuel Bellin research fund (support to P.A.J.), and the Ellison Foundation Scholar (support to J.A.E.). We also thank Mike Warring and Andrew Cosgrove, for FACS analysis, and Tatiana Zolotarev, for technical histology assistance. J.G.C. is an employee and shareholder of Pfizer. P.A.J. has received research support from Pfizer. P.A.J. and J.A.E. are founders of Gatekeeper Pharmaceuticals. NR 35 TC 478 Z9 501 U1 4 U2 47 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 JAN 19 PY 2010 VL 17 IS 1 BP 77 EP 88 DI 10.1016/j.ccr.2009.11.022 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 554YA UT WOS:000274471300011 PM 20129249 ER PT J AU Verhaak, RGW Hoadley, KA Purdom, E Wang, V Qi, Y Wilkerson, MD Miller, CR Ding, L Golub, T Mesirov, JP Alexe, G Lawrence, M O'Kelly, M Tamayo, P Weir, BA Gabriel, S Winckler, W Gupta, S Jakkula, L Feiler, HS Hodgson, JG James, CD Sarkaria, JN Brennan, C Kahn, A Spellman, PT Wilson, RK Speed, TP Gray, JW Meyerson, M Getz, G Perou, CM Hayes, DN AF Verhaak, Roel G. W. Hoadley, Katherine A. Purdom, Elizabeth Wang, Victoria Qi, Yuan Wilkerson, Matthew D. Miller, C. Ryan Ding, Li Golub, Todd Mesirov, Jill P. Alexe, Gabriele Lawrence, Michael O'Kelly, Michael Tamayo, Pablo Weir, Barbara A. Gabriel, Stacey Winckler, Wendy Gupta, Supriya Jakkula, Lakshmi Feiler, Heidi S. Hodgson, J. Graeme James, C. David Sarkaria, Jann N. Brennan, Cameron Kahn, Ari Spellman, Paul T. Wilson, Richard K. Speed, Terence P. Gray, Joe W. Meyerson, Matthew Getz, Gad Perou, Charles M. Hayes, D. Neil CA Canc Genome Atlas Res Network TI Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1 SO CANCER CELL LA English DT Article ID NEURAL STEM-CELLS; RECURSIVE PARTITIONING ANALYSIS; MALIGNANT GLIOMA; MOLECULAR SUBTYPES; MULTIFORME TUMORS; COPY NUMBER; EXPRESSION; MUTATIONS; RECEPTOR; REVEALS AB The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies. C1 [Hoadley, Katherine A.; Qi, Yuan; Wilkerson, Matthew D.; Miller, C. Ryan; Perou, Charles M.; Hayes, D. Neil] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Verhaak, Roel G. W.; Golub, Todd; Mesirov, Jill P.; Alexe, Gabriele; Lawrence, Michael; O'Kelly, Michael; Tamayo, Pablo; Weir, Barbara A.; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Meyerson, Matthew; Getz, Gad] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Verhaak, Roel G. W.; Golub, Todd; Mesirov, Jill P.; Alexe, Gabriele; Lawrence, Michael; O'Kelly, Michael; Tamayo, Pablo; Weir, Barbara A.; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Meyerson, Matthew; Getz, Gad] Harvard Univ, Cambridge, MA 02142 USA. [Verhaak, Roel G. W.; Lawrence, Michael; O'Kelly, Michael; Weir, Barbara A.; Winckler, Wendy; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hoadley, Katherine A.; Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Qi, Yuan; Wilkerson, Matthew D.; Hayes, D. Neil] Univ N Carolina, Div Med Oncol, Dept Internal Med, Chapel Hill, NC 27599 USA. [Miller, C. Ryan] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Purdom, Elizabeth; Speed, Terence P.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Wang, Victoria; Perou, Charles M.] Univ Calif Berkeley, Grp Biostat, Berkeley, CA 94720 USA. [Ding, Li; Wilson, Richard K.] Washington Univ, Sch Med, Dept Genet, Genome Ctr, St Louis, MO 63108 USA. [Golub, Todd] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Dept Pediat Oncol, Boston, MA 02115 USA. [Jakkula, Lakshmi; Feiler, Heidi S.; Spellman, Paul T.; Gray, Joe W.] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. [Hodgson, J. Graeme; James, C. David] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Sarkaria, Jann N.] Mayo Clin, Dept Radiat Oncol, Rochester, MN 55905 USA. [Brennan, Cameron] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [Kahn, Ari] SRI Int, Fairfax, VA 22033 USA. [Speed, Terence P.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. RP Hayes, DN (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. EM hayes@med.unc.edu RI Speed, Terence /B-8085-2009; leng, xianwei/F-9073-2011; Meyerson, Matthew/E-7123-2012; James, Charles/E-2721-2012; Miller, Ryan/B-9365-2008; OI Speed, Terence /0000-0002-5403-7998; James, Charles/0000-0002-1027-203X; Miller, Ryan/0000-0002-0096-8762; Brennan, Cameron/0000-0003-4064-8891; Hayes, D. Neil/0000-0001-6203-7771; Perou, Charles/0000-0001-9827-2247 FU US Department of Energy; US National Institutes of Health [U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563, P50CA58223, RR023248, CA108961, CA127716, NS49720, CA097257, DE-AC02-05CH11231]; Dutch Cancer Society KWF FX We thank the members of TCGA Research Network, in particular Lynda Chin, for reviewing this manuscript. We thank Michele Hayward for editorial assistance. This work was supported by the following grants from the US Department of Energy and the US National Institutes of Health: U54HG003067 and U54HG003079 to R. K. W.; U54HG003273, U24CA126543, and U24CA126544 to C.M.P., U24CA126546 to M.M.; U24CA126551 to J.W.G.; U24CA126554, U24CA126561, U24CA126563, and P50CA58223 to C.M.P., RR023248 to D.N.H.; CA108961 to J.N.S.; CA127716 to J.N.S.; NS49720 to C.D.J.; CA097257 to C.D.J.; and DE-AC02-05CH11231 to J.W.G.). R.G.W.V. is supported by a Fellowship from the Dutch Cancer Society KWF. NR 50 TC 2000 Z9 2040 U1 52 U2 262 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 JAN 19 PY 2010 VL 17 IS 1 BP 98 EP 110 DI 10.1016/j.ccr.2009.12.020 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 554YA UT WOS:000274471300013 PM 20129251 ER PT J AU Schnabel, RB Larson, MG Yamamoto, JF Sullivan, LM Pencina, MJ Meigs, JB Tofler, GH Selhub, J Jacques, PF Wolf, PA Magnani, JW Ellinor, PT Wang, TJ Levy, D Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Larson, Martin G. Yamamoto, Jennifer F. Sullivan, Lisa M. Pencina, Michael J. Meigs, James B. Tofler, Geoffrey H. Selhub, Jacob Jacques, Paul F. Wolf, Philip A. Magnani, Jared W. Ellinor, Patrick T. Wang, Thomas J. Levy, Daniel Vasan, Ramachandran S. Benjamin, Emelia J. TI Relations of Biomarkers of Distinct Pathophysiological Pathways and Atrial Fibrillation Incidence in the Community SO CIRCULATION LA English DT Article DE atrial fibrillation; biomarkers; epidemiology; arrhythmia; risk assessment ID NATRIURETIC PEPTIDE LEVELS; POPULATION-BASED COHORT; C-REACTIVE PROTEIN; CARDIOVASCULAR EVENTS; RISK-FACTORS; SECULAR TRENDS; HEART-FAILURE; PREVALENCE; PREDICTORS; STROKE AB Background-Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial. Methods and Results-In 3120 Framingham cohort participants (mean age 58.4 +/- 9.7 years, 54% women), we related 10 biomarkers that represented inflammation (C-reactive protein and fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP] and N-terminal proatrial natriuretic peptide), oxidative stress (homocysteine), the renin-angiotensin-aldosterone system (renin and aldosterone), thrombosis and endothelial function (D-dimer and plasminogen activator inhibitor type 1), and microvascular damage (urinary albumin excretion; n = 2673) to incident AF (n = 209, 40% women) over a median follow-up of 9.7 years (range 0.05 to 12.8 years). In multivariable-adjusted analyses, the biomarker panel was associated with incident AF (P<0.0001). In stepwise-selection models (P<0.01 for entry and retention), log-transformed BNP (hazard ratio per SD 1.62, 95% confidence interval 1.41 to 1.85, P<0.0001) and C-reactive protein (hazard ratio 1.25, 95% confidence interval 1.07 to 1.45, P<0.004) were chosen. The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95% confidence interval 0.75 to 0.81) to 0.80 (95% confidence interval 0.78 to 0.83) and showed an integrated discrimination improvement of 0.03 (95% confidence interval 0.02 to 0.04, P<0.0001), with 34.9% relative improvement in reclassification analysis. The combined analysis of BNP and C-reactive protein did not appreciably improve risk prediction over the model that incorporated BNP in addition to the risk factors. Conclusions-BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention requires further investigation. (Circulation. 2010; 121: 200-207.) C1 [Schnabel, Renate B.; Larson, Martin G.; Wolf, Philip A.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Framingham Study, Framingham, MA 01702 USA. [Schnabel, Renate B.; Larson, Martin G.; Wolf, Philip A.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Larson, Martin G.; Pencina, Michael J.] Boston Univ, Sch Med, Dept Math & Stat, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Magnani, Jared W.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Mem Med Dept, Boston, MA 02118 USA. [Magnani, Jared W.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Neurol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Yamamoto, Jennifer F.; Sullivan, Lisa M.; Pencina, Michael J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Ellinor, Patrick T.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Tofler, Geoffrey H.] Royal N Shore Hosp, Sydney, NSW, Australia. [Selhub, Jacob; Jacques, Paul F.] Tufts Univ, Jean Mayer Dept Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM emelia@bu.edu RI Schnabel, Renate/F-6527-2014; OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health/National Heart, Lung, and Blood Institute [N01-IIC-25195, 6R01-NS 17950]; National Institutes of Health [1R01HL092577-01A1, HL064753, HL076784, AG028321, 1 RO1HL71039, K24 HL04334, K24, DK080140]; American Diabetes Association; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/1-1] FX This study was supported by National Institutes of Health/National Heart, Lung, and Blood Institute contracts N01-IIC-25195 and 6R01-NS 17950; National Institutes of Health grants 1R01HL092577-01A1 (Drs Ellinor and Benjamin), HL064753, HL076784, and AG028321 (Dr Benjamin), and 1 RO1HL71039 (Dr Vasan); National Institutes of Health Research career award K24 HL04334 (Dr Vasan) and K24, DK080140 (Dr Meigs); an American Diabetes Association career development award (Dr Meigs); and Deutsche Forschungsgemeinschaft (German Research Foundation) research fellowship SCHN 1149/1-1 (Dr Schnabel). NR 45 TC 119 Z9 127 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 19 PY 2010 VL 121 IS 2 BP 200 EP U45 DI 10.1161/CIRCULATIONAHA.109.882241 PG 16 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 544XK UT WOS:000273693500005 PM 20048208 ER PT J AU Rigotti, NA Pipe, AL Benowitz, NL Arteaga, C Garza, D Tonstad, S AF Rigotti, Nancy A. Pipe, Andrew L. Benowitz, Neal L. Arteaga, Carmen Garza, Dahlia Tonstad, Serena TI Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease A Randomized Trial SO CIRCULATION LA English DT Article DE cardiovascular diseases; cerebrovascular disorders; peripheral vascular diseases; smoking; trials ID RECEPTOR PARTIAL AGONIST; NICOTINE REPLACEMENT THERAPY; SUSTAINED-RELEASE BUPROPION; CORONARY-HEART-DISEASE; TRANSDERMAL NICOTINE; TOBACCO DEPENDENCE; PLACEBO AB Background-Smoking cessation is a key component of secondary cardiovascular disease prevention. Varenicline, a partial alpha 4 beta 2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with cardiovascular disease are unknown. Methods and Results-A multicenter, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease. Participants received varenicline (1 mg twice daily) or placebo, along with smoking-cessation counseling, for 12 weeks. Follow-up lasted 52 weeks. The primary end point was carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 (last 4 weeks of treatment). The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval [CI], 4.18 to 8.93) and weeks 9 through 52 (19.2% versus 7.2%; odds ratio, 3.14; 95% CI, 1.93 to 5.11). The varenicline and placebo groups did not differ significantly in cardiovascular mortality (0.3% versus 0.6%; difference, -0.3%; 95% CI, -1.3 to 0.7), all-cause mortality (0.6% versus 1.4%; difference, -0.8%; 95% CI, -2.3 to 0.6), cardiovascular events (7.1% versus 5.7%; difference, 1.4%; 95% CI, -2.3 to 5.0), or serious adverse events (6.5% and 6.0%; difference, 0.5%; 95% CI, -3.1 to 4.1). As a result of adverse events, 9.6% of varenicline and 4.3% of placebo participants discontinued study drug. Conclusions-Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety. Clinical Trial Registration Information-URL: http://www.clinicaltrials.gov/ct2/show/NCT00282984. Unique identifier: NCT00282984. (Circulation. 2010; 121: 221-229.) C1 [Rigotti, Nancy A.] Harvard Univ, Tobacco Res & Treatment Ctr, Div Gen Med, Dept Med,Sch Med,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pipe, Andrew L.] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. [Benowitz, Neal L.] Univ Calif San Francisco, Div Clin Pharmacol & Expt Therapeut, Dept Med & Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Arteaga, Carmen; Garza, Dahlia] Pfizer Inc, New York, NY USA. [Tonstad, Serena] Ullevaal Univ Hosp, Dept Prevent Cardiol, Oslo, Norway. RP Rigotti, NA (reprint author), Harvard Univ, Tobacco Res & Treatment Ctr, Div Gen Med, Dept Med,Sch Med,Massachusetts Gen Hosp, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM nrigotti@partners.org FU Pfizer Inc.; sanofi-aventis; Nabi Biopharmaceuticals; Bristol-Myers Squibb; Johnson Johnson; GlaxoSmithKline; Merrell-Dow FX This study was funded by Pfizer Inc. Editorial support for the development of this manuscript was provided by Alexandra Bruce, PhD, of UBC Scientific Solutions and was funded by Pfizer Inc.; Drs Rigotti, Pipe, Benowitz, and Tonstad have consulted for Pfizer. Dr Rigotti has been the site principal investigator for clinical trials of smoking cessation medications funded by Pfizer, sanofi-aventis, and Nabi Biopharmaceuticals. Dr Pipe has received educational and research support in the past from Bristol-Myers Squibb, Johnson & Johnson, GlaxoSmithKline, and Merrell-Dow. NR 24 TC 156 Z9 163 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 19 PY 2010 VL 121 IS 2 BP 221 EP U76 DI 10.1161/CIRCULATIONAHA.109.869008 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 544XK UT WOS:000273693500008 PM 20048210 ER PT J AU Du, D Xu, FL Yu, LH Zhang, CY Lu, XF Yuan, HX Huang, Q Zhang, F Bao, HY Jia, LH Wu, XW Zhu, XL Zhang, XH Zhang, Z Chen, ZJ AF Du, Dan Xu, Feilai Yu, Lihou Zhang, Chenyi Lu, Xuefeng Yuan, Haixin Huang, Qin Zhang, Fan Bao, Hongyan Jia, Lianghui Wu, Xunwei Zhu, Xueliang Zhang, Xiaohui Zhang, Zhe Chen, Zhengjun TI The Tight Junction Protein, Occludin, Regulates the Directional Migration of Epithelial Cells SO DEVELOPMENTAL CELL LA English DT Article ID DISTINCT ROLES; RHO-GTPASES; TYROSINE PHOSPHORYLATION; MEMBRANE-PROTEIN; OXIDATIVE STRESS; LEADING-EDGE; POLARITY; CDC42; POLARIZATION; COMPLEX AB Cell polarity proteins regulate tight junction formation and directional migration in epithelial cells. To date, the mechanism by which these polarity proteins assemble at the leading edge of migrating epithelial cells remains unclear. We report that occludin, a transmembrane protein, is localized at the leading edge of migrating cells and regulates directional cell migration. During migration, occludin knockdown disrupted accumulation of aPKC-Par3 and PATJ at the leading edge, and led to a disorganized microtubule network and defective reorientation of the microtubule organization center (MTOC). Phosphorylation of occludin at tyrosine 473 residue allowed recruitment of p85 alpha to the leading edge via association with its C-terminal SH2 domain. Loss of occludin attenuated activation of PI3K, leading to disorganization of the actin cytoskeleton and reduced cell protrusions. Our data indicate that occludin is required for the leading-edge localization of polarity proteins aPKC-Par3 and PATJ and promotes cell protrusion by regulating membrane-localized activation of PI3K. C1 [Du, Dan; Xu, Feilai; Yu, Lihou; Zhang, Chenyi; Lu, Xuefeng; Yuan, Haixin; Huang, Qin; Zhang, Fan; Bao, Hongyan; Jia, Lianghui; Zhang, Xiaohui; Zhang, Zhe; Chen, Zhengjun] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China. [Zhu, Xueliang] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Key Lab Mol Cell Biol, Shanghai 200031, Peoples R China. [Wu, Xunwei] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Chen, ZJ (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China. EM zjchen@sibs.ac.cn RI Yu, Lihou/A-8865-2015; Du, Dan/D-6106-2017 OI Du, Dan/0000-0002-3470-2890 FU National Natural Science Foundation of China [30730055, 30871270, 30623002]; National Key Scientific Program of China [2007CB914504]; National High Technology and Development Program of China [2006AA021308]; Chinese Academy of Sciences [KSCX2-YW-R-108, KSCX1-YW-R-67]; Program of Shanghai Subject [08XD14051] FX We thank Dangsheng Li for critical comments on the manuscript. We also thank Cord Brakebusch and Shaohua Li for providing Rac1-/- ES cells. This research was supported by grants from National Natural Science Foundation of China (30730055, 30871270, and 30623002), from the National Key Scientific Program of China (2007CB914504), from the National High Technology and Development Program of China (2006AA021308), from the Chinese Academy of Sciences (KSCX2-YW-R-108 and KSCX1-YW-R-67), and also from the Program of Shanghai Subject Chief Scientist (08XD14051). NR 64 TC 55 Z9 57 U1 4 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD JAN 19 PY 2010 VL 18 IS 1 BP 52 EP 63 DI 10.1016/j.devcel.2009.12.008 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 546RZ UT WOS:000273829800008 PM 20152177 ER PT J AU Moore, SA Januzzi, JL AF Moore, Stephanie A. Januzzi, James L., Jr. TI Found in Translation Soluble ST2 and Heart Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE ST2; cardiac magnetic resonance; myocardial infarction; remodeling; aldosterone ID RECEPTOR FAMILY-MEMBER; ACUTE MYOCARDIAL-INFARCTION; ACUTE DYSPNEA; SERUM-LEVELS; FAILURE; BIOMARKER; MORTALITY C1 [Moore, Stephanie A.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Moore, Stephanie A.] Massachusetts Gen Hosp, Sect Heart Failure, Boston, MA 02114 USA. [Moore, Stephanie A.] Harvard Univ, Sch Med, Boston, MA USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM JJanuzzi@partners.org NR 12 TC 4 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 19 PY 2010 VL 55 IS 3 BP 251 EP 253 DI 10.1016/j.jacc.2009.08.049 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 543XI UT WOS:000273613100011 PM 20117404 ER PT J AU Shen, Y Liu, J Estiu, G Isin, B Ahn, YY Lee, DS Barabasi, AL Kapatral, V Wiest, O Oltvai, ZN AF Shen, Y. Liu, J. Estiu, G. Isin, B. Ahn, Y-Y. Lee, D-S. Barabasi, A-L. Kapatral, V. Wiest, O. Oltvai, Z. N. TI Blueprint for antimicrobial hit discovery targeting metabolic networks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antibiotics; flux balance analysis; virtual screening ID CARRIER PROTEIN TRANSACYLASE; RESISTANT STAPHYLOCOCCUS-AUREUS; FATTY-ACID SYNTHASE; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; ANTIBIOTIC PROPERTIES; GENE-EXPRESSION; RECONSTRUCTION; GENOME; INHIBITOR AB Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy. C1 [Shen, Y.; Estiu, G.; Wiest, O.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Shen, Y.; Liu, J.; Isin, B.; Oltvai, Z. N.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA. [Shen, Y.; Liu, J.; Isin, B.; Oltvai, Z. N.] Univ Pittsburgh, Dept Computat Biol, Pittsburgh, PA 15261 USA. [Ahn, Y-Y.; Lee, D-S.; Barabasi, A-L.] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Ahn, Y-Y.; Lee, D-S.; Barabasi, A-L.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Ahn, Y-Y.; Lee, D-S.; Barabasi, A-L.] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Ahn, Y-Y.; Lee, D-S.; Barabasi, A-L.] Northeastern Univ, Dept Comp Sci, Boston, MA 02115 USA. [Ahn, Y-Y.; Lee, D-S.; Barabasi, A-L.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Kapatral, V.] Integrated Genom Inc, Chicago, IL 60612 USA. RP Wiest, O (reprint author), Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. EM owiest@nd.edu; oltvai@pitt.edu RI Lee, Deok-Sun/D-1335-2011 FU NIAID [U01-0700499]; ChemistryBiochemistry-Biology Interface (CBBI) Program [NIGMS T32-075762] FX We thank Drs. I. Bahar, D. Tobi, B. Chen, and B. Shoichet for help with the structural analyses and Dr. R. Lange (Actelion Pharmaceuticals Ltd., Switzerland) for providing plasmids, pDSNdeIacpPec and pDSNdeIacpSec. This research was supported by NIAID U01-0700499 (to Z. N. O., A-L. B., V. K., and O. W.) and by a travel grant (Y. S.) from the ChemistryBiochemistry-Biology Interface (CBBI) Program at the University of Notre Dame, supported by training Grant NIGMS T32-075762. NR 40 TC 65 Z9 66 U1 0 U2 13 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 JAN 19 PY 2010 VL 107 IS 3 BP 1082 EP 1087 DI 10.1073/pnas.0909181107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100026 PM 20080587 ER PT J AU Hayashida, T Takahashi, F Chiba, N Brachtel, E Takahashi, M Godin-Heymann, N Gross, KW Vivanco, MDM Wijendran, V Shioda, T Sgroi, D Donahoe, PK Maheswaran, S AF Hayashida, Tetsu Takahashi, Fumiyuki Chiba, Naokazu Brachtel, Elena Takahashi, Motomi Godin-Heymann, Nadia Gross, Kenneth W. Vivanco, Maria D. M. Wijendran, Vasuki Shioda, Toshihiro Sgroi, Dennis Donahoe, Patricia K. Maheswaran, Shyamala TI HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE breast cancer; ErbB; TGF-beta; angiogenesis; epithelial to mesenchymal transition ID EPITHELIAL-MESENCHYMAL TRANSITION; EPIDERMAL-GROWTH-FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; HOMEODOMAIN PROTEIN; EXPRESSION RATIO; TGF-BETA; IN-VIVO; CELLS; ANGIOGENESIS; INHIBITOR AB The mechanisms underlying tumoral secretion of signaling molecules into the microenvironment, which modulates tumor cell fate, angiogenesis, invasion, and metastasis, are not well understood. Aberrant expression of transcription factors, which has been implicated in the tumorigenesis of several types of cancers, may provide a mechanism that induces the expression of growth and angiogenic factors in tumors, leading to their local increase in the tumor microenvironment, favoring tumor progression. In this report, we demonstrate that the transcription factor HOXB9 is overexpressed in breast carcinoma, where elevated expression correlates with high tumor grade. HOXB9 induces the expression of several angiogenic factors (VEGF, bFGF, IL-8, and ANGPTL-2), as well as ErbB (amphiregulin, epiregulin, and neuregulins) and TGF-beta, which activate their respective pathways, leading to increased cell motility and acquisition of mesenchymal phenotypes. In vivo, HOXB9 promotes the formation of large, well-vascularized tumors that metastasize to the lung. Thus, deregulated expression of HOXB9 contributes to breast cancer progression and lung metastasis by inducing several growth factors that alter tumor-specific cell fates and the tumor stromal microenvironment. C1 [Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Charlestown, MA 02129 USA. [Donahoe, Patricia K.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Hayashida, Tetsu; Takahashi, Fumiyuki; Chiba, Naokazu; Takahashi, Motomi; Maheswaran, Shyamala] Massachusetts Gen Hosp, Dept Surg, Charlestown, MA 02129 USA. [Hayashida, Tetsu; Takahashi, Fumiyuki; Chiba, Naokazu; Takahashi, Motomi; Godin-Heymann, Nadia; Shioda, Toshihiro; Sgroi, Dennis; Maheswaran, Shyamala] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Brachtel, Elena; Sgroi, Dennis] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. [Gross, Kenneth W.] Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. [Vivanco, Maria D. M.] CIC bioGUNE, Cell Biol & Stem Cells Unit, Derio 48160, Bizkaia, Spain. [Wijendran, Vasuki] Brandeis Univ, Foster Biomed Res Lab, Waltham, MA 02254 USA. RP Donahoe, PK (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Charlestown, MA 02129 USA. EM pdonahoe@partners.org; maheswaran@helix.mgh.harvard.edu RI Vivanco, Maria/G-2393-2011; cancer, biogune/H-7276-2012 OI Vivanco, Maria/0000-0002-9540-247X; FU National Institutes of Health/National Cancer Institute [CA89138]; [PDF0600282]; [KG090412] FX We thank Drs. Kurt J. Isselbacher, Daniel A. Haber, and Jeffrey Settleman for critically reading this manuscript. This work was supported by National Institutes of Health/National Cancer Institute Grant CA89138 and Susan G. Komen for the Cure Grants PDF0600282 and KG090412 (to S. M.). NR 44 TC 66 Z9 67 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 19 PY 2010 VL 107 IS 3 BP 1100 EP 1105 DI 10.1073/pnas.0912710107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100029 PM 20080567 ER PT J AU Pancera, M Majeed, S Ban, YEA Chen, L Huang, CC Kong, L Kwon, YD Stuckey, J Zhou, TQ Robinson, JE Schief, WR Sodroski, J Wyatt, R Kwong, PD AF Pancera, Marie Majeed, Shahzad Ban, Yih-En Andrew Chen, Lei Huang, Chih-chin Kong, Leopold Kwon, Young Do Stuckey, Jonathan Zhou, Tongqing Robinson, James E. Schief, William R. Sodroski, Joseph Wyatt, Richard Kwong, Peter D. TI Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV-1 viral spike; molecular motion; protein architecture; receptor-triggered entry; type 1 fusion protein ID MEMBRANE-FUSION; BINDING-SITE; VIRAL ENTRY; GLYCOPROTEIN; ANTIBODY; NEUTRALIZATION; CD4; HEMAGGLUTININ; RECEPTOR; DEFINITION AB The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug-and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded beta-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate-and structurally plastic-layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanismin which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated beta-sandwich and providing for conformational diversity used in immune evasion. A "layered" gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a beta-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions. C1 [Pancera, Marie; Majeed, Shahzad; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Kwon, Young Do; Stuckey, Jonathan; Zhou, Tongqing; Wyatt, Richard; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Ban, Yih-En Andrew; Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Robinson, James E.] Tulane Univ, Med Ctr, Dept Pediat, New Orleans, LA 70112 USA. [Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program of the NIH; Melinda Gates Foundation Grand Challenges in Global Heath Initiative; NIH; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank A. Finzi, M. Gerstein, B. Korber, H. Langedijk, G. Nabel, R. Sanders, Q. Sattentau, L. Shapiro, M. Shastri, I. Wilson, and members of the Structural Biology Section, Vaccine Research Center, for discussions or comments on the manuscript; J. Skinner for assistance with statistical analysis; S. Subramaniam for ligand-oriented cryoelectron tomograms; D. Dimitrov for antibodies X5, m6, and m9; M. Fung for antibody 5A8, M. Posner for antibody F105, W. Hendrickson for support, advice, and guidance during the early stages of the project, and the NIH AIDS Research and Reference Reagent Program for CD4. Support for this work was provided by the Intramural Research Program of the NIH, by the International AIDS Vaccine Initiative, by a grant from the Bill and Melinda Gates Foundation Grand Challenges in Global Heath Initiative, and by grants from the NIH. Use of insertion device 22 (Southeast Region Collaborative Access Team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under Contract no. W-31-109-Eng-38. Atomic coordinates and structure factors for the structure of gp120with intact gp41-interactive region in complex with CD4 and antibody 48d for both orthorhombic and tetragonal crystal forms have been deposited with the Protein Data Bank under the accession codes 3JWD and 3JWO, respectively. NR 35 TC 184 Z9 188 U1 4 U2 25 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 JAN 19 PY 2010 VL 107 IS 3 BP 1166 EP 1171 DI 10.1073/pnas.0911004107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100040 PM 20080564 ER PT J AU Bansal, A Carlson, J Yan, JY Akinsiku, OT Schaefer, M Sabbaj, S Bet, A Levy, DN Heath, S Tang, JM Kaslow, RA Walker, BD Ndung'u, T Goulder, PJ Heckerman, D Hunter, E Goepfert, PA AF Bansal, Anju Carlson, Jonathan Yan, Jiyu Akinsiku, Olusimidele T. Schaefer, Malinda Sabbaj, Steffanie Bet, Anne Levy, David N. Heath, Sonya Tang, Jianming Kaslow, Richard A. Walker, Bruce D. Ndung'u, Thumbi Goulder, Philip J. Heckerman, David Hunter, Eric Goepfert, Paul A. TI CD8 T cell response and evolutionary pressure to HIV-1 cryptic epitopes derived from antisense transcription SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRAL LOAD; CLASS-I; INFECTION; VACCINE; RNA; ASSOCIATIONS; LYMPHOCYTES; EXPRESSION; CHALLENGE AB Retroviruses pack multiple genes into relatively small genomes by encoding several genes in the same genomic region with overlapping reading frames. Both sense and antisense HIV-1 transcripts contain open reading frames for known functional proteins as well as numerous alternative reading frames (ARFs). At least some ARFs have the potential to encode proteins of unknown function, and their antigenic properties can be considered as cryptic epitopes (CEs). To examine the extent of active immune response to virally encoded CEs, we analyzed human leukocyte antigen class I-associated polymorphisms in HIV-1 gag, pol, and nef genes from a large cohort of South Africans with chronic infection. In all, 391 CEs and 168 conventional epitopes were predicted, with the majority (307; 79%) of CEs derived from antisense transcripts. In further evaluation of CD8 T cell responses to a subset of the predicted CEs in patients with primary or chronic infection, both sense- and antisense-encoded CEs were immunogenic at both stages of infection. In addition, CEs often mutated during the first year of infection, which was consistent with immune selection for escape variants. These findings indicate that the HIV-1 genome might encode and deploy a large potential repertoire of unconventional epitopes to enhance vaccine-induced antiviral immunity. C1 [Bansal, Anju; Yan, Jiyu; Sabbaj, Steffanie; Heath, Sonya; Tang, Jianming; Goepfert, Paul A.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Akinsiku, Olusimidele T.; Bet, Anne; Tang, Jianming; Goepfert, Paul A.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Kaslow, Richard A.] Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. [Carlson, Jonathan; Heckerman, David] Microsoft Res, Redmond, WA 98052 USA. [Schaefer, Malinda; Hunter, Eric] Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Atlanta, GA 30329 USA. [Schaefer, Malinda; Hunter, Eric] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30329 USA. [Levy, David N.] NYU, Coll Dent, Dept Basic Sci, New York, NY 10010 USA. [Walker, Bruce D.; Ndung'u, Thumbi; Goulder, Philip J.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. [Walker, Bruce D.; Ndung'u, Thumbi; Goulder, Philip J.] Harvard Univ, Boston, MA 02129 USA. [Walker, Bruce D.; Ndung'u, Thumbi; Goulder, Philip J.] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Program, ZA-4013 Durban, South Africa. [Goulder, Philip J.] Univ Oxford, Dept Pediat, Oxford OX1 3SY, England. RP Goepfert, PA (reprint author), Univ Alabama, Dept Med, Birmingham, AL 35294 USA. EM ABansal@uab.edu; paulg@uab.edu OI Sabbaj, Steffanie/0000-0003-4052-6819; Tang, Jianming/0000-0003-0137-7486; Ndung'u, Thumbi/0000-0003-2962-3992 FU National Institutes of Health (NIH) [R21 AI 73103, R01 AI 084772, AI 64060, P30 AI 050409]; Bill and Melinda Gates Foundation [37874]; University of Alabama at Birmingham-Centers for AIDS Research [P30 AI 027767]; Microsoft Research Corporation FX This work was supported by National Institutes of Health (NIH) grants R21 AI 73103 and R01 AI 084772 and Bill and Melinda Gates Foundation grant 37874 (all to P. A. Goepfert), a University of Alabama at Birmingham-Centers for AIDS Research supplement to grant P30 AI 027767 (to A. Bansal), and NIH grants AI 64060 and P30 AI 050409 (to E. Hunter), and the Microsoft Research Corporation (J. Carlson and D. Heckerman). NR 40 TC 41 Z9 42 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 18 PY 2010 VL 207 IS 1 BP 51 EP 59 DI 10.1084/jem.20092060 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 544WO UT WOS:000273690800006 PM 20065064 ER PT J AU Berger, CT Carlson, JM Brumme, CJ Hartman, KL Brumme, ZL Henry, LM Rosato, PC Piechocka-Trocha, A Brockman, MA Harrigan, PR Heckerman, D Kaufmann, DE Brander, C AF Berger, Christoph T. Carlson, Jonathan M. Brumme, Chanson J. Hartman, Kari L. Brumme, Zabrina L. Henry, Leah M. Rosato, Pamela C. Piechocka-Trocha, Alicja Brockman, Mark A. Harrigan, P. Richard Heckerman, David Kaufmann, Daniel E. Brander, Christian TI Viral adaptation to immune selection pressure by HLA class I-restricted CTL responses targeting epitopes in HIV frameshift sequences SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; OPEN READING FRAME; CELL RESPONSES; INITIATION CODON; AMINO-ACIDS; RNA GENOME; SET-POINT; INFECTION; TYPE-1 AB CD8(+) cytotoxic T lymphocyte (CTL)-mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03-restricted +2 frame-encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level. C1 [Berger, Christoph T.; Brumme, Chanson J.; Hartman, Kari L.; Brumme, Zabrina L.; Henry, Leah M.; Rosato, Pamela C.; Piechocka-Trocha, Alicja; Brockman, Mark A.; Kaufmann, Daniel E.; Brander, Christian] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. [Berger, Christoph T.; Brumme, Chanson J.; Hartman, Kari L.; Brumme, Zabrina L.; Henry, Leah M.; Rosato, Pamela C.; Piechocka-Trocha, Alicja; Brockman, Mark A.; Kaufmann, Daniel E.; Brander, Christian] Harvard Univ, Boston, MA 02129 USA. [Carlson, Jonathan M.; Heckerman, David] Microsoft Res, Seattle, WA 98033 USA. [Brumme, Zabrina L.; Brockman, Mark A.; Harrigan, P. Richard] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC V6B 5S8, Canada. [Brumme, Zabrina L.; Brockman, Mark A.] Simon Fraser Univ, Burnaby, BC V5A 4Y7, Canada. [Harrigan, P. Richard] Univ British Columbia, Div Aids, Vancouver, BC V6Z 1Y6, Canada. [Brander, Christian] Inst Catalana Recerca & Estudis Avancats, Barcelona 08010, Spain. [Brander, Christian] Hosp Badalona Germans Trias & Pujol, Irsicaixa HIV Res Inst HIVACAT, Barcelona 08916, Spain. RP Brander, C (reprint author), Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. EM cbrander@irsicaixa.es OI Brander, Christian/0000-0002-0548-5778; Brumme, Chanson/0000-0003-2722-5288; Brockman, Mark/0000-0001-6432-1426 FU National Institutes of Health [R01 A1-067077]; Swiss National Science Foundation [PBBSP3-123141]; Freiwillige Akademische Gesellschaft Basel; Canadian Institutes for Health Research FX The work was supported by a grant from the National Institutes of Health (R01 A1-067077 to C. Brander and D. E. Kaufmann). C. T. Berger is supported by a postdoctoral fellowship from the Swiss National Science Foundation (PBBSP3-123141) and by the Freiwillige Akademische Gesellschaft Basel. Z. L. Brumme was supported by a postdoctoral fellowship and, currently, a New Investigator award from the Canadian Institutes for Health Research. C. Brander is an Institucio Catalana de Recerca i Estudis Avancats Senior Research Professor at the Irsicaixa AIDS Research Institute. NR 61 TC 35 Z9 35 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JAN 18 PY 2010 VL 207 IS 1 BP 61 EP 75 DI 10.1084/jem.20091808 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 544WO UT WOS:000273690800007 PM 20065065 ER PT J AU Haghgooie, R Toner, M Doyle, PS AF Haghgooie, Ramin Toner, Mehmet Doyle, Patrick S. TI Squishy Non-Spherical Hydrogel Microparticles SO MACROMOLECULAR RAPID COMMUNICATIONS LA English DT Article DE crosslinking; deformable; hydrogel; microparticle; stop flow lithography ID MECHANICAL-PROPERTIES; MICROFLUIDIC DEVICE; FLOW LITHOGRAPHY; PHOTOPOLYMERIZATION; PHAGOCYTOSIS; CAPILLARIES; ERYTHROCYTE; GEOMETRY; DESIGN; TARGET AB Recent advances in the synthesis of polymeric colloids have opened the doors to new advanced materials. There is strong interest in using these new techniques to produce particles that mimic and/or interact with biological systems. An important characteristic of biological systems that has not yet been exploited in synthetic polymeric colloids is their wide range of deformability. A canonical example of this is the human red blood cell (RBC) which exhibits extreme reversible deformability under flow. Here we report the synthesis of soft polymeric colloids with sizes and shapes that mimic those of the RBC. Additionally, we demonstrate that the mechanical flexibility of the colloids can be reproducibly varied over a large range resulting in RBC-like deformability under physiological flow conditions. These materials have the potential to impact the interaction between biological and synthetic systems. C1 [Doyle, Patrick S.] MIT, Cambridge, MA 02139 USA. [Haghgooie, Ramin; Toner, Mehmet] Shriners Hosp Children, Massachusetts Gen Hosp, BioMEMS Resource Ctr, Ctr Engn Med & Surg Serv, Charlestown, MA 02129 USA. [Haghgooie, Ramin; Toner, Mehmet] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Doyle, PS (reprint author), MIT, 77 Massachusetts Ave,Room 66-270, Cambridge, MA 02139 USA. EM pdoyle@mit.edu FU MIT-MGH Postdoctoral Fellowship; National Institute of Biomedical Imaging and Bioengineering [P41 EB002503]; John Simon Guggenheim Foundation; Rothschild-Yvette Mayent-Institute Curie Fellowship FX We thank Octavio Hurtado for assistance with microfabrication and David J. Quinn for useful discussions on design of the constriction devices. This work was supported in part by the MIT-MGH Postdoctoral Fellowship in Translational Research and the National Institute of Biomedical Imaging and Bioengineering (BioMEMS Resource Center, P41 EB002503). PSD acknowledges support from the John Simon Guggenheim Foundation and the Rothschild-Yvette Mayent-Institute Curie Fellowship. NR 27 TC 56 Z9 56 U1 1 U2 32 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1022-1336 J9 MACROMOL RAPID COMM JI Macromol. Rapid Commun. PD JAN 18 PY 2010 VL 31 IS 2 SI SI BP 128 EP 134 DI 10.1002/marc.200900302 PG 7 WC Polymer Science SC Polymer Science GA 551SJ UT WOS:000274229600004 PM 21590884 ER PT J AU Harjes, DI Dubach, JM Rosenzweig, A Das, S Clark, HA AF Harjes, Daniel I. Dubach, J. Matthew Rosenzweig, Anthony Das, Saumya Clark, Heather A. TI Ion-Selective Optodes Measure Extracellular Potassium Flux in Excitable Cells SO MACROMOLECULAR RAPID COMMUNICATIONS LA English DT Article DE biological applications for polymers; fluorescence; microstructure; sensors ID SINGLE LIVING CELLS; OPTICAL NANOSENSORS; CARDIAC-ARRHYTHMIA; CHEMICAL-ANALYSIS; PEBBLE SENSORS; BULK OPTODES AB Optodes have been used for detection of ionic concentrations and fluxes for several years. However, their uses in biomedical applications have not yet been fully explored. This study investigates optodes as a potential sensor platform for monitoring cellular ion flux with attendant implications in the field of drug screening and toxicology. A prototype system was developed to quantitatively measure extracellular potassium flux from a monolayer of cardiomyocytes. Optodes were created and immobilized on a glass coverslip for fluorescent imaging. The system detected potassium (K(+)) ion flux during the repolarization phase of the cardiac action potential and further detected a decrease in the magnitude of the flux in the presence of a known K(+) channel inhibitor by optically monitoring local K(+) ion concentrations during field stimulation of the cardiomyocyte monolayer. C1 [Harjes, Daniel I.; Dubach, J. Matthew; Clark, Heather A.] Charles Stark Draper Lab Inc, Biomed Engn Grp, Cambridge, MA 02139 USA. [Rosenzweig, Anthony; Das, Saumya] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02155 USA. [Das, Saumya] Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02114 USA. RP Clark, HA (reprint author), Charles Stark Draper Lab Inc, Biomed Engn Grp, 555 Technol Sq, Cambridge, MA 02139 USA. EM hclark@draper.com RI Clark, Heather/D-5247-2013 FU National Institutes of Health National Institute of General Medical Sciences [R01 GM084366]; Draper Internal Research and Development; Leducq Foundation Network of Research Excellence; Maxwell Hurston Charitable Foundation; National Institutes of Health/NHLBI [K08 HL081319] FX We thank Dr. Ling Li and Dr. Chunyang Xiao for technical help with myocyte preparations. This work was supported by a grant from the National Institutes of Health National Institute of General Medical Sciences (R01 GM084366) and Draper Internal Research and Development. AR also gratefully acknowledges support from the Leducq Foundation Network of Research Excellence, Judith and David Ganz, and the Maxwell Hurston Charitable Foundation. SD acknowledges the support of the Harvard-MIT Health Sciences and Technology Clinical Investigation Training Program Grant and is also supported by a grant from the National Institutes of Health/NHLBI (K08 HL081319). NR 10 TC 11 Z9 11 U1 0 U2 13 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1022-1336 J9 MACROMOL RAPID COMM JI Macromol. Rapid Commun. PD JAN 18 PY 2010 VL 31 IS 2 SI SI BP 217 EP 221 DI 10.1002/marc.200900297 PG 5 WC Polymer Science SC Polymer Science GA 551SJ UT WOS:000274229600014 PM 21590894 ER PT J AU Heath, JA Clarke, NE Donath, SM McCarthy, M Anderson, VA Wolfe, J AF Heath, John A. Clarke, Naomi E. Donath, Susan M. McCarthy, Maria Anderson, Vicki A. Wolfe, Joanne TI Symptoms and suffering at the end of life in children with cancer: an Australian perspective SO MEDICAL JOURNAL OF AUSTRALIA LA English DT Article ID PEDIATRIC PALLIATIVE CARE; HOME-CARE; DYING CHILDREN; CIRCUMSTANCES; DEATH AB Objective: To examine the symptoms, level of suffering, and care of Australian children with cancer at the end of life. Design, setting and participants: In a study conducted at the Royal Children's Hospital, Melbourne, parents of children who had died of cancer over the period 1996-2004 were interviewed between February 2004 and August 2006. Parents also completed and returned self-report questionnaires. Main outcome measures: Proportions of children suffering from and treated for various symptoms; proportion of children receiving cancer-directed therapy at the end of life; proportion of children whose treatment of symptoms was successful; location of death. Results: Of 193 eligible families, 96 (50%) were interviewed. All interviews were conducted in person, and occurred a mean of 4.5 years (SD, 2.1 years) after the child's death. Eighty-four per cent of parents reported that their child had suffered "a lot" or "a great deal" from at least one symptom in their last month of life - most commonly pain (46%), fatigue (43%) and poor appetite (30%). Children who received cancer-directed therapy during the end-of-life period (47%) suffered from a greater number of symptoms than those who did not receive treatment (P = 0.03), but the severity of symptoms did not differ between these groups. Of the children treated for specific symptoms, treatment was successful in 47% of those with pain, 18% of those with fatigue and 17% of those with poor appetite. Of the 61 families who felt they had time to plan where their child would die, 89% preferred to have their child die at home. The majority of children (61%) died at home. Of those who died in hospital, less than a quarter died in the intensive care unit. Conclusions: Relatively high rates of death at home and low rates of unsuccessful medical interventions suggest a realistic approach at the end of life for Australian children dying of cancer. However, many suffer from unresolved symptoms, and greater attention should be paid to palliative care for these children. MJA 2010; 192: 71-75 C1 [Heath, John A.; McCarthy, Maria] Royal Childrens Hosp, Childrens Canc Ctr, Psychooncol Program, Melbourne, Vic, Australia. [Donath, Susan M.] Murdoch Childrens Res Inst, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Anderson, Vicki A.] Royal Childrens Hosp, Dept Psychol, Melbourne, Vic, Australia. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA. RP Heath, JA (reprint author), Royal Childrens Hosp, Childrens Canc Ctr, Psychooncol Program, Melbourne, Vic, Australia. EM john.heath@rch.org.au OI Donath, Susan/0000-0003-2489-3977 NR 20 TC 33 Z9 35 U1 1 U2 9 PU AUSTRALASIAN MED PUBL CO LTD PI PYRMONT PA LEVEL 2, 26-32 PYRMONT BRIDGE RD, PYRMONT, NSW 2009, AUSTRALIA SN 0025-729X J9 MED J AUSTRALIA JI Med. J. Aust. PD JAN 18 PY 2010 VL 192 IS 2 BP 71 EP 75 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 552CN UT WOS:000274264600006 PM 20078405 ER PT J AU Tartar, JL McKenna, JT Ward, CP McCarley, RW Strecker, RE Brown, RE AF Tartar, Jaime L. McKenna, James T. Ward, Christopher P. McCarley, Robert W. Strecker, Robert E. Brown, Ritchie E. TI Sleep fragmentation reduces hippocampal CA1 pyramidal cell excitability and response to adenosine SO NEUROSCIENCE LETTERS LA English DT Article DE Sleep interruption; Input resistance; Whole cell; A1 receptor ID CENTRAL-NERVOUS-SYSTEM; RAT HIPPOCAMPUS; IN-VITRO; SYNAPTIC PLASTICITY; BASAL FOREBRAIN; DEPRIVATION; RECEPTORS; NEURONS; BRAIN; SITE AB Sleep fragmentation (SF) impairs the restorative/cognitive benefits of sleep via as yet unidentified alterations in neural physiology. Previously,we found that hippocampal synaptic plasticity and spatial learning are impaired in a rat model of SF which utilizes a treadmill to awaken the animals every 2 min, mimicking the frequency of awakenings observed in human sleep apnea patients. Here, we investigated the cellular mechanisms responsible for these effects, using whole-cell patch-clamp recordings. 24 h of SF decreased the excitability of hippocampal CA1 pyramidal neurons via decreased input resistance, without alterations in other intrinsic membrane or action potential properties (when compared to cage controls, or to exercise controls that experienced the same total amount of treadmill movement as SF rats). Contrary to our initial prediction, the hyperpolarizing response to bath applied adenosine (30 mu M) was reduced in the CA1 neurons of SF treated rats. Our initial prediction was based on the evidence that sleep loss upregulates cortical adenosine A1 receptors; however, the present findings are consistent with a very recent report that hippocampal A1 receptors are not elevated by sleep loss. Thus. increased adenosinergic inhibition is unlikely to be responsible for reduced hippocampal long-term potentiation in SF rats. Instead, the reduced excitability of CA1 pyramidal neurons observed here may contribute to the loss of hippocampal long-term potentiation and hippocampus-dependent cognitive impairments associated with sleep disruption. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Brown, Ritchie E.] VA Boston Healthcare Syst, Brockton, MA 02301 USA. Harvard Univ, Sch Med, Brockton, MA 02301 USA. RP Brown, RE (reprint author), VA Boston Healthcare Syst, Res 151-C,940 Belmont St, Brockton, MA 02301 USA. EM ritchie_brown@hms.harvard.edu RI McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Ward, Christopher/0000-0001-9932-3894; Tartar, Jaime/0000-0002-3452-0579; Brown, Ritchie/0000-0002-7164-4132 FU [NHBLI-P50 HL060292]; [NHLBI-T32 HL0790] FX We thank John Franco for care of the animals. This research was supported by VA, NHBLI-P50 HL060292 (RES and RWM) and NHLBI-T32 HL07901 (JLT). NR 30 TC 22 Z9 23 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 18 PY 2010 VL 469 IS 1 BP 1 EP 5 DI 10.1016/j.neulet.2009.11.032 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 556CN UT WOS:000274565500001 PM 19914331 ER PT J AU Li, CQ Pastila, RK Pitsillides, C Runnels, JM Puoris'haag, M Cote, D Lin, CP AF Li, Chunqiang Pastila, Riikka K. Pitsillides, Costas Runnels, Judith M. Puoris'haag, Mehron Cote, Daniel Lin, Charles P. TI Imaging leukocyte trafficking in vivo with two-photon-excited endogenous tryptophan fluorescence SO OPTICS EXPRESS LA English DT Article ID LASER-SCANNING MICROSCOPY; NONMELANOMA SKIN-CANCER; ULTRAVIOLET MICROSCOPY; MULTIPHOTON MICROSCOPY; CONFOCAL MICROSCOPY; 3-PHOTON EXCITATION; BONE-MARROW; INFLAMMATION; MIGRATION; PROTEINS AB We describe a new method for imaging leukocytes in vivo by exciting the endogenous protein fluorescence in the ultraviolet (UV) spectral region where tryptophan is the major fluorophore. Two-photon excitation near 590 nm allows noninvasive optical sectioning through the epidermal cell layers into the dermis of mouse skin, where leukocytes can be observed by video-rate microscopy to interact dynamically with the dermal vascular endothelium. Inflammation significantly enhances leukocyte rolling, adhesion, and tissue infiltration. After exiting the vasculature, leukocytes continue to move actively in tissue as observed by time-lapse microscopy, and are distinguishable from resident autofluorescent cells that are not motile. Because the new method alleviates the need to introduce exogenous labels, it is potentially applicable for tracking leukocytes and monitoring inflammatory cellular reactions in humans. (C) 2010 Optical Society of America C1 [Li, Chunqiang; Pastila, Riikka K.; Pitsillides, Costas; Runnels, Judith M.; Puoris'haag, Mehron; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA. [Li, Chunqiang; Pastila, Riikka K.; Pitsillides, Costas; Runnels, Judith M.; Puoris'haag, Mehron; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Pastila, Riikka K.] Radiat & Nucl Safety Author, FI-00881 Helsinki, Finland. [Pitsillides, Costas] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Runnels, Judith M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cote, Daniel] Univ Laval, Univ Laval Robert Giffard, Ctr Rech, Quebec City, PQ G1J2G3, Canada. RP Li, CQ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, 185 Cambridge St, Boston, MA 02115 USA. EM Li.Chunqiang@mgh.harvard.edu RI Cote, Daniel/D-5185-2011 FU National Institutes of Health [CA111519-01]; Johnson Johnson Inc.; Academy of Finland; Jenny and Antti Wihuri Foundation FX We thank Drs. R. Rox Anderson, Nikiforos Kollias and Paulo Bargo for insightful discussions about skin imaging. We also thank Dr. Irene Ghobrial for supplying cultured multiple myeloma cells. Our work was supported by grants from the National Institutes of Health (CA111519-01), Johnson & Johnson Inc. (C. P. L.), Academy of Finland, and Jenny and Antti Wihuri Foundation (R. K. P.). NR 31 TC 26 Z9 26 U1 2 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 JAN 18 PY 2010 VL 18 IS 2 BP 988 EP 999 DI 10.1364/OE.18.000988 PG 12 WC Optics SC Optics GA 547BP UT WOS:000273860400062 PM 20173920 ER PT J AU Graham, DP Savas, L White, D El-Serag, R Laday-Smith, S Tan, G El-Serag, HB AF Graham, D. P. Savas, L. White, D. El-Serag, R. Laday-Smith, S. Tan, G. El-Serag, H. B. TI Irritable bowel syndrome symptoms and health related quality of life in female veterans SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID FUNCTIONAL GASTROINTESTINAL DISORDERS; POSTTRAUMATIC-STRESS-DISORDER; GENERALIZED ANXIETY DISORDER; GULF-WAR VETERANS; WOMEN VETERANS; PSYCHOMETRIC PROPERTIES; MEDICAL PATIENTS; SURVEY SF-36; PREVALENCE; INVENTORY AB P>Background The status and determinants of health-related quality of life (HRQOL) in female veterans with and without irritable bowel syndrome (IBS) are unknown. Aim To compare HRQOL in female veterans with and without IBS symptoms and examine the contribution of post-traumatic stress disorder, depression and anxiety to HRQOL. Methods A cross-sectional study of 339 female veterans. Self-report questionnaires were used to evaluate IBS symptoms, post-traumatic stress disorder, depression, anxiety and HRQOL. Results Symptoms consistent with IBS were present in 33.5% of participants. Female veterans with IBS symptoms had significant reductions in physical component score and 5 of 8 Health Related Quality of Life subscales and on 7 of 8 Irritable Bowel Syndrome Quality Of Life subscales than female veterans without IBS symptoms. Compared with the US general female population, female veterans had significantly lower Health Related Quality of Life physical component score and mental component scores (MCS) irrespective of IBS symptom status. Differences in the MCS score were most explained by depression, while those in the physical component score were most explained by anxiety. Conclusions Irritable bowel syndrome symptoms in female veterans are associated with considerable reduction in HRQOL. However, female veterans, regardless of IBS symptom status, have lower HRQOL compared with the general US female population. Aliment Pharmacol Ther 31, 261-273. C1 [Graham, D. P.; White, D.; El-Serag, H. B.] Michael E DeBakey Dept Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Hlth Serv Res & Dev Serv, Houston, TX USA. [Graham, D. P.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Savas, L.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Savas, L.] Baylor Coll Med, Dept Family & Community Med, Houston, TX 77030 USA. [White, D.; El-Serag, H. B.] Michael E DeBakey Dept Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX USA. [White, D.; El-Serag, H. B.] Baylor Coll Med, Gastroenterol Sect, Houston, TX 77030 USA. [El-Serag, R.; Laday-Smith, S.] Michael E DeBakey Dept Vet Affairs Med Ctr, Womens Hlth Ctr, Houston, TX USA. [Tan, G.] Baylor Coll Med, Dept Anesthesiol & Phys Med & Rehabil, Houston, TX 77030 USA. RP Graham, DP (reprint author), Houston VA Med Ctr 152, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. EM david.graham@med.va.gov RI Graham, David /J-1158-2014 FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [H-17978]; Novartis pharmaceuticals; Public Health Service [DK56338]; National Institute of Health [K-24 DK078154-03]; National Research Service [5 T32 HP10031-09] FX Disclosure of personal interests: Hashem El-Serag has served as a consultant and an advisory board member for Novartis Pharmaceuticals. None of the authors is an employee, owns stocks or shares, or has patents that constitute a conflict of interest. Hashem B. ElSerag was responsible for the study design. Hashem B. El-Serag and David P. Graham were responsible for the interpretation of results and manuscript. Data analysis was done by David P. Graham. All authors reviewed and revised the manuscript of the paper and approved its final version. All analyses and writing was conducted solely by the listed authors. There are no conflicts of interest. The views expressed in this article are those of the author(s) and do not necessarily represent the views of the Department of Veterans Affairs. Declaration of funding interests: The research reported/outlined here was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (HSR&D, project H-17978). This work was also supported in part by a grant from Novartis pharmaceuticals to Dr El-Serag, and by a Public Health Service Grant DK56338 which funds the Texas Medical Center Digestive Disease Center. Dr El-Serag was supported by National Institute of Health grant K-24 DK078154-03. Dr Savas was supported by the National Research Service Award 5 T32 HP10031-09 funded by the Health Resources and Services. NR 59 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN 15 PY 2010 VL 31 IS 2 BP 261 EP 273 DI 10.1111/j.1365-2036.2009.04159.x PG 13 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 533ZH UT WOS:000272864600011 PM 19814746 ER PT J AU Huang, ES Turner, BG Fernandez-Del-Castillo, C Brugge, WR Hur, C AF Huang, E. S. Turner, B. G. Fernandez-Del-Castillo, C. Brugge, W. R. Hur, C. TI Pancreatic cystic lesions: clinical predictors of malignancy in patients undergoing surgery SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PAPILLARY MUCINOUS NEOPLASMS; PATHOLOGICAL CORRELATION; ENDOSCOPIC ULTRASOUND; DIAGNOSIS; TUMORS; DUCT; CT; RESECTION; ACCURACY; OBSERVE AB P>Background Despite advances in cross-sectional imaging and the use of molecular markers, distinguishing between benign and malignant cysts remains a clinical challenge. Aims To identify both preoperative clinical and cyst characteristics at the time of EUS that predict malignancy. Methods A retrospective analysis was performed on consecutive patients with pancreatic cysts who underwent endoscopic ultrasound (EUS) and surgical resection from May 1996 to December 2007 at a tertiary centre. Clinical history, EUS characteristics, cytology, tumour markers and surgical histology were collected. Predictors of malignancy were determined by univariate and multivariate analysis using logistic regression. Results A total of 153 patients underwent a EUS and subsequent surgical intervention.Of the 153 patients, 57 (37%) had a histological diagnosis of malignancy. On univariate analysis, older age (P < 0.001), male gender (P = 0.010), jaundice (P = 0.039), history of other malignancy (P = 0.036), associated mass in cyst (P = 0.004) and malignant cytology (P < 0.001) were found to be associated with malignancy. History of pancreatitis (P = 0.008) and endoscopist impression of pseudocyst (P = 0.001) were found to be associated with benign cysts. Multivariate analysis found that only older age [Odds ratio (OR), 1.04; 95% confidence interval (CI), 1.01-1.08], male gender (OR, 2.26; 95% CI, 1.08-4.73) and malignant cytology (OR, 6.60; 95% CI, 2.02-21.58) were independent predictors of malignancy. Conclusions Older age, male gender and malignant cytology from EUS predict malignancy at surgical resection. These characteristics may be used to estimate the probability of malignancy in a cyst and aid in management. Aliment Pharmacol Ther 31, 285-294. C1 [Huang, E. S.; Turner, B. G.; Brugge, W. R.; Hur, C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Fernandez-Del-Castillo, C.] Massachusetts Gen Hosp, Dept Gen Surg, Boston, MA 02114 USA. [Huang, E. S.; Hur, C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Huang, E. S.; Turner, B. G.; Fernandez-Del-Castillo, C.; Brugge, W. R.; Hur, C.] Harvard Univ, Sch Med, Boston, MA USA. RP Huang, ES (reprint author), 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM eshuang@partners.org OI Hur, Chin/0000-0002-2819-7576 FU National Institutes of Health [T32DK007191, K07CA107060] FX Declaration of personal interests: None. Declaration of funding interests: This study was funded in part by National Institutes of Health, grant numbers T32DK007191 (ESH, BGT) and K07CA107060 (CH). NR 36 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN 15 PY 2010 VL 31 IS 2 BP 285 EP 294 DI 10.1111/j.1365-2036.2009.04173.x PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 533ZH UT WOS:000272864600013 PM 19845568 ER PT J AU Sarosiek, I Selover, KH Katz, LA Semler, JR Wilding, GE Lackner, JM Sitrin, MD Kuo, B Chey, WD Hasler, WL Koch, KL Parkman, HP Sarosiek, J McCallum, RW AF Sarosiek, I. Selover, K. H. Katz, L. A. Semler, J. R. Wilding, G. E. Lackner, J. M. Sitrin, M. D. Kuo, B. Chey, W. D. Hasler, W. L. Koch, K. L. Parkman, H. P. Sarosiek, J. McCallum, R. W. TI The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; BOWEL BACTERIAL OVERGROWTH; GASTROINTESTINAL TRANSIT; DIABETIC GASTROPARESIS; CONSTIPATION; PH; SCINTIGRAPHY; SYMPTOMS; CAPSULE; MEAL AB P>Background Wireless pH and pressure motility capsule (wireless motility capsule) technology provides a method to assess regional gastrointestinal transit times. Aims To analyse data from a multi-centre study of gastroparetic patients and healthy controls and to compare regional transit times measured by wireless motility capsule in healthy controls and gastroparetics (GP). Methods A total of 66 healthy controls and 34 patients with GP (15 diabetic and 19 idiopathic) swallowed wireless motility capsule together with standardized meal (255 kcal). Gastric emptying time (GET), small bowel transit time (SBTT), colon transit time (CTT) and whole gut transit time (WGTT) were calculated using the wireless motility capsule. Results Gastric emptying time, CTT and WGTT but not SBTT were significantly longer in GP than in controls. Eighteen percent of gastroparetic patients had delayed WGTT. Both diabetic and idiopathic aetiologies of gastroparetics had significantly slower WGTT (P < 0.0001) in addition to significantly slower GET than healthy controls. Diabetic gastroparetics additionally had significantly slower CTT than healthy controls (P = 0.0054). Conclusions In addition to assessing gastric emptying, regional transit times can be measured using wireless motility capsule. The prolongation of CTT in gastroparetic patients indicates that dysmotility beyond the stomach in GP is present, and it could be contributing to symptom presentation. Aliment Pharmacol Ther 31, 313-322. C1 [Sarosiek, I.; Sarosiek, J.; McCallum, R. W.] Univ Kansas, Med Ctr, Ctr Gastrointestinal Nerve & Muscle Funct & GI Mo, Kansas City, KS 66103 USA. [Selover, K. H.; Semler, J. R.] SmartPill Corp, Buffalo, NY USA. [Katz, L. A.] SUNY Buffalo, Dept ofMedicine, Sch Med, Buffalo, NY 14260 USA. [Wilding, G. E.] SUNY Buffalo, Dept Biostat, Buffalo, NY 14260 USA. [Lackner, J. M.] SUNY Buffalo, Behav Med Clin, Dept Gastroenterol Hepatol & Nutr, Sch Med, Buffalo, NY 14260 USA. [Sitrin, M. D.] SUNY Buffalo, Western New York VA Med Ctr, Div Gastroenterol Hepatol & Nutr, Dept Med, Buffalo, NY 14260 USA. [Kuo, B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Chey, W. D.; Hasler, W. L.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Koch, K. L.] Wake Forest Univ, Gastroenterol Sect, Baptist Med Ctr, Winston Salem, NC 27109 USA. [Parkman, H. P.] Temple Univ, Gastroenterol Sect, Dept Med, Sch Med, Philadelphia, PA 19122 USA. RP Sarosiek, I (reprint author), Texas Tech Univ, HSC, Paul Foster Sch Med, 4800 Albertson Ave, El Paso, TX 79905 USA. EM Irene.sarosiek@ttuhsc.edu FU SmartPill Corporation, Buffalo, New York; NYSTAR [C020118]; NIH [DK069614] FX Disclosure of personal interests: Drs I and J Sarosiek and Dr M Sitrin did not receive funding support from The SmartPill Corporation. Drs Chey, Hasler, Kuo, Lackner, McCallum, Parkman, Koch and Katz serve as speakers, consultants, or advisory board members for The SmartPill Corporation and have received research funding from The SmartPill Corporation. Dr Wilding serves as a consultant to The SmartPill Corporation. Dr Semler and Ms Selover are employees of The SmartPill Corporation; Dr Semler owns stock in The SmartPill Corporation. Dr I Sarosiek authored the manuscript; all other listed authors provided insightful edits, feedback and approval of the final manuscript. Declaration of funding interests: The study was sponsored by The SmartPill Corporation, Buffalo, New York, manufacturers of the SmartPill GI Monitoring System, and partially supported by NYSTAR grant C020118 and NIH grant DK069614. NR 42 TC 50 Z9 51 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN 15 PY 2010 VL 31 IS 2 BP 313 EP 322 DI 10.1111/j.1365-2036.2009.04162.x PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 533ZH UT WOS:000272864600016 PM 19814743 ER PT J AU Hage, FG Agel, R Aljaroudi, WL Heo, J Pothineni, K Hansalia, S Lawson, D Dubovsky, E Iskandrian, AE AF Hage, Fadi G. Agel, Raed Aljaroudi, Wad L. Heo, Jaekyeong Pothineni, Koteswara Hansalia, Sachin Lawson, David Dubovsky, Eva Iskandrian, Ami E. TI Correlation Between Serum Cardiac Markers and Myocardial Infarct Size Quantified by Myocardial Perfusion Imaging in Patients With Hypertrophic Cardiomyopathy After Alcohol Septal Ablation SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID BRAIN NATRIURETIC PEPTIDE; PHOTON-EMISSION-TOMOGRAPHY; TROPONIN-T; EJECTION FRACTION; CREATINE-KINASE; TC-99M-SESTAMIBI; REPERFUSION; EXPRESSION; BIOMARKERS; SERIAL AB Myocardial infarct (MI) size is a well-established prognostic marker but the association of serum markers with MI size, as measured by myocardial perfusion imaging (MPI), has not been well studied in patients with hypertrophic cardiomyopathy (NC) after alcohol septal ablation (ASA). Creatine kinase (CK), CK-MB, troponin I, and brain natriuretic peptide were measured before and at multiple points after ASA in patients with HC and were correlated with MI size measured by MPI. MPI at rest was performed in 54 patients with HC at a median of 2 days after ASA. CK, CK-MB, and troponin I increased after ASA to peak levels at 12 hours and their cumulative levels (area under the curve) showed significant correlation with size of MI by MPI (r = 0.544, 0.408, and 0.477, p <0.001, 0.003, and 0.001, respectively). The best marker was level of CK at 12 hours (r = 0.609, p <0.0001) after ASA. Brain natriuretic peptide level did not change significantly after ASA (p = 1.0) and only weakly correlated with MI size by MPI (r = 0.130, p = 0.007). In conclusion, CK, CK-MB, and troponin I measured at 12 hours, at peak, and as the area under the curve correlated well with infarct size, but CK level at 12 hours was the best marker. CK continues to be a useful marker of MI size despite the introduction of newer, more specific markers, especially when infarct onset is known with certainty as in patients with HC undergoing ASA. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:261-266) C1 [Hage, Fadi G.; Agel, Raed; Aljaroudi, Wad L.; Heo, Jaekyeong; Pothineni, Koteswara; Hansalia, Sachin; Lawson, David; Dubovsky, Eva; Iskandrian, Ami E.] Univ Alabama, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.; Agel, Raed] Birmingham Vet Affairs Med Ctr, Div Cardiol, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama, Div Cardiovasc Dis, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 25 TC 7 Z9 8 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 JAN 15 PY 2010 VL 105 IS 2 BP 261 EP 266 DI 10.1016/j.amjcard.2009.08.680 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602JW UT WOS:000278136400023 PM 20102929 ER PT J AU Kesavan, Y Giovannucci, E Fuchs, CS Michaud, DS AF Kesavan, Yamini Giovannucci, Edward Fuchs, Charles S. Michaud, Dominique S. TI A Prospective Study of Magnesium and Iron Intake and Pancreatic Cancer in Men SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; diet; iron, dietary; magnesium; pancreatic neoplasms ID C-REACTIVE PROTEIN; FOOD FREQUENCY QUESTIONNAIRE; MALE HEALTH-PROFESSIONALS; TOTAL-ENERGY-INTAKE; DRINKING-WATER; DIETARY MAGNESIUM; INSULIN-RESISTANCE; DIABETES-MELLITUS; COLORECTAL-CANCER; OXIDATIVE STRESS AB Many studies have investigated the relation between magnesium and iron intake and diabetes and, separately, between diabetes and pancreatic cancer. However, no known study has examined the direct association of magnesium and iron intake with pancreatic cancer risk. The authors obtained magnesium and iron intake data using food frequency questionnaires from the US male Health Professionals Follow-up Study, which began in 1986. During 851,476 person-years and 20 years of follow-up, 300 pancreatic cancer cases were documented. Cox proportional hazards models were used to estimate relative risks, adjusting for age, smoking, and body mass index. No associations were observed between magnesium or iron intake and pancreatic cancer (highest vs. lowest quintile: relative risk (RR) = 0.94, 95% confidence interval (CI): 0.66, 1.32 and RR = 0.93, 95% CI: 0.65, 1.34, respectively). Similarly, iron or magnesium supplement use was not related to pancreatic cancer. A statistically significant inverse relation was noted between magnesium and pancreatic cancer for subjects with a body mass index of >= 25 kg/m(2) (RR = 0.67, 95% CI: 0.46, 0.99; P-trend = 0.04). Although, overall, no relation between magnesium or iron intake and pancreatic cancer was observed in this cohort of men, an inverse association with magnesium was suggested among overweight individuals, which should be examined in other studies. C1 [Michaud, Dominique S.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. [Kesavan, Yamini; Giovannucci, Edward; Michaud, Dominique S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Giovannucci, Edward; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Michaud, DS (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM d.michaud@imperial.ac.uk RI Michaud, Dominique/I-5231-2014 FU National Cancer Institute; National Institutes of Health, Bethesda, Maryland [CA124908] FX This study was supported by grants from the National Cancer Institute, National Institutes of Health, Bethesda, Maryland ( grant CA124908). NR 55 TC 11 Z9 11 U1 0 U2 2 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 JAN 15 PY 2010 VL 171 IS 2 BP 233 EP 241 DI 10.1093/aje/kwp373 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 539AD UT WOS:000273224700011 PM 20022893 ER PT J AU Chen, GD Alberts, CJ Rodriguez, W Toner, M AF Chen, Grace D. Alberts, Catharina J. Rodriguez, William Toner, Mehmet TI Concentration and Purification of Human Immunodeficiency Virus Type 1 Virions by Microfluidic Separation of Superparamagnetic Nanoparticles SO ANALYTICAL CHEMISTRY LA English DT Article ID RESOURCE-LIMITED SETTINGS; HIV-1 VIRAL LOAD; MAGNETIC NANOPARTICLES; CELL-SEPARATION; ON-CHIP; SAMPLES; CAPTURE; SYSTEMS; MIXER; MICROCHANNELS AB The low concentration and complex sample matrix of many clinical and environmental viral samples presents a significant challenge in the development of low cost, point-of-care viral assays. To address this problem, we investigated the use of a microfluidic passive magnetic separator combined with on-chip mixer to both purify and concentrate whole-particle human immunodeficiency virus type 1 (HIV-1) virions. Virus-containing plasma samples are first mixed to allow specific binding of the viral particles with antibody-conjugated superparamagnetic nanoparticles, and several passive mixer geometries were assessed for their mixing efficiencies. The virus-nanoparticle complexes are then separated from the plasma in a novel magnetic separation chamber, where packed micrometer-sized ferromagnetic particles serve as high magnetic gradient concentrators for an externally applied magnetic field. Thereafter, a viral lysis buffer was flowed through the chip and the released HIV proteins were assayed off-chip. Viral protein extraction efficiencies of 62% and 45% were achieved at 10 and 30 mu L/min throughputs, respectively. More importantly, an 80-fold concentration was observed for an initial sample volume of 1 mL and a 44-fold concentration for an initial sample volume of 0.5 mL. The system is broadly applicable to microscale sample preparation of any viral sample and can be used for nucleic acid extraction as well as 40-80-fold enrichment of target viruses. C1 [Chen, Grace D.; Alberts, Catharina J.; Toner, Mehmet] Massachusetts Gen Hosp, BioMEMS Resource Ctr, Charlestown, MA 02129 USA. [Rodriguez, William] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. RP Rodriguez, W (reprint author), Daktari Diagnost Inc, Arlington, MA 02476 USA. EM wrodriguez@daktaridx.com; mtoner@hms.harvard.edu FU Center for Integration of Medicine and Innovative Technology [09-441]; National Institute of Biomedical Imaging and Bioengineering [P41 EB002503] FX We thank Mr. Octavio Hurtado for technical support with microfabrication procedures and Ms. Alicja Trocha for assistance with the biosafety of HIV handling. We thank Partners AIDS Research Center for provision of HIV samples and use of tissue Culture facilities. This work was supported by the Center for Integration of Medicine and Innovative Technology under Grant 09-441 and the National Institute of Biomedical Imaging and Bioengineering under Grant P41 EB002503 (BioMEMS Resource Center). NR 39 TC 50 Z9 52 U1 4 U2 56 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JAN 15 PY 2010 VL 82 IS 2 BP 723 EP 728 DI 10.1021/ac9024522 PG 6 WC Chemistry, Analytical SC Chemistry GA 542HR UT WOS:000273484200039 PM 19954210 ER PT J AU Chou, RC Dinarello, CA Ferry, JA Dal Cin, P AF Chou, Richard C. Dinarello, Charles A. Ferry, Judith A. Dal Cin, Paola TI A 36-Year-Old Woman With Recurrent High-Grade Fevers, Hypotension, and Hypertriglyceridemia SO ARTHRITIS CARE & RESEARCH LA English DT Article ID MACROPHAGE-ACTIVATION SYNDROME; JUVENILE IDIOPATHIC ARTHRITIS; APOPTOSIS-INDUCING LIGAND; ONSET STILLS-DISEASE; MYELODYSPLASTIC SYNDROMES; SCHNITZLER-SYNDROME; CYCLOSPORINE-A; BONE-MARROW; EXPRESSION; ANAKINRA C1 [Ferry, Judith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Dinarello, Charles A.] Univ Colorado Sch Med Denver, Aurora, CO USA. [Dal Cin, Paola] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Chou, RC (reprint author), Dartmouth Hitchcock Med Ctr, Rheumatol Sect, Dept Med, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM Richard.C.Chou@hitchcock.org NR 36 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JAN 15 PY 2010 VL 62 IS 1 BP 128 EP 136 DI 10.1002/acr.20024 PG 9 WC Rheumatology SC Rheumatology GA 639MI UT WOS:000280978500018 PM 20191502 ER PT J AU Shinozaki, S Inoue, Y Yang, W Fukaya, M Carter, EA Ming-Yu, Y Fischman, A Tompkins, R Kaneki, M AF Shinozaki, Shohei Inoue, Yoko Yang, Wen Fukaya, Makiko Carter, Edward A. Ming-Yu, Young Fischman, Alan Tompkins, Ronald Kaneki, Masao TI Farnesyltransferase inhibitor improved survival following endotoxin challenge in mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Farnesylation; Statin; HMG-CoA reductase; Lipopolysaccharide; Caspase-3; c-Jun NH(2)-terminal kinase; Liver; Spleen ID NITRIC-OXIDE SYNTHASE; TUMOR-NECROSIS-FACTOR; ATHEROSCLEROSIS DEVELOPMENT; REDUCTASE INHIBITORS; STATIN TREATMENT; SYRIAN-HAMSTERS; CELL APOPTOSIS; SEVERE SEPSIS; LIVER-DAMAGE; SEPTIC SHOCK AB Endotoxemia plays an important role in the pathogenesis of sepsis and is accompanied by dysregulated apoptosis of immune and non-immune cells. Treatment with statins reduces mortality in rodent models of sepsis and endotoxemia. Inhibition of protein isoprenylation, including farnesylation, has been proposed as a mechanism to mediate the lipid-lowering-independent effects of statins. Nonetheless, the effects of the inhibition of isoprenylation have not yet been studied. To investigate the role of farnesylation, we evaluated the effects of farnesyltransferase inhibitor and statin on survival following lipopolysaccharide (LPS) challenge in mice. Both simvastatin (2 mg/kg BW) and FTI-277 (20 mg/kg BW) treatment improved survival by twofold after LPS injection, as compared with vehicle alone (p < 0.01). LPS-induced cleavage (activation) of caspase-3, an indicator of apoptotic change, and increased protein expression of proapoptotic molecules, Bax and Bim, and activation of c-Jun NH(2)-terminal kinase (JNK/SAPK) in the liver and spleen were attenuated by both simvastatin and FTI-277. These results demonstrate that farnesyltransferase inhibitor as well as statin significantly reduced LPS-induced mortality in mice. Our findings also suggest that inhibition of protein farnesylation may contribute to the lipid-lowering-independent protective effects of statins in endotoxemia, and that protein farnesylation may play a role in LPS-induced stress response, including JNK/SAPK activation, and apoptotic change. Our data argue that farnesyltransferase may be a potential molecular target for treating patients with endotoxemia. (c) 2009 Elsevier Inc. All rights reserved. C1 [Shinozaki, Shohei; Yang, Wen; Fukaya, Makiko; Carter, Edward A.; Ming-Yu, Young; Fischman, Alan; Tompkins, Ronald; Kaneki, Masao] Shriners Hosp Children, Boston, MA 02114 USA. [Shinozaki, Shohei; Inoue, Yoko; Yang, Wen; Fukaya, Makiko; Kaneki, Masao] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Carter, Edward A.; Ming-Yu, Young; Tompkins, Ronald] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Burns & Trauma, Boston, MA 02114 USA. [Fischman, Alan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Nucl Med, Boston, MA 02114 USA. RP Kaneki, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, 149 13th St, Charlestown, MA 02129 USA. EM mkaneki@partners.org FU National Institutes of Health [GM21700, DK58127]; Shriners Hospitals for Children FX This work was supported by grants from the National Institutes of Health, GM21700 (R. Tompkins) and DK58127 (M. Kaneki), and the Shriners Hospitals for Children (M. Kaneki, R. Tompkins, A. Fischman, Y. Ming-Yu). NR 51 TC 19 Z9 20 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 15 PY 2010 VL 391 IS 3 BP 1459 EP 1464 DI 10.1016/j.bbrc.2009.12.094 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 550AL UT WOS:000274097800030 PM 20034462 ER PT J AU Nahas, Z Anderson, BS Borckardt, J Arana, AB George, MS Reeves, ST Takacs, I AF Nahas, Ziad Anderson, Berry S. Borckardt, Jeff Arana, Ashley B. George, Mark S. Reeves, Scott T. Takacs, Istvan TI Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anterior poles; brain stimulation; cingulate; depression; epidural cortical stimulation; frontal lobes; medial prefrontal cortex ID VAGUS NERVE-STIMULATION; DEEP BRAIN-STIMULATION; TRANSCRANIAL MAGNETIC STIMULATION; MOTOR CORTEX STIMULATION; MAJOR DEPRESSION; NEUROPATHIC PAIN; RATING-SCALE; OUTCOMES; BURDEN; VNS AB Background: Treatment-resistant depression presents a serious challenge to both patients and clinicians. The anterior and midlateral prefrontal cortices play complementary roles in integrating emotional and cognitive experiences and in modulating subcortical regions. Both regions offer a distinct opportunity for targeted antidepressant treatments. We chose to pilot the safety and therapeutic benefits of chronic and intermittent epidural prefrontal cortical stimulation (EpCS) in patients with treatment-resistant depression. Methods: We enrolled five adults with an average of 5.8 failed antidepressant treatments in their current depressive episode. All subjects underwent comprehensive clinical assessments, detailed neuropsychological testing, and presurgical magnetic resonance imaging. Four cortical stimulation paddle leads were stereotactically placed bilaterally over the anterior frontal poles and midlateral prefrontal cortex. We also acquired a postsurgical computed tomography scan and repeatedly assessed clinical outcomes over time of EpCS as an adjunctive treatment to constant medications. Results: All patients tolerated the therapy. At 7-month follow-up, the average improvement from preimplant baseline on the Hamilton Rating Scale for Depression and the Inventory of Depressive Symptoms-Self-Report were 54.9% (+/- 37.7) and 60.1% (+/- 34.1), respectively. Three implanted subjects reached remission. One patient's left hemisphere leads were explanted 12 weeks postsurgery because of a scalp infection. Conclusions: Bilateral EpCS over anterior and mid lateral frontal cortex is a promising new technology for treatment-resistant depression. Future double-blind studies are warranted. C1 [Nahas, Ziad; Anderson, Berry S.; Borckardt, Jeff; Arana, Ashley B.; George, Mark S.] Med Univ S Carolina, Dept Psychiat, Mood Disorders Program & Brain Stimulat Lab, Charleston, SC 29425 USA. [Nahas, Ziad; George, Mark S.; Takacs, Istvan] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Borckardt, Jeff; Reeves, Scott T.] Med Univ S Carolina, Dept Anesthesia & Perioperat Med, Charleston, SC 29425 USA. [George, Mark S.] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [Takacs, Istvan] Med Univ S Carolina, Dept Neurosurg, Charleston, SC 29425 USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Nahas, Z (reprint author), Inst Psychiat, 67 President St, Charleston, SC 29425 USA. EM nahasz@musc.edu FU National Alliance of Research for Depression and Schizophrenia (NARSAD) Independent Investigator Award; Mood Disorders Program; The Brain Stimulation Laboratory; General Clinical Research Center; Center for Advanced Imaging Research at the Medical University of South Carolina; Medtronic, Inc.; The National Institute of Mental Health (NIMH); National Alliance Research for Schizophrenia and Depression; Hope for Depression Research, Neuronetics, Inc.; Cyberonics, Inc.; GlaxoSmithKline; Jazz Pharmaceuticals; National Institute on Drug Abuse; National Institute of Neurological Disorders and Stroke; Ralph H. Johnson VA Medical Center FX This study was funded primarily by a National Alliance of Research for Depression and Schizophrenia (NARSAD) Independent Investigator Award to ZN. It was also made possible with general funds from the Mood Disorders Program, The Brain Stimulation Laboratory, the General Clinical Research Center, the Center for Advanced Imaging Research at the Medical University of South Carolina, Medtronic, Inc. (Minneapolis, MN donated the devices, but was otherwise not involved in the study particularly data acquisition, analysis, or drafting the article. We thank Mark Rise (Medtronic, Inc.) for technical assistance ill stimulation setups and Sarah Coker (now a postgraduate year I psychiatry resident at Medical University of South Carolina [MUSC]) for assistance in, The accuracy, of lead placement analysis I. S.; Dr. Nahas reports having received consulting fees from Neuronetics, Inc. and Cyberonics, Inc.; research funding from the The National Institute of Mental Health (NIMH), National Alliance Research for Schizophrenia and Depression, Hope for Depression Research, Neuronetics, Inc., Cyberonics, Inc., Medtronic, Inc. (in the form of device donations for this study), Brainsway, and Integra. Dr. George reports research funding from GlaxoSmithKline, Jazz Pharmaceuticals, NIMH, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke. and the Ralph H. Johnson VA Medical Center. Dr. George reported consulting for , Bristol-Meyers-Squibb, DarPharma, , Jazz Pharmaceuticals, Parke Davis, Aspect Medical, Brainsway (unpaid) , Cephos (unpaid), Cyberonics, Inc., Dantex, MediPhysics/Amersham, Neuronetics, Inc. (unpaid), and Neuropace. Dr. George also reported that The Medical University of South Carolina has filed eight patents or invention disclosures under his name regarding brain imaging and brain stimulation. Dr, Borckardt receives The National Institute for Neurological Disorders and Stroke and The National Institute of Nursing Research at the National Institutes Health, Cyberonics, Inc., and the Neurosciences Institute at MUSC. Dr. Borckardt is a consultant for Neuropace. Dr. Reeves, Dr. Tackacs, Mr. Anderson, and Ms. Arana reported no biomedical financial interests or potential conflicts of interest. NR 59 TC 42 Z9 43 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2010 VL 67 IS 2 BP 101 EP 109 DI 10.1016/j.biopsych.2009.08.021 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 538RN UT WOS:000273201800003 PM 19819427 ER PT J AU Kenney, LB Nancarrow, CM Najita, J Vrooman, LM Rothwell, M Recklitis, C Li, FP Diller, L AF Kenney, Lisa B. Nancarrow, Cheryl Medeiros Najita, Julie Vrooman, Lynda M. Rothwell, Monica Recklitis, Christopher Li, Frederick P. Diller, Lisa TI Health Status of the Oldest Adult Survivors of Cancer During Childhood SO CANCER LA English DT Article DE childhood cancer survivor; health status; late effects; premature mortality ID LONG-TERM SURVIVORS; TUMOR STUDY-GROUP; 5-YEAR SURVIVORS; WILMS-TUMOR; HODGKINS-DISEASE; ADOLESCENT CANCER; LATE MORTALITY; RISK; NEOPLASMS; RADIOTHERAPY AB BACKGROUND: Young adult survivors of childhood cancer have an increased risk for treatment-related morbidity and mortality. In this study, the authors assessed how treatment for childhood cancer affects older-adult health and health practices. METHODS: One hundred seven adults treated for childhood cancer between 1947 and 1968, known to have survived past age 50 years, were identified from a single-institution cohort established in 1975. Updated vital status on eligible cases was obtained from public records. Survivors and a control group of their age-matched siblings and cousins completed a mailed survey to assess physical and social function, healthcare practices, and the prevalence of common adult illnesses. RESULTS: Of the 107 survivors known to be alive at age 50 years, 16 were deceased at follow-up; 7 deaths could be associated with prior treatment (second malignancy in radiation field [3], small bowel obstruction after abdominal radiation [2], and cardiac disease after chest irradiation [2]). The 55 survivors (median age, 56 years; range, 51-71 years), and 32 family controls (median age, 58 years; range, 48-70 years), reported similar health practices, health-related quality of life, and social function. However, survivors reported more frequent visits to healthcare providers (P < .05), more physical impairments (P < .05), fatigue (P = .02), hypertension (P = .001), and coronary artery disease (P = .01). An increased risk of hypertension was associated with nephrectomy during childhood (odds ratio, 18.9; 95% confidence interval, 3.0-118.8). CONCLUSIONS: The oldest adult survivors of childhood cancer continue to be at risk for treatment-related complications that potentially decrease their life expectancy and compromise their quality of life. Cancer 2010;116:497-505. (C) 2010 American Cancer Society. C1 [Kenney, Lisa B.; Nancarrow, Cheryl Medeiros; Vrooman, Lynda M.; Rothwell, Monica; Recklitis, Christopher; Diller, Lisa] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kenney, Lisa B.; Vrooman, Lynda M.; Recklitis, Christopher; Diller, Lisa] Childrens Hosp, Dept Hematol Oncol, Boston, MA 02115 USA. [Kenney, Lisa B.; Vrooman, Lynda M.; Recklitis, Christopher; Diller, Lisa] Harvard Univ, Sch Med, Boston, MA USA. [Najita, Julie] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Najita, Julie] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Li, Frederick P.] Dana Farber Canc Inst, Dept Populat Sci, Boston, MA 02115 USA. RP Kenney, LB (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, D321,44 Binney St, Boston, MA 02115 USA. EM Lisa_Kenney@DFCI.harvard.edu FU David B. Perini, Jr Quality of Life Clinic at the Dana-Farber Cancer Institute; Carl J. Herzog Foundation FX Supported by the David B. Perini, Jr Quality of Life Clinic at the Dana-Farber Cancer Institute and the Carl J. Herzog Foundation. NR 42 TC 10 Z9 10 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 JAN 15 PY 2010 VL 116 IS 2 BP 497 EP 505 DI 10.1002/cncr.24718 PG 9 WC Oncology SC Oncology GA 546QT UT WOS:000273826000033 PM 19908254 ER PT J AU Wang, WY Niendorf, KB Patel, D Blackford, A Marroni, F Sober, AJ Parmigiani, G Tsao, H AF Wang, Wenyi Niendorf, Kristin B. Patel, Devanshi Blackford, Amanda Marroni, Fabio Sober, Arthur J. Parmigiani, Giovanni Tsao, Hensin TI Estimating CDKN2A Carrier Probability and Personalizing Cancer Risk Assessments in Hereditary Melanoma Using MelaPRO SO CANCER RESEARCH LA English DT Article ID GERMLINE MUTATIONS; PANCREATIC-CANCER; FAMILY-HISTORY; BREAST-CANCER; BRCA1; SUSCEPTIBILITY; STATISTICS; OVARIAN; MODEL AB Personalized cancer risk assessment remains an essential imperative in postgenomic cancer medicine. In hereditary melanoma, germline CDKN2A mutations have been reproducibly identified in melanoma-prone kindreds worldwide. However, genetic risk counseling for hereditary melanoma remains clinically challenging. To address this challenge, we developed and validated MelaPRO, an algorithm that provides germline CDKN2A mutation probabilities and melanoma risk to individuals from melanoma-prone families. MelaPRO builds on comprehensive genetic information, and uses Mendelian modeling to provide fine resolution and high accuracy. In an independent validation of 195 individuals from 167 families, MelaPRO exhibited good discrimination with a concordance index (C) of 0.86 [95% confidence intervals (95% CI), 0.75-0.97] and good calibration, with no significant difference between observed and predicted carriers (26; 95% CI, 20-35, as compared with 22 observed). In cross-validation, MelaPRO outperformed the existing predictive model MELPREDICT (C, 0.82; 95% CI, 0.61-0.93), with a difference of 0.05 (95% CI, 0.007-0.17). MelaPRO is a clinically accessible tool that can effectively provide personalized risk counseling for all members of hereditary melanoma families. Cancer Res; 70(2); 552-9. (C)2010 AACR. C1 [Sober, Arthur J.; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wang, Wenyi] Stanford Univ, Dept Biochem, Stanford Genome Technol Ctr, Stanford, CA 94305 USA. [Wang, Wenyi] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Niendorf, Kristin B.] Univ Minnesota, Minneapolis, MN USA. [Patel, Devanshi; Tsao, Hensin] Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Blackford, Amanda] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Marroni, Fabio] Inst Appl Genom, Udine, Italy. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 622 Bartlett Hall,48 Blossom St, Boston, MA 02114 USA. EM htsao@partners.org OI Marroni, Fabio/0000-0002-1556-5907 FU American Cancer Society [RSG MGO-112970]; National Cancer Institute [P50 CA-93683, R01CA105090-01A1] FX Grant Support; American Cancer Society grant RSG MGO-112970 (H. Tsao and G. Parmigiani); National Cancer Institute grant nos. P50 CA-93683 (H. Tsao) and R01CA105090-01A1 (G. Parmigiani); and the generous philanthropic donors to the Massachusetts General Hospital. NR 22 TC 13 Z9 14 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 JAN 15 PY 2010 VL 70 IS 2 BP 552 EP 559 DI 10.1158/0008-5472.CAN-09-2653 PG 8 WC Oncology SC Oncology GA 607FW UT WOS:000278485500015 PM 20068151 ER PT J AU Davis, IJ McFadden, AW Zhang, YX Coxon, A Burgess, TL Wagner, AJ Fisher, DE AF Davis, Ian J. McFadden, Andrew W. Zhang, Yixiang Coxon, Angela Burgess, Teresa L. Wagner, Andrew J. Fisher, David E. TI Identification of the Receptor Tyrosine Kinase c-Met and Its Ligand, Hepatocyte Growth Factor, as Therapeutic Targets in Clear Cell Sarcoma SO CANCER RESEARCH LA English DT Article ID MALIGNANT-MELANOMA; SOFT PARTS; SCATTER FACTOR; LUNG-CANCER; MUTATIONS; APONEUROSES; TENDONS; TRANSLOCATION; INHIBITION; TUMORS AB Clear cell sarcoma (CCS), a childhood tumor of the tendons and aponeuroses, is uniformly fatal once it has metastasized because of its profound therapeutic resistance. CCS is characterized by production of a chimeric transcription factor, EWS-ATF1, which is formed as the result of a disease-specific chromosomal translocation. EWS-ATF1 activates the melanocyte transcription factor MITF, which in turn activates transcription of c-Met, an oncogenic receptor tyrosine kinase recently shown to be activated in CCS. Based on this connection, we hypothesized that c-Met inhibition may offer a strategy to treat CCS, as an indirect tactic to defeat a transforming pathway downstream of EWS-ATF1. Here, we show that primary CCS and CCS-derived cell lines express c-Met, which is activated in an autocrine fashion by its ligand hepatocyte growth factor (HGF)/scatter factor in some CCS cell lines. c-Met expression is critical for CCS invasion, chemotaxis, and survival. Blocking c-Met activity with a small-molecule inhibitor (SU11274) or a neutralizing antibody to its ligand HGF (AMG 102) significantly reduced CCS cell growth in culture. Similarly, AMG 102 significantly suppressed in vivo tumor growth in an autocrine xenograft model of CCS. Collectively, these findings suggest the HGF: c-Met signaling axis as a candidate therapeutic target to improve clinical management of CCS. Cancer Res; 70(2); 639-45. (C)2010 AACR. C1 [Davis, Ian J.; McFadden, Andrew W.] Univ N Carolina, N Carolina Childrens Hosp, Lineberger Comprehens Canc Ctr, Dept Pediat, Chapel Hill, NC 27599 USA. [Davis, Ian J.; McFadden, Andrew W.] Univ N Carolina, N Carolina Childrens Hosp, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Coxon, Angela; Burgess, Teresa L.] Amgen Inc, Dept Oncol Res, Thousand Oaks, CA 91320 USA. [Davis, Ian J.; Fisher, David E.] Dana Farber Canc Inst, Ludwig Ctr Canc Res, Dept Pediat Oncol, Boston, MA 02115 USA. [Zhang, Yixiang; Wagner, Andrew J.] Dana Farber Canc Inst, Ludwig Ctr Canc Res, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Davis, Ian J.; Fisher, David E.] Childrens Hosp Boston, Dept Med, Div Hematol Oncol, Boston, MA USA. [Wagner, Andrew J.; Fisher, David E.] Harvard Univ, Sch Med, Boston, MA USA. RP Davis, IJ (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, C-B 7295, Chapel Hill, NC 27599 USA. EM ian_davis@med.unc.edu; dfisher3@partners.org FU NIH [K08CA100400, R01CA102309]; Doris Duke Medical Research Foundation; Adelson Medical Research Foundation; Melanoma Research Alliance; V Foundation for Cancer Research; Rita Allen Foundation; Corn-Hammond Fund for Pediatric Oncology FX Grant Support; NIH grant K08CA100400 (I.J. Davis), R01CA102309 (D. E. Fisher), and the Doris Duke Medical Research Foundation (D. E. Fisher). D. E. Fisher is Distinguished Clinical Investigator of the Doris Duke Medical Research Foundation and also gratefully acknowledges support from the NIH, the Adelson Medical Research Foundation, and the Melanoma Research Alliance. I.J. Davis gratefully acknowledges support from the V Foundation for Cancer Research, the Rita Allen Foundation, and the Corn-Hammond Fund for Pediatric Oncology. NR 39 TC 47 Z9 52 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 JAN 15 PY 2010 VL 70 IS 2 BP 639 EP 645 DI 10.1158/0008-5472.CAN-09-1121 PG 7 WC Oncology SC Oncology GA 607FW UT WOS:000278485500024 PM 20068147 ER PT J AU Schatton, T Schutte, U Frank, NY Zhan, QA Hoerning, A Robles, SC Zhou, J Hodi, FS Spagnoli, GC Murphy, GF Frank, MH AF Schatton, Tobias Schuette, Ute Frank, Natasha Y. Zhan, Qian Hoerning, Andre Robles, Susanne C. Zhou, Jun Hodi, F. Stephen Spagnoli, Giulio C. Murphy, George F. Frank, Markus H. TI Modulation of T-Cell Activation by Malignant Melanoma Initiating Cells SO CANCER RESEARCH LA English DT Article ID CANCER STEM-CELLS; ACUTE MYELOID-LEUKEMIA; CLASS-I EXPRESSION; METASTATIC MELANOMA; ANTITUMOR IMMUNITY; B-CELLS; IDENTIFICATION; IMMUNOTHERAPY; ANTIGEN; CHEMORESISTANCE AB Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. Thus, only a restricted minority of tumorigenic malignant cells may possess the phenotypic and functional characteristics needed to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis. Tumorigenic ABCB5(+) malignant melanoma initiating cells (MMICs) possessed the capacity to preferentially inhibit IL-2-dependent T-cell activation and to support, in a B7.2-dependent manner, induction of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Compared with melanoma bulk cell populations, ABCB5(+) MMICs displayed lower levels of MHC class I, aberrant positivity for MHC class II, and lower expression levels of the melanoma-associated antigens MART-1, ML-IAP, NY-ESO-1, and MAGE-A. Additionally, these tumorigenic ABCB5(+) subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1, both in established melanoma xenografts and in clinical tumor specimens. In immune activation assays, MMICs inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5(-)melanoma cell populations. Moreover, coculture with ABCB5(+) MMICs increased the abundance of Tregs, in a B7.2 signaling-dependent manner, along with IL-10 production by mitogen-activated PBMCs. Consistent with these findings, MMICs also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T-cell modulatory functions of ABCB5(+) melanoma subpopulations and suggest specific roles for these MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance. Cancer Res; 70(2); 697-708. (C)2010 AACR. C1 [Schatton, Tobias; Schuette, Ute; Hoerning, Andre; Robles, Susanne C.; Frank, Markus H.] Childrens Hosp Boston, Transplantat Res Ctr, Boston, MA 02115 USA. [Frank, Natasha Y.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Zhan, Qian; Murphy, George F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Frank, Markus H.] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Zhou, Jun; Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Frank, Natasha Y.] VA Boston Healthcare Syst, Dept Med, W Roxbury, MA USA. [Spagnoli, Giulio C.] Univ Basel Hosp, Dept Biomed, Inst Surg Res, CH-4031 Basel, Switzerland. RP Frank, MH (reprint author), Childrens Hosp Boston, Transplantat Res Ctr, 300 Longwood Ave, Boston, MA 02115 USA. EM markus.frank@childrens.harvard.edu RI Frank, Markus/O-1625-2014 OI Frank, Markus/0000-0002-1312-0488 FU NIH/National Cancer Institute [1RO1CA113796-01A1, 1R01CA138231-01, 2P50CA093683-06A20006]; American Heart Association Founders Affiliate FX Grant Support; NIH/National Cancer Institute grants 1RO1CA113796-01A1 and 1R01CA138231-01 (M. H. Frank) and grant 2P50CA093683-06A20006 (M. H. Frank and G. F. Murphy). T. Schatton is the recipient of a Postdoctoral Fellowship Award from the American Heart Association Founders Affiliate. NR 50 TC 90 Z9 96 U1 0 U2 12 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 JAN 15 PY 2010 VL 70 IS 2 BP 697 EP 708 DI 10.1158/0008-5472.CAN-09-1592 PG 12 WC Oncology SC Oncology GA 607FW UT WOS:000278485500030 PM 20068175 ER PT J AU Pantuck, AJ An, JB Liu, HR Rettig, MB AF Pantuck, Allan J. An, Jiabin Liu, Huiren Rettig, Matthew B. TI NF-kappa-Dependent Plasticity of the Epithelial to Mesenchymal Transition Induced by Von Hippel-Lindau Inactivation in Renal Cell Carcinomas SO CANCER RESEARCH LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; TUMOR-SUPPRESSOR GENE; E-CADHERIN; B ACTIVATION; CANCER; VHL; TRANSCRIPTION; EXPRESSION; PROTEIN; HIF-1-ALPHA AB The critical downstream signaling consequences contributing to renal cancer as a result of loss of the tumor suppressor gene von Hippel-Lindau (VHL) have yet to be fully elucidated. Here, we report that VHL loss results in an epithelial to mesenchymal transition (EMT). In studies of paired isogenic cell lines, VHL silencing increased the levels of N-cadherin and vimentin and reduced the levels of E-cadherin relative to the parental VHL(+) cell line, which displayed the opposite profile. VHL(+) cells grew as clusters of cuboidal and rhomboid cells, whereas VHL-silenced cells took on an elongated, fibroblastoid morphology associated with a more highly invasive character in Matrigel chamber assays. Based on earlier evidence that VHL loss can activate NF-kappa B, a known mediator of EMT, we tested whether NF-kappa B contributed to VHL-mediated effects on EMT. On pharmacologic or molecular inhibition of NF-kappa B, VHL-silenced cells regained expression of E-cadherin, lost expression of N-cadherin, and reversed their highly invasive phenotype. Introducing a pVHL-resistant hypoxia-inducible factor 1 alpha (HIF1 alpha) mutant (HIF alpha(M)) into VHL(+) cells heightened NF-kappa B activity, phenocopying EMT effects produced by VHL silencing. Conversely, inhibiting the heightened NF-kappa B activity in this setting reversed the EMT phenotype. Taken together, these results suggest that VHL loss induces an EMT that is largely dependent on HIF alpha-induced NF-kappa B. Our findings rationalize targeting the NF-kappa B pathway as a therapeutic strategy to treat renal tumors characterized by biallelic VHL inactivation. Cancer Res; 70(2); 752-61. (C)2010 AACR. C1 [Pantuck, Allan J.; Rettig, Matthew B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Rettig, Matthew B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [An, Jiabin; Liu, Huiren; Rettig, Matthew B.] Vet Affairs Greater Los Angeles Healthcare Syst W, Dept Med, Los Angeles, CA USA. RP Rettig, MB (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Box 951738, Los Angeles, CA 90095 USA. EM mrettig@mednet.ucla.edu FU Department of Veterans Affairs; Pom Wonderful FX Grant Support; Department of Veterans Affairs Merit Review Program (M. B. Rettig) and Pom Wonderful (A.J. Pantuck). NR 31 TC 42 Z9 46 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 JAN 15 PY 2010 VL 70 IS 2 BP 752 EP 761 DI 10.1158/0008-5472.CAN-09-2211 PG 10 WC Oncology SC Oncology GA 607FW UT WOS:000278485500035 PM 20068166 ER PT J AU Coetzee, GA Jia, L Frenkel, B Henderson, BE Tanay, A Haiman, CA Freedman, ML AF Coetzee, Gerhard A. Jia, Li Frenkel, Baruch Henderson, Brian E. Tanay, Amos Haiman, Christopher A. Freedman, Matthew L. TI A systematic approach to understand the functional consequences of non-protein coding risk regions SO CELL CYCLE LA English DT Article DE GWAS; cancer risk; SNP; functionality ID COLORECTAL-CANCER; HUMAN GENOME; PROMOTERS; RS6983267; ENHANCERS; VARIANTS; SEQ AB A primary goal of genetic association studies is to elucidate genes and novel biological mechanisms involved in disease. Recently, genome-wide association studies have identified many common genetic variants that are significantly associated with complex diseases such as cancer. In contrast to Mendelian disorders, a sizable fraction of the variants lies outside known protein-coding regions; therefore, understanding their biological consequences presents a major challenge in human genetics. Here we describe an integrated framework to allow nonprotein coding loci to be annotated with respect to regulatory functions. This will facilitate identification of target genes as well as prioritize variants for functional testing. C1 [Coetzee, Gerhard A.; Jia, Li; Frenkel, Baruch; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Tanay, Amos] Weizmann Inst Sci, IL-76100 Rehovot, Israel. [Freedman, Matthew L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Freedman, Matthew L.] Broad Inst, Cambridge, MA USA. RP Coetzee, GA (reprint author), Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. EM coetzee@usc.edu; freedman@broadinstitute.org FU NIH [R01 CA109147, R01 CA129435]; Prostate Cancer Foundation; Whittier Foundation; American Cancer Society Institutional [IRG-58-007-48]; Mayer Foundation; Snyder Medical Foundation; DanaFarber/Harvard Cancer Center Prostate Cancer SPORE; National Cancer Institute [5P50CA90381]; Israeli Science Foundation FX Work from the authors referred to in this paper was supported by the NIH R01 CA109147 (G. A. C.) and R01 CA129435 (M. L. F.), the Prostate Cancer Foundation (G. A. C.), the Whittier Foundation (G. A. C. and C. A. H.), the American Cancer Society Institutional Research Grant IRG-58-007-48 (L. J.), the Mayer Foundation (M. L. F.) the H. L. Snyder Medical Foundation (M. L. F.), the DanaFarber/Harvard Cancer Center Prostate Cancer SPORE (National Cancer Institute Grant No. 5P50CA90381), the Israeli Science Foundation (A. T.), the J. Harold and Edna L. LaBriola Chair in Genetic Orthopaedic Research (held by B. F.). M. L. F. is a Howard Hughes Medical Institute Physician- Scientist Early Career Awardee. NR 15 TC 8 Z9 8 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JAN 15 PY 2010 VL 9 IS 2 BP 256 EP 259 PG 4 WC Cell Biology SC Cell Biology GA 550PG UT WOS:000274139800021 PM 20023379 ER PT J AU Wang, N Tilly, JL AF Wang, Ning Tilly, Jonathan L. TI Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads SO CELL CYCLE LA English DT Article DE histone deacetylase; epigenetics; retinoic acid; Stra8; germ cell; oogenesis; spermatogenesis; meiosis; ovary; testis ID PREMATURE OVARIAN FAILURE; INHIBITOR TRICHOSTATIN-A; RETINOIC ACID; BONE-MARROW; MEIOSIS; MOUSE; MICE; OOGENESIS; RECEPTORS; PROTEIN AB The meiotic cell cycle is required for production of fertilization-competent gametes. Germ cell meiotic commitment requires expression of Stimulated by retinoic acid gene 8 (Stra8), which is transcriptionally activated by retinoic acid (RA). Meiotic suppression in embryonic male germ cells is believed to result from sex-specific differences in CYP26B1-catalyzed RA metabolism in the developing gonads. Here we show in mice that RA-induced Stra8 transcription is epigenetically controlled and requires a co-activator that binds proximal to the RA response elements (RAREs) in the Stra8 promoter. Embryonic male germ cells exposed in utero to the class I/II histone deacetylase (HDAC) inhibitor, trichostatin-A (TSA), show premature Stra8 activation and meiotic entry without altered Cyp26b1 expression. We also show that Stra8 expression is detectable and physiologically regulated in adult mouse ovaries. Further, oogenesis induction in adult females using TSA is associated with Stra8 activation, and these events are absent in mice deficient in the RA precursor vitamin A. Finally, all of the actions of TSA in premeiotic germ cells in vitro and in mouse ovaries in vivo can be reproduced with the small molecule HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA). Thus, the ability of RA to transcriptionally induce expression of the meiosis-commitment gene, Stra8, is epigenetically controlled and this process involves a novel co-activator that functions upstream of the RAREs. These events not only coordinate the sex-specific timing of meiotic entry during embryogenesis, but also contribute to the regulation of oogenesis in adult female mammals. C1 [Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Tilly, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, Boston, MA 02115 USA. EM jtilly@partners.org FU National Institute on Aging [R37-AG012279]; Rubin Shulsky Philanthropic Fund; Henry and Vivian Rosenberg Philanthropic Fund; Sea Breeze Foundation; Vincent Memorial Research Funds; Massachusetts General Hospital Fund FX We thank N.B. Hecht for MSY2 antibody; J. Dean for MATER antibody; D. C. Page for testes from adult wild-type and Stra8-null mice; J. Teixeira, K. Selesniemi and L. Prickett for technical assistance; and Y. Niikura for helpful discussions. This work was supported by National Institute on Aging MERIT Award R37-AG012279, the Rubin Shulsky Philanthropic Fund, the Henry and Vivian Rosenberg Philanthropic Fund, the Sea Breeze Foundation, and Vincent Memorial Research Funds. N. Wang is a recipient of a Massachusetts General Hospital Fund for Medical Discovery award. NR 39 TC 29 Z9 30 U1 0 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JAN 15 PY 2010 VL 9 IS 2 BP 339 EP 349 PG 11 WC Cell Biology SC Cell Biology GA 550PG UT WOS:000274139800030 PM 20009537 ER PT J AU Walensky, RP Kuritzkes, DR AF Walensky, Rochelle P. Kuritzkes, Daniel R. TI The Impact of The President's Emergency Plan for AIDS Relief (PEPfAR) beyond HIV and Why It Remains Essential SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; SURVIVAL; OUTCOMES; MOTHER; CARE AB Recent debate has addressed whether global health financing should prioritize interventions that maximize lives saved; focus on the young; and are most economically efficient (most cost-effective). In particular, some have argued that an expansion of the President's Emergency Plan for AIDS Relief (PEPfAR) is not the best use of international health funding, and that extending funding to treat diarrheal and respiratory disease could save more lives at substantially lower costs. We examine the methods of cost-effectiveness analysis and why their application, without context, may not be appropriate for priority setting in this fashion. We further address the substantial impact PEPfAR has achieved in general and more specifically toward improving maternal and child health and why continued PEPfAR investment remains essential. C1 [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.; Kuritzkes, Daniel R.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Walensky, Rochelle P.; Kuritzkes, Daniel R.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM rwalensky@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU NIAID NIH HHS [R01 AI058736] NR 34 TC 27 Z9 28 U1 0 U2 3 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 JAN 15 PY 2010 VL 50 IS 2 BP 272 EP 275 DI 10.1086/649214 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536UK UT WOS:000273069100018 PM 19947830 ER PT J AU Berin, I Engmann, LL Benadiva, CA Schmidt, DW Nulsen, JC Maier, DB AF Berin, Inna Engmann, Lawrence L. Benadiva, Claudio A. Schmidt, David W. Nulsen, John C. Maier, Donald B. TI Transfer of two versus three embryos in women less than 40 years old undergoing frozen transfer cycles SO FERTILITY AND STERILITY LA English DT Article DE Frozen embryo transfer; number of embryos to transfer; IVF; frozen cycle outcome; multiple pregnancy ID IN-VITRO FERTILIZATION; THAWED EMBRYOS; CRYOPRESERVATION; IMPLANTATION; CONCEPTION; COHORT; RATES; RISK AB Objective: To compare outcomes of frozen embryo transfer (FET) cycles when two or three embryos were transferred in women aged <40 years. Design: Retrospective chart review. Setting: A university-affiliated IVF program. Patient(s): Women undergoing FET cycles between January 2004 and December 2005. Intervention(S): Transfer of two or three embryos. Main Outcome Measure(s): Clinical pregnancy rate (PR), multiple pregnancy rate (MPR), and live birth rate (LBR). Result(s): In patients aged <35 (n = 145), two versus three embryo group had similar PR and LBR, but the MPR was significantly higher in the three-embryo group (41% for three embryos vs. 9.4% for two embryos). Clinical pregnancy in the fresh cycle from which the frozen embryos were obtained did not affect the PR, and an increase in MPR was still observed. In patients aged 35 to 39 (n = 93), there were no differences in the PR, MPR, or LBR between the two groups. Conclusion(S): Transfer of two instead of three frozen embryos in patients <35 years old resulted in a significant decrease in MPR without compromising PR or LBR. Transferring additional embryos when a patient had an unsuccessful fresh cycle was not warranted. In the age group 35-39 years, transferring two instead of three embryos did not decrease PR or LBR, and had no effect on the risk of high-order multiples. (Fertil Steril (R) 2010;93:355-9. (C)2010 by American Society for Reproductive Medicine.) C1 [Berin, Inna; Engmann, Lawrence L.; Benadiva, Claudio A.; Schmidt, David W.; Nulsen, John C.; Maier, Donald B.] Univ Connecticut, Ctr Hlth, Dept Obstet & Gynecol, Ctr Adv Reprod Serv,Div Reprod Endocrinol & Infer, Farmington, CT USA. RP Berin, I (reprint author), Massachusetts Gen Hosp, Div Reprod Endocrinol & Infertil, Vincent OB GYN Serv, 55 Fruit St,YAW 10-A, Boston, MA 02114 USA. EM inna_berin@yahoo.com NR 16 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JAN 15 PY 2010 VL 93 IS 2 BP 355 EP 359 DI 10.1016/j.fertnstert.2009.01.101 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 554KL UT WOS:000274433800006 PM 19324343 ER PT J AU Gundogan, F Bianchi, DW Scherjon, SA Roberts, DJ AF Gundogan, Fusun Bianchi, Diana W. Scherjon, Sicco A. Roberts, Drucilla J. TI Placental pathology in egg donor pregnancies SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 14th Meeting of the International-Federation-of-Placental-Associations/12th Meeting of the European-Placenta-Group (IFPA/EPG) CY SEP 10-13, 2008 CL Seggau Castle, AUSTRIA SP Int Federat Placenta Assoc, European Placenta Grp DE Egg donation; placenta; pathology; immunology ID IN-VITRO FERTILIZATION; MATERNAL FLOOR INFARCTION; UNKNOWN ETIOLOGY; OOCYTE DONATION; IMMUNE INTERACTIONS; CHRONIC VILLITIS; REFERENCE VALUES; T-CELLS; PREECLAMPSIA; APOPTOSIS AB Objective: To determine placental pathology and immune response at the maternal-fetal interface in pregnancies conceived by IVF via egg donation compared with nondonor IVF pregnancies. Design: Retrospective case-control study. Setting: Academic medical center. Patient(S): The study population included 20 egg donor and 33 nondonor IVF pregnancies of >24 weeks' gestation. Intervention(s): None. Main Outcome Measure(s): Perinatal complications (gestational hypertension, abruption, preterm delivery, cesarean section), microscopic features indicating ail immune response and trophoblast damage, and characterization of inflammatory cells using immunohistochemistry. Result(S): There was ail increase in gestational hypertension and preterm delivery in egg donor pregnancies. Dense fibrinoid deposition in the basal plate with severe chronic deciduitis containing significantly increased numbers of T helper and natural killer cells were demonstrated in egg donor placentas. Trophoblast damage was also increased in the preterm egg donor group. Conclusion(S): There are significant histological and immunohistochemical differences between the placentas of egg donor and nondonor IVF pregnancies. The increased immune activity and fibrinoid deposition at the maternal-fetal interface of egg donor pregnancies Could represent a host versus graft rejection-like phenomenon. (Fertil Steril (R) 2010;93:397-404. (C)2010 by American Society for Reproductive Medicine.) C1 [Gundogan, Fusun] Brown Univ, Women & Infants Hosp, Dept Pathol, Providence, RI 02905 USA. [Bianchi, Diana W.] Tufts Med Ctr, Dept Pediat, Boston, MA USA. [Scherjon, Sicco A.] Leiden Univ, Med Ctr, Dept Obstet, Leiden, Netherlands. [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Gundogan, F (reprint author), Brown Univ, Women & Infants Hosp, Dept Pathol, 101 Dudley St, Providence, RI 02905 USA. EM fgundogan@wihri.org NR 38 TC 26 Z9 27 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JAN 15 PY 2010 VL 93 IS 2 BP 397 EP 404 DI 10.1016/j.fertnstert.2008.12.144 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 554KL UT WOS:000274433800013 PM 19249031 ER PT J AU Quaas, AM Missmer, SA Ginsburg, ES AF Quaas, Alexander M. Missmer, Stacey A. Ginsburg, Elizabeth S. TI Gonadotropin-releasing hormone antagonist use is associated with increased pregnancy rates in ovulation induction-intrauterine insemination to in vitro fertilization conversions, independent of age and estradiol level on the day of human chorionic gonadotropin administration SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 63rd Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 13-17, 2007 CL Washington, DC SP Amer Soc Reprod Med DE OI/IUI to IVF conversions; GnRH antagonists; pregnancy rate ID OVARIAN HYPERSTIMULATION; GNRH ANTAGONISTS; STIMULATION; CYCLES AB Objective: To determine whether the use of GnRH antagonist in cycles converted from ovulation induction-IUI to IVF affects cycle outcome and, pregnancy rates. Design: Retrospective cohort study. Setting: Academic research institution. Patient(s): One hundred eighty-two consecutive patients with ovulation induction-IUI to IVF conversions undergoing oocyte retrieval conducted at our institution from 2004 to 2006. Intervention(s): The relation between observation of fetal heartbeat and GnRH antagonist exposure was evaluated with use of multivariable logistic regression. The difference in intermediate cycle outcomes by antagonist exposure was estimated with use of linear regression. Main Outcome Measure(s): Fetal cardiac activity on early ultrasound, intermediate cycle parameters. Result(s): For patients given treatment with a GnRH antagonist, the odds ratio for achieving pregnancy was 2.13 (95% confidence interval = 1.03-4.39) compared with untreated patients, independent of age and E(2) levels on day of hCG. Patients given antagonist had 1.6 more follicles and 2.1 more oocytes retrieved, 1.9 more mature oocytes, and 2.3 more fertilized oocytes, and the fertilization rate was 9.7% higher. Conclusion(s): Gonadotropin-releasing hormone antagonist use in ovulation induction-IUI to IVF conversions was associated with increased pregnancy rates and improved intermediate cycle parameters, controlled for age and E(2) levels on day of hCG. Addition of a GnRH antagonist should be considered in ovulation induction-IUI to IVF conversions. (Fertil Steril(R) 2010;93:605-8. (C)2010 by American Society for Reproductive Medicine.) C1 [Quaas, Alexander M.; Missmer, Stacey A.; Ginsburg, Elizabeth S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Reprod Endocrinol, Boston, MA 02115 USA. RP Quaas, AM (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, 55 Fruit St, Boston, MA 02114 USA. EM aquaas@partners.org NR 15 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JAN 15 PY 2010 VL 93 IS 2 BP 605 EP 608 DI 10.1016/j.fertnstert.2009.01.109 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 554KL UT WOS:000274433800040 PM 19324340 ER PT J AU Okuya, M Kurosawa, H Kikuchi, J Furukawa, Y Matsui, H Aki, D Matsunaga, T Inukai, T Goto, H Altura, RA Sugita, K Arisaka, O Look, AT Inaba, T AF Okuya, Mayuko Kurosawa, Hidemitsu Kikuchi, Jiro Furukawa, Yusuke Matsui, Hirotaka Aki, Daisuke Matsunaga, Takayuki Inukai, Takeshi Goto, Hiroaki Altura, Rachel A. Sugita, Kenich Arisaka, Osamu Look, A. Thomas Inaba, Toshiya TI Up-regulation of Survivin by the E2A-HLF Chimera Is Indispensable for the Survival of t(17;19)-positive Leukemia Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APOPTOSIS-INDUCING FACTOR; ACUTE-LYMPHOBLASTIC-LEUKEMIA; HEMATOPOIETIC PROGENITOR CELLS; PRO-B LYMPHOCYTES; TRANSCRIPTION FACTOR; IN-VIVO; ANTIAPOPTOTIC ACTIVITY; DOWNSTREAM TARGET; GENE-EXPRESSION; E2A GENE AB The E2A-HLF fusion transcription factor generated by t(17;19)(q22;p13) translocation is found in a small subset of pro-B cell acute lymphoblastic leukemias (ALLs) and promotes leukemogenesis by substituting for the antiapoptotic function of cytokines. Here we show that t(17;19)(+) ALL cells express Survivin at high levels and that a dominant negative mutant of E2A-HLF suppresses Survivin expression. Forced expression of E2A-HLF in t(17;19)(-) leukemia cells up-regulated Survivin expression, suggesting that Survivin is a downstream target of E2A-HLF. Analysis using a counterflow centrifugal elutriator revealed that t(17;19)(+) ALL cells express Survivin throughout the cell cycle. Reporter assays revealed that E2A-HLF induces survivin expression at the transcriptional level likely through indirect down-regulation of a cell cycle-dependent cis element in the promoter region. Down-regulation of Survivin function by a dominant negative mutant of Survivin or reduction of Survivin expression induced massive apoptosis throughout the cell cycle in t(17;19)(+) cells mainly through caspase-independent pathways involving translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. AIF knockdown conferred resistance to apoptosis caused by down-regulation of Survivin function. These data indicated that reversal of AIF translocation by Survivin, which is induced by E2A-HLF throughout the cell cycle, is one of the key mechanisms in the protection of t(17;19)(+) leukemia cells from apoptosis. C1 [Okuya, Mayuko; Kurosawa, Hidemitsu; Matsunaga, Takayuki; Sugita, Kenich; Arisaka, Osamu] Dokkyo Med Univ, Dept Pediat, Sch Med, Mibu, Tochigi 3210293, Japan. [Matsui, Hirotaka; Aki, Daisuke; Inaba, Toshiya] Hiroshima Univ, Dept Mol Oncol, Res Inst Radiat Biol & Med, Hiroshima 7348553, Japan. [Inukai, Takeshi] Univ Yamanashi, Sch Med, Dept Pediat, Yamanashi 4093898, Japan. [Goto, Hiroaki] Yokohama City Univ, Sch Med, Dept Pediat, Kanagawa 2360004, Japan. [Altura, Rachel A.] Brown Univ, Warren Alpert Med Sch, Dept Pediat, Providence, RI 02903 USA. [Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Kurosawa, H (reprint author), Dokkyo Med Univ, Dept Pediat, Sch Med, Mibu, Tochigi 3210293, Japan. EM hidekuro@dokkyomed.ac.jp FU Japan Society for Promotion of Science [18591201]; Dokkyo Medical University FX This work was supported by Grant-in-aid for Scientific Research (C) 18591201 from the Japan Society for Promotion of Science (to H. K.) and a young investigator award from Dokkyo Medical University (to M. O.). NR 43 TC 9 Z9 10 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 15 PY 2010 VL 285 IS 3 BP 1850 EP 1860 DI 10.1074/jbc.M109.023762 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 541PJ UT WOS:000273429100031 PM 19887369 ER PT J AU Astier, AL Beriou, G Eisenhaure, TM Anderton, SM Hafler, DA Hacohen, N AF Astier, Anne L. Beriou, Gaelle Eisenhaure, Thomas M. Anderton, Stephen M. Hafler, David A. Hacohen, Nir TI RNA Interference Screen in Primary Human T Cells Reveals FLT3 as a Modulator of IL-10 Levels SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; TYROSINE KINASE RECEPTOR; MULTIPLE-SCLEROSIS; HEMATOPOIETIC-CELLS; MESSENGER-RNA; HUMAN HOMOLOG; MURINE FLT3; LIGAND; EXPRESSION; GENE AB Functional studies of human primary immune cells have been hampered by the lack of tools to silence gene functions. In this study, we report the application of a lentiviral RNA interference library in primary human T cells. Using a subgenomic short hair RNA library targeting similar to 1000 signaling genes, we identified novel genes that control the levels of IL-10 produced. IL-10 is a potent anti-inflammatory cytokine secreted by several cell types, including T regulatory type 1 cells, a subset of T regulatory cells that exert their suppressive activity through IL-10 secretion. FLT3, a known hematopoeitic growth factor, was found to be a negative regulator of IL-10 levels in activated T cells. This was based on several observations. First, FLT3 and its ligand (FL) were both induced by T cell activation. Second, silencing of FLT3 led to increased IL-10 levels, whereas addition of FL suppressed IL-10 secretion and increased FLT3 surface levels. Third, engagement of CD46, a known inducer of T regulatory type 1 cells, upregulated surface FLT3, and secreted FL, which then inhibited IL-10 production by T cells. Hence, FL and FLT3 form a novel regulatory feedback loop that limits IL-10 production in T cells. Our results identified FLT3 as a new regulator of T cell function and offer a strategy to genetically dissect specific pathways in T cells. The Journal of Immunology, 2010, 184: 685-693. C1 [Astier, Anne L.; Anderton, Stephen M.] Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Edinburgh EH16 4TJ, Midlothian, Scotland. [Astier, Anne L.; Beriou, Gaelle; Hafler, David A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Astier, Anne L.; Beriou, Gaelle; Eisenhaure, Thomas M.; Hafler, David A.; Hacohen, Nir] Broad Inst Harvard, Cambridge, MA 02142 USA. [Astier, Anne L.; Beriou, Gaelle; Eisenhaure, Thomas M.; Hafler, David A.; Hacohen, Nir] MIT, Cambridge, MA 02142 USA. [Eisenhaure, Thomas M.; Hacohen, Nir] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. RP Astier, AL (reprint author), Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, 47 Little France Crescent, Edinburgh EH16 4TJ, Midlothian, Scotland. EM a.astier@ed.ac.uk OI Astier, Anne/0000-0002-0144-3431 FU National Institutes of Health [U19 AI070352, AI046130, P01 A1039671]; National Multiple Sclerosis Society [859/07]; National Institute of Neurological Disorders and Stroke [NS24247] FX The work was supported by National Institutes of Health grants to N.H. (U19 AI070352) and by grants from the National Multiple Sclerosis Society and from the National Institute of Health to D.A.H. (P01 AI045757, U19 AI046130, U19 AI070352, P01 A1039671). D.A.H. has a Jacob Javits Merit Award (NS24247) from the National Institute of Neurological Disorders and Stroke. A.A. was supported by an advanced fellowship from the National Multiple Sclerosis Society followed by a research grant from the Multiple Sclerosis Society (U.K.) (859/07). NR 49 TC 15 Z9 15 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 JAN 15 PY 2010 VL 184 IS 2 BP 685 EP 693 DI 10.4049/jimmunol.0902443 PG 9 WC Immunology SC Immunology GA 541UT UT WOS:000273447100019 PM 20018615 ER PT J AU Ahuja, SK He, WJ AF Ahuja, Sunil K. He, Weijing TI Double-Edged Genetic Swords and Immunity: Lesson from CCR5 and Beyond SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID WEST-NILE-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; CHEMOKINE RECEPTOR CCR5; MACROPHAGE-TROPIC HIV-1; IN-VITRO; MIP-1 ALPHA; VIRAL ENTRY; INFECTION; DENSITY; SUSCEPTIBILITY C1 [Ahuja, Sunil K.; He, Weijing] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ahuja, Sunil K.; He, Weijing] Univ Texas Hlth Sci Ctr San Antonio, Vet Adm Res Ctr AIDS & HIV Infect 1, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Ahuja, SK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr,Rm 5-009R, San Antonio, TX 78229 USA. EM ahujas@uthscsa.edu FU NIAID NIH HHS [R37 AI046326]; PHS HHS [R37046326] NR 43 TC 5 Z9 5 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2010 VL 201 IS 2 BP 171 EP 174 DI 10.1086/649427 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200001 PM 20025529 ER PT J AU Warren, HS Fitting, C Hoff, E Adib-Conquy, M Beasley-Topliffe, L Tesini, B Liang, XY Valentine, C Hellman, J Hayden, D Cavaillon, JM AF Warren, H. Shaw Fitting, Catherine Hoff, Eva Adib-Conquy, Minou Beasley-Topliffe, Laura Tesini, Brenda Liang, Xueya Valentine, Catherine Hellman, Judith Hayden, Douglas Cavaillon, Jean-Marc TI Resilience to Bacterial Infection: Difference between Species Could Be Due to Proteins in Serum SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TUMOR-NECROSIS-FACTOR; STAPHYLOCOCCAL-ENTEROTOXIN-B; MONOCLONAL-ANTIBODIES; ENDOTOXIN; LIPOPOLYSACCHARIDE; MICE; TOLERANCE; SUSCEPTIBILITY; CELLS; SEPSIS AB Vertebrates vary in resistance and resilience to infectious diseases, and the mechanisms that regulate the trade-off between these often opposing protective processes are not well understood. Variability in the sensitivity of species to the induction of damaging inflammation in response to equivalent pathogen loads (resilience) complicates the use of animal models that reflect human disease. We found that induction of proinflammatory cytokines from macrophages in response to inflammatory stimuli in vitro is regulated by proteins in the sera of species in inverse proportion to their in vivo resilience to lethal doses of bacterial lipopolysaccharide over a range of 10,000-fold. This finding suggests that proteins in serum rather than intrinsic cellular differences may play a role in regulating variations in resilience to microbe-associated molecular patterns between species. The involvement of circulating proteins as key molecules raises hope that the process might be manipulated to create better animal models and potentially new drug targets. C1 [Warren, H. Shaw; Hoff, Eva; Beasley-Topliffe, Laura; Tesini, Brenda; Liang, Xueya; Valentine, Catherine] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Hellman, Judith] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Hayden, Douglas] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Fitting, Catherine; Adib-Conquy, Minou; Cavaillon, Jean-Marc] Inst Pasteur, Cytokines & Inflammat Unit, Paris, France. RP Warren, HS (reprint author), Massachusetts Gen Hosp E, Infect Dis Unit, 149 13th St,5th Floor, Charlestown, MA 02129 USA. EM swarren1@partners.org FU National Institutes of Health [AI059010, GM59694]; Shriners Hospitals for Children [8720]; Institut Pasteur FX National Institutes of Health (grants AI059010 and GM59694); Shriners Hospitals for Children (grant 8720); Institut Pasteur (institutional funding). NR 38 TC 70 Z9 71 U1 1 U2 10 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 JAN 15 PY 2010 VL 201 IS 2 BP 223 EP 232 DI 10.1086/649557 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200009 PM 20001600 ER PT J AU Gandhi, RT Bosch, RJ Aga, E Albrecht, M Demeter, LM Dykes, C Bastow, B Para, M Lai, J Siliciano, RF Siliciano, JD Eron, JJ AF Gandhi, Rajesh T. Bosch, Ronald J. Aga, Evgenia Albrecht, Mary Demeter, Lisa M. Dykes, Carrie Bastow, Barbara Para, Michael Lai, Jun Siliciano, Robert F. Siliciano, Janet D. Eron, Joseph J. CA AIDS Clinical Trials Grp A5173 Tea TI No Evidence for Decay of the Latent Reservoir in HIV-1-Infected Patients Receiving Intensive Enfuvirtide-Containing Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CD4(+) T-CELLS; HIV-1; INFECTION; VIRUS; REPLICATION; VIREMIA; DENSITY AB Human immunodeficiency virus type 1 (HIV-1) persists in a latent reservoir of infected resting memory CD4 cells in patients receiving antiretroviral therapy. We assessed whether multitarget therapy with enfuvirtide, 2 reverse-transcriptase inhibitors, and a ritonavir-boosted protease inhibitor leads to decay of this reservoir. Nineteen treatment-naive patients initiated this regimen; 9 experienced virologic suppression and continued enfuvirtide-containing therapy for at least 48 weeks. In enfuvirtide-treated patients with virological suppression, there was no decay of the latent reservoir (95% confidence interval for half-life, 11 months to infinity). The stability of the latent reservoir despite intensive therapy suggests that new strategies are needed to eradicate HIV-1 from this reservoir. (ClinicalTrials.gov identifier: NCT00051831.) C1 [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bosch, Ronald J.; Aga, Evgenia] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Albrecht, Mary] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Demeter, Lisa M.; Dykes, Carrie] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Bastow, Barbara; Para, Michael] Social & Sci Syst, Silver Spring, MD USA. [Lai, Jun; Siliciano, Robert F.; Siliciano, Janet D.] Johns Hopkins Sch Med, Baltimore, MD USA. [Siliciano, Robert F.] Howard Hughes Med Inst, Baltimore, MD USA. [Para, Michael] Ohio State Univ, Columbus, OH 43210 USA. [Eron, Joseph J.] Univ N Carolina, Chapel Hill, NC USA. RP Gandhi, RT (reprint author), Massachusetts Gen Hosp, GRJ 504,55 Fruit St, Boston, MA 02114 USA. EM rgandhi@partners.org FU NCRR NIH HHS [M01 RR000046, M01 RR000046-48, P20 RR011126, P20 RR011126-049001, UL1 RR025780]; NIAID NIH HHS [P30 AI054907, P30 AI050410, P30 AI054907-01, P30 AI078498, P30 AI078498-01, R01 AI066992, R01 AI066992-05, U01 AI027665, U01 AI027665-13, U01 AI038855, U01 AI038855-05, U01 AI038858, U01 AI038858-06, U01 AI068634, U01 AI068634-04, U01 AI068636, U01 AI068636-04, U01 AI069415, U01 AI069415-03, U01 AI069423, U01 AI069423-03, U01 AI069450, U01 AI069450-03, U01 AI069472, U01 AI069472-03, U01 AI069474, U01 AI069495, U01 AI069511, U01 AI069532, UM1 AI068634, UM1 AI068636, UM1 AI069450, UM1 AI069474, UM1 AI069532] NR 15 TC 44 Z9 44 U1 0 U2 1 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 JAN 15 PY 2010 VL 201 IS 2 BP 293 EP 296 DI 10.1086/649569 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200016 PM 20001856 ER PT J AU Peleg, AY Pillai, S Mylonakis, E Moellering, RC Eliopoulos, GM AF Peleg, Anton Y. Pillai, Satish Mylonakis, Eleftherios Moellering, Robert C., Jr. Eliopoulos, George M. TI Is High Vancomycin Minimum Inhibitory Concentration a Good Marker to Predict the Outcome of Methicillin-Resistant Staphylococcus aureus Bacteremia? Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID AGR C1 [Peleg, Anton Y.; Pillai, Satish; Moellering, Robert C., Jr.; Eliopoulos, George M.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Peleg, Anton Y.; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Peleg, Anton Y.; Pillai, Satish; Mylonakis, Eleftherios; Moellering, Robert C., Jr.; Eliopoulos, George M.] Harvard Univ, Sch Med, Boston, MA USA. RP Peleg, AY (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. EM apeleg@bidmc.harvard.edu OI Peleg, Anton/0000-0002-2296-2126 NR 9 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2010 VL 201 IS 2 BP 312 EP 313 DI 10.1086/649571 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200020 ER PT J AU Xu, HY Song, LK Kim, M Holmes, MA Kraft, Z Sellhorn, G Reinherz, EL Stamatatos, L Strong, RK AF Xu, Hengyu Song, Likai Kim, Mikyung Holmes, Margaret A. Kraft, Zane Sellhorn, George Reinherz, Ellis L. Stamatatos, Leonidas Strong, Roland K. TI Interactions between Lipids and Human Anti-HIV Antibody 4E10 Can Be Reduced without Ablating Neutralizing Activity SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MONOCLONAL-ANTIBODIES; MEMBRANE-PROTEINS; EPITOPE; GP41; 2F5; GLYCOPROTEIN; TRYPTOPHAN; RESIDUES; BINDING AB Human 4E10 is one of the broadest-specificity, HIV-1-neutralizing monoclonal antibodies known, recognizing a membrane-proximal linear epitope on gp41. The lipid cross-reactivity of 4E10 has been alternately suggested either to contribute to the apparent rarity of 4E10-like antibody responses in HIV infections, through elimination by B-cell tolerance mechanisms to self-antigens, or to contribute to neutralization potency by virus-specific membrane binding outside of the membrane-proximal external region (MPER). To investigate how 4E10 interacts with membrane and protein components, and whether such interactions contribute to neutralization mechanisms, we introduced two mutations into 4E10 Fv constructs, Trp to Ala at position 100 in the heavy chain [W(H100)A] and Gly to Glu at position 50 in the light chain [G(L50)E], selected to disrupt potential lipid interactions via different mechanisms. Wild-type and mutant Fvs all bound with the same affinity to peptides and monomeric and trimeric gp140s, but the affinities for gp140s were uniformly 10-fold weaker than to peptides. 4E10 Fv binding responses to liposomes in the presence or absence of MPER peptides were weak in absolute terms, consistent with prior observations, and both mutations attenuated interactions even further, as predicted. The W(H100) A mutation reduced neutralization efficiency against four HIV-1 isolates, but the G(L50) E mutation increased potency across the same panel. Electron paramagnetic resonance experiments showed that the W(H100) A mutation, but not the G(L50) E mutation, reduced the ability of 4E10 to extract MPER peptides from membranes. These results show that 4E10 nonspecific membrane binding is separable from neutralization, which is achieved through specific peptide/ lipid orientation changes. C1 [Xu, Hengyu; Holmes, Margaret A.; Strong, Roland K.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Song, Likai; Kim, Mikyung; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Kim, Mikyung; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Kim, Mikyung; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Song, Likai; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Kraft, Zane; Sellhorn, George; Stamatatos, Leonidas] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Stamatatos, Leonidas] Univ Washington, Dept Global Hlth, Seattle, WA 98109 USA. RP Strong, RK (reprint author), Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1100 Fairview Ave N,Mail Stop A3-023, Seattle, WA 98109 USA. EM rstrong@fhcrc.org FU Bill & Melinda Gates Foundation FX This research was conducted as part of the Collaboration for AIDS Vaccine Discovery with support from the Bill & Melinda Gates Foundation. NR 42 TC 33 Z9 35 U1 3 U2 8 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 JAN 15 PY 2010 VL 84 IS 2 BP 1076 EP 1088 DI 10.1128/JVI.02113-09 PG 13 WC Virology SC Virology GA 535TN UT WOS:000272994300038 PM 19906921 ER PT J AU Miura, T Brumme, CJ Brockman, MA Brumme, ZL Pereyra, F Block, BL Trocha, A John, M Mallal, S Harrigan, PR Walker, BD AF Miura, Toshiyuki Brumme, Chanson J. Brockman, Mark A. Brumme, Zabrina L. Pereyra, Florencia Block, Brian L. Trocha, Alicja John, Mina Mallal, Simon Harrigan, P. Richard Walker, Bruce D. TI HLA-Associated Viral Mutations Are Common in Human Immunodeficiency Virus Type 1 Elite Controllers (vol 83, pg 3407, 2009) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Miura, Toshiyuki] Massachusetts Gen Hosp, Ragon Inst, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Div Aids, Boston, MA 02115 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. Royal Perth Hosp, Ctr Clin Immunol & Biomed Stat, Perth, WA, Australia. Murdoch Univ, Perth, WA, Australia. British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. Univ British Columbia, Fac Med, Div Aids, Vancouver, BC, Canada. RP Miura, T (reprint author), Massachusetts Gen Hosp, Ragon Inst, Charlestown, MA 02129 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2010 VL 84 IS 2 BP 1212 EP 1212 DI 10.1128/JVI.02204-09 PG 1 WC Virology SC Virology GA 535TN UT WOS:000272994300053 ER PT J AU Malik, S Jiang, SM Garee, JP Verdin, E Lee, AV O'Malley, BW Zhang, M Belaguli, NS Oesterreich, S AF Malik, Simeen Jiang, Shiming Garee, Jason P. Verdin, Eric Lee, Adrian V. O'Malley, Bert W. Zhang, Mao Belaguli, Narasimhaswamy S. Oesterreich, Steffi TI Histone Deacetylase 7 and FoxA1 in Estrogen-Mediated Repression of RPRM SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BREAST-CANCER CELLS; NUCLEAR RECEPTOR COREPRESSOR; GENOME-WIDE ANALYSIS; NF-KAPPA-B; GENE-EXPRESSION; ANDROGEN-RECEPTOR; TRANSCRIPTION FACTORS; RESPONSE ELEMENTS; DOWN-REGULATION; BINDING-SITES AB Activation of estrogen receptor alpha (ER alpha)results in both induction and repression of gene transcription; while mechanistic details of estrogen induction are well described, details of repression remain largely unknown. We characterized several ER alpha-repressed targets and examined in detail the mechanism for estrogen repression of Reprimo (RPRM), a cell cycle inhibitor. Estrogen repression of RPRM is rapid and robust and requires a tripartite interaction between ER alpha, histone deacetylase 7 (HDAC7), and FoxA1. HDAC7 is the critical HDAC needed for repression of RPRM; it can bind to ER alpha and represses ER alpha's transcriptional activity-this repression does not require HDAC7's deacetylase activity. We further show that the chromatin pioneer factor FoxA1, well known for its role in estrogen induction of genes, is recruited to the RPRM promoter, is necessary for repression of RPRM, and interacts with HDAC7. Like other FoxA1 recruitment sites, the RPRM promoter is characterized by H3K4me1/me2. Estrogen treatment causes decreases in H3K4me1/me2 and release of RNA polymerase II (Pol II) from the RPRM proximal promoter. Overall, these data implicate a novel role for HDAC7 and FoxA1 in estrogen repression of RPRM, a mechanism which could potentially be generalized to many more estrogen-repressed genes and hence be important in both normal physiology and pathological processes. C1 [Malik, Simeen; Jiang, Shiming; Garee, Jason P.; Lee, Adrian V.; Oesterreich, Steffi] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Malik, Simeen; Garee, Jason P.; Lee, Adrian V.; O'Malley, Bert W.; Oesterreich, Steffi] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Lee, Adrian V.; Oesterreich, Steffi] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Verdin, Eric] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA. [Verdin, Eric] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Zhang, Mao; Belaguli, Narasimhaswamy S.] Michael E DeBakey Vet Affairs Med Ctr, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. RP Oesterreich, S (reprint author), 1 Baylor Plaza,MS 600, Houston, TX 77030 USA. EM steffio@breastcenter.tmc.edu OI Verdin, Eric/0000-0003-3703-3183 FU Department of Defense Breast Cancer Research Program [BC043880]; NIH [R01 CA097213, P01030195]; SPORE pilot [CA58183]; Nancy Owen Foundation FX This work was supported by a Department of Defense Breast Cancer Research Program grant (BC043880) ( S. Malik), NIH grants R01 CA097213 and P01030195 ( S. Oesterreich), a SPORE pilot grant (CA58183) ( S. Oesterreich), and a Nancy Owen Foundation grant ( S. Oesterreich). NR 73 TC 30 Z9 31 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN 15 PY 2010 VL 30 IS 2 BP 399 EP 412 DI 10.1128/MCB.00907-09 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 535GL UT WOS:000272955200004 PM 19917725 ER PT J AU Feliers, D Kasinath, BS AF Feliers, Denis Kasinath, Balakuntalam S. TI Mechanism of VEGF expression by high glucose in proximal tubule epithelial cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Renin-angiotensin system; VEGF; Glucose; Epithelial cells; Kidney ID ENDOTHELIAL GROWTH-FACTOR; RENIN-ANGIOTENSIN SYSTEM; MESSENGER-RNA TRANSLATION; RAT MESANGIAL CELLS; DIABETIC-NEPHROPATHY; CONVERTING-ENZYME; CARDIAC-HYPERTROPHY; II PRODUCTION; FACTOR-BETA; ACTIVATION AB Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. VEGF expression is increased in proximal tubules of mice with type 1 diabetes. In mouse proximal tubular epithelial cells (MCT) cultured with 30 mM glucose (HG) for 24 h, VEGF expression is increased at the protein and the mRNA level, suggesting a transcriptional mechanism. HG stimulation of VEGF synthesis is prevented by captopril, an inhibitor of angiotensin-converting enzyme, and, by losartan, a specific antagonist of angiotensin type 1 receptor (AT1), suggesting that VEGF synthesis is mediated by Ang II. Synthesis of angiotensinogen (AGT), a precursor of angiotensin II, is increased in MCTs cultured in HG. Although synthesis of renin and ACE is not affected by HG, their activity, is increased in the conditioned medium. Concentrations of Ang I and Ang II are also increased in conditioned medium from HG-treated MCTs and captopril prevents increased Ang II, but not Ang 1, synthesis. Finally, AT1 is activated in MCTs treated with HG, and its activation is prevented by captopril and losartan. The ERK pathway is activated by HG within minutes of stimulation and lasting for up to 24 h. The initial phase of ERK activation is due to HG itself and leads to AGT upregulation and the sustained phase is mediated for the most part by Ang II-activated AT1 receptor and leads to increased VEGF synthesis. These data show that: (1) HG increases AGT synthesis and activation of renin and ACE by MCTs, leading to local production of Ang I and Ang II. (2) Ang II activates endogenous AT1 and stimulates synthesis of VEGF. (3) HG activation of ERK starts within minutes and lasts for up to 24h. Early ERK activation is involved in AGT upregulation and sustained ERK activation, mediated via AT1, is responsible for VEGF synthesis. In conclusion, our study shows that MCTs express an endogenous renin-angiotensin system that is activated by high glucose to stimulate the synthesis of VEGF, through activation of the ERK pathway. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Feliers, Denis; Kasinath, Balakuntalam S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Nephrol, OBrien Kidney Res Ctr, San Antonio, TX 78229 USA. [Kasinath, Balakuntalam S.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Feliers, D (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med Nephrol, OBrien Kidney Res Ctr, Mail Code 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM feliers@uthscsa.edu FU American Heart Association [RO1 DK077295]; VA Research Service Merit Review FX This work was supported by grants from the American Heart Association (DF), RO1 DK077295 (BSK), and VA Research Service Merit Review Grant (BSK). We thank Dr. E. Neilson for mouse proximal tubular epithelial cells. NR 69 TC 11 Z9 14 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 15 PY 2010 VL 314 IS 1 BP 136 EP 142 DI 10.1016/j.mce.2009.09.009 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 523VC UT WOS:000272101700016 PM 19765632 ER PT J AU Bader, B Walker, RH Vogel, M Prosiegel, M McIntosh, J Danek, A AF Bader, Benedikt Walker, Ruth H. Vogel, Mathias Prosiegel, Mario McIntosh, Jacqueline Danek, Adrian TI Tongue Protrusion and Feeding Dystonia: A Hallmark of Chorea-Acanthocytosis SO MOVEMENT DISORDERS LA English DT Letter C1 [Bader, Benedikt; Danek, Adrian] Univ Munich, Neurol Klin & Poliklin, Munich, Germany. [Walker, Ruth H.] Mt Sinai Sch Med, New York, NY USA. [Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY USA. [Vogel, Mathias] Klinikum Bogenhausen, Clin Neuropsychol, Munich, Germany. [Prosiegel, Mario] Ctr Dysphagia, Fachklin Bad Heilbiunn, Bad Heilbrunn, Germany. [McIntosh, Jacqueline] Wolfson Neurorehabil Ctr, London, England. RP Bader, B (reprint author), Univ Munich, Neurol Klin & Poliklin, Munich, Germany. RI Danek, Adrian/G-7339-2011 OI Danek, Adrian/0000-0001-8857-5383 NR 7 TC 18 Z9 23 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN 15 PY 2010 VL 25 IS 1 BP 127 EP 129 DI 10.1002/mds.22863 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 554HD UT WOS:000274425200024 PM 19938148 ER PT J AU Kremen, WS Prom-Wormley, E Panizzon, MS Eyler, LT Fischl, B Neale, MC Franz, CE Lyons, MJ Pacheco, J Perry, ME Stevens, A Schmitt, JE Grant, MD Seidman, LJ Thermenos, HW Tsuang, MT Eisen, SA Dale, AM Fennema-Notestine, C AF Kremen, William S. Prom-Wormley, Elizabeth Panizzon, Matthew S. Eyler, Lisa T. Fischl, Bruce Neale, Michael C. Franz, Carol E. Lyons, Michael J. Pacheco, Jennifer Perry, Michele E. Stevens, Allison Schmitt, J. Eric Grant, Michael D. Seidman, Larry J. Thermenos, Heidi W. Tsuang, Ming T. Eisen, Seth A. Dale, Anders M. Fennema-Notestine, Christine TI Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study SO NEUROIMAGE LA English DT Article DE Heritability; Twins; Magnetic resonance imaging (MRI); Brain structure; Cortical thickness ID HUMAN CEREBRAL-CORTEX; MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; CORTICAL THICKNESS; COGNITIVE PERFORMANCE; TWIN DESIGN; RELIABILITY; SEGMENTATION; MULTIVARIATE; VOLUME AB The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences oil human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51-59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences oil the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic Studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kremen, William S.; Panizzon, Matthew S.; Eyler, Lisa T.; Franz, Carol E.; Perry, Michele E.; Tsuang, Ming T.; Fennema-Notestine, Christine] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Kremen, William S.; Tsuang, Ming T.] Univ Calif San Diego, Ctr Behav Genom, La Jolla, CA 92093 USA. [Kremen, William S.; Eyler, Lisa T.; Tsuang, Ming T.] VA San Diego Healthcare Syst, La Jolla, CA USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. [Fischl, Bruce; Pacheco, Jennifer; Stevens, Allison] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Fischl, Bruce; Pacheco, Jennifer; Stevens, Allison] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyons, Michael J.; Grant, Michael D.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Perry, Michele E.] Univ Calif San Diego, Dept Cognit Neurosci, La Jolla, CA 92093 USA. [Seidman, Larry J.; Thermenos, Heidi W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Eisen, Seth A.] Dept Vet Affairs, Washington, DC USA. [Eisen, Seth A.] Washington Univ, Dept Med, St Louis, MO USA. [Eisen, Seth A.] Washington Univ, Dept Psychiat, St Louis, MO 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 Kremen, WS (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr MC 0738, La Jolla, CA 92093 USA. EM wkremen@ucsd.edu RI Lyons, Michael/B-6119-2011; Dale, Anders/A-5180-2010; OI Lyons, Michael/0000-0001-6516-9219; Fennema-Notestine, Christine/0000-0002-6527-6361 FU National Institute on Aging [AG022381, AG018384, AG018386, AG022982]; National Center for Research Resources [P41-RR14075]; NCRR BIRN Morphometric [BIRN002]; National Institute for Biomedical Imaging and Bioengineering [R01EB006758]; National Institute for Neurological Disorders and Stroke [R01 NS052585-01]; Mental Illness and Neuroscience Discovery (MIND) Institute,; National Alliance for Medical Image Computing (NAMIC); National Institutes of Health through the NIH Roadmap for Medical Research [U54 EB005149]; Ellison Medical Foundation; U.S. Department of Veterans Affairs; Vietnam Era Twin (VET) Registry; Department of Defense; the National Personnel Records Center; National Archives and Records Administration; Internal Revenue Service; National Opinion Research Center; National Research Council; National Academy of Sciences; Institute for Survey Research, Temple University FX Funded by the National Institute on Aging (AG022381, AG018384, AG018386, AG022982): the National Center for Research Resources (P41-RR14075; NCRR BIRN Morphometric Project BIRN002); the National Institute for Biomedical Imaging and Bioengineering (R01EB006758); the National Institute for Neurological Disorders and Stroke (R01 NS052585-01); and the Mental Illness and Neuroscience Discovery (MIND) Institute, part of the National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant U54 EB005149. Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation. The U.S. Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. Numerous organizations have provided invaluable assistance in the conduct of this study, including the Department of Defense; the National Personnel Records Center, National Archives and Records Administration; the Internal Revenue Service; the National Opinion Research Center: the National Research Council, National Academy of Sciences; and the Institute for Survey Research, Temple University. Most importantly, the authors gratefully acknowledge the continued cooperation and participation of the members of the VET Registry and their families. Without their contribution this research would not have been possible. NR 49 TC 94 Z9 94 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2010 VL 49 IS 2 BP 1213 EP 1223 DI 10.1016/j.neuroimage.2009.09.043 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400008 PM 19786105 ER PT J AU Takahashi, E Dai, GP Wang, RP Ohki, K Rosen, GD Galaburda, AM Grant, PE Wedeen, VJ AF Takahashi, Emi Dai, Guangping Wang, Ruopeng Ohki, Kenichi Rosen, Glenn D. Galaburda, Albert M. Grant, P. Ellen Wedeen, Van J. TI Development of cerebral fiber pathways in cats revealed by diffusion spectrum imaging SO NEUROIMAGE LA English DT Article DE Diffusion Spectrum Imaging; Tractography; Development; Thalamo-cortical tracts; Cat ID WHITE-MATTER DEVELOPMENT; FETAL-BRAIN DEVELOPMENT; MAGNETIC-RESONANCE; VISUAL-CORTEX; MICROSTRUCTURAL DEVELOPMENT; ANATOMICAL CHARACTERIZATION; PREMATURE-INFANTS; WATER DIFFUSION; TENSOR MRI; IN-UTERO AB Examination of the three-dimensional axonal pathways in the developing brain is key to understanding the formation of cerebral connectivity. By tracing fiber pathways throughout the entire brain, diffusion tractography provides information that cannot be achieved by conventional anatomical MR imaging or histology. However, standard diffusion tractography (based on diffusion tensor imaging, or DTI) tends to terminate in brain areas with low water diffusivity, indexed by low diffusion fractional anisotropy (FA), which can be Caused by crossing fibers as well as fibers with less myelin. For this reason, DTI tractography is not effective for delineating the Structural changes that occur in the developing brain, where the process of myelination is incomplete, and where crossing fibers exist in greater numbers than in the adult brain. Unlike DTI, diffusion spectrum imaging (DSI) can define multiple directions of water diffusivity; as such, diffusion tractography based on DSI provides marked flexibility for delineation of fiber tracts in areas where the fiber architecture is complex and multidirectional, even in areas of low FA. In this study, we showed that FA values were lower in the white matter of newborn (postnatal day 0; P0) cat brains than in the white matter of infant (P35) and juvenile (P100) cat brains. These results correlated well with histological myelin stains of the white matter: the newborn kitten brain has much less myelin than that found in cat brains at later stages of development. Using DSI tractography, we successfully identified structural changes in thalamo-cortical and cortico-cortical association tracts in cat brains from one stage of development to another. in newborns, the main body of the thalamo-cortical tract was smooth, and fibers branching from it were almost straight, while the main body became more complex and branching fibers became Curved reflecting gyrification in the older cats. Cortico-cortical tracts in the temporal lobe were smooth in newborns, and they formed a sharper angle in the later stages of development. The cingulum bundle and superior longitudinal fasciculus became more visible with time. Within the first month after birth, structural changes occurred in these tracts that coincided with the formation of the gyri. These results show that DSI tractography has the potential for mapping morphological changes in low FA areas associated with growth and development. The technique may also be applicable to the study of other forms of brain plasticity, including future Studies in vivo. (C) 2009 Elsevier Inc. All rights reserved. C1 [Takahashi, Emi; Grant, P. Ellen] Harvard Univ, Sch Med, Dept Med, Div Newborn Med,Childrens Hosp Boston, Boston, MA 02115 USA. [Takahashi, Emi; Dai, Guangping; Grant, P. Ellen; Wedeen, Van J.] Harvard Univ, Dept Radiol, Sch Med, Charlestown, MA USA. [Takahashi, Emi; Dai, Guangping; Wang, Ruopeng; Grant, P. Ellen; Wedeen, Van J.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ohki, Kenichi] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Rosen, Glenn D.; Galaburda, Albert M.] Harvard Univ, Sch Med, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Grant, P. Ellen] Harvard Univ, Dept Radiol, Childrens Hosp Boston, Sch Med, Boston, MA 02115 USA. RP Takahashi, E (reprint author), Harvard Univ, Sch Med, Dept Med, Div Newborn Med,Childrens Hosp Boston, Boston, MA 02115 USA. EM emi@nmr.mgh.harvard.edu OI Rosen, Glenn/0000-0001-8281-5446 FU NIH [RO1 MH 64044]; National Science Foundation [PHY 0855161, PHY 0855453]; Ellison Medical Foundation [208556] FX We greatly appreciate Nichole Eusemann for her helpful editorial comments. This work was supported by NIH (RO1 MH 64044), the National Science Foundation PHY 0855161, PHY 0855453 and the Ellison Medical Foundation #208556. NR 75 TC 32 Z9 34 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2010 VL 49 IS 2 BP 1231 EP 1240 DI 10.1016/j.neuroimage.2009.09.002 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400010 PM 19747553 ER PT J AU Sinke, CBA Sorger, B Goebel, R de Gelder, B AF Sinke, C. B. A. Sorger, B. Goebel, R. de Gelder, B. TI Tease or threat? Judging social interactions from bodily expressions SO NEUROIMAGE LA English DT Article DE Emotion; Bodily expressions; Threat; fMRI; Social interaction; Attention ID FUNCTIONAL SPECIALIZATION; SELECTIVE ATTENTION; PREFRONTAL CORTEX; BODY EXPRESSIONS; FMRI; AMYGDALA; EMOTION; BRAIN; RESPONSES; PERCEPTION AB We casually observe many interactions that do not really concern us. Yet sometimes we need to be able to rapidly appraise whether an interaction between two people represents a real threat for one of them Father than an innocent tease. Using functional magnetic resonance imaging, we investigated whether small differences in the body language of two interacting people are picked up by the brain even if observers are performing an unrelated task. Fourteen participants were scanned while watching 3-s movies (192 trials and 96 scrambles) showing a male person either threatening or teasing a female one. In one task condition, observers categorized the interaction as threatening or teasing, and in the other, they monitored randomly appearing dots and categorized the color. Our results clearly show that right amygdala responds more to threatening than to teasing situations irrespective of the observers' task. When observers' attention is not explicitly directed to the situation, this heightened amygdala activation goes together with increased activity in body sensitive regions in fusiform gyrus, extrastriate body area-human motion complex and superior temporal sulcus and is associated with a better behavioral performance of the participants during threatening situations. In addition, regions involved in action observation (inferior frontal gyrus, temporoparietal junction, and inferior parietal lobe) and preparation (premotor, putamen) show increased activation for threat videos. Also regions involved in processing moral violations (temporoparietal junction, hypothalamus) reacted selectively to the threatening interactions. Taken together, our results show which brain regions react selectively to witnessing a threatening interaction even if the situation is not attended because the observers perform an unrelated task. (C) 2009 Elsevier Inc. All rights reserved. C1 [Sinke, C. B. A.; de Gelder, B.] Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [Sinke, C. B. A.; Sorger, B.; Goebel, R.] Maastricht Univ, Dept Cognit Neurosci, Maastricht, Netherlands. [de Gelder, B.] Harvard Univ, Sch Med, Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Charlestown, MA USA. RP de Gelder, B (reprint author), Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. EM B.deGelder@uvt.nl FU EU [FDP6-NEST-043403] FX This project was funded in part by EU project COBOL (FDP6-NEST-043403). NR 48 TC 40 Z9 41 U1 5 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2010 VL 49 IS 2 BP 1717 EP 1727 DI 10.1016/j.neuroimage.2009.09.065 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400055 PM 19804836 ER PT J AU Marsolek, CJ Deason, RG Ketz, NA Ramanathan, P Bernat, EM Steele, VR Patrick, CJ Verfaellie, M Schnyer, DM AF Marsolek, Chad J. Deason, Rebecca G. Ketz, Nicholas A. Ramanathan, Pradeep Bernat, Edward M. Steele, Vaughn R. Patrick, Christopher J. Verfaellie, Mieke Schnyer, David M. TI Identifying objects impairs knowledge of other objects: A relearning explanation for neural repetition effect SO NEUROIMAGE LA English DT Article ID CORTICAL ACTIVITY; TEMPORAL CORTEX; INFEROTEMPORAL CORTEX; NEUROIMAGING EVIDENCE; CEREBRAL-CORTEX; MEMORY; SUPPRESSION; MECHANISMS; REPRESENTATIONS; RECOGNITION AB Different items in long-term knowledge are stored in the neocortex as partially overlapping representations that can be altered slightly with usage. This encoding scheme affords well-documented benefits, but potential costs have not been well explored. Here we use functional magnetic resonance imaging (fMRI), neurocomputational modeling, and electrophysiological measures to show that strengthening some visual object representations not only enhances the subsequent ability to identify those (repeated) objects-an effect long known as repetition priming-but also impairs the ability to identify other (non-repeated) objects-a new effect labeled antipriming. As a result, the non-repeated objects elicit increased neural activity likely for the purpose of reestablishing their previously weakened representations. These results suggest a novel reevaluation of the ubiquitously observed repetition effect on neural activity, and they indicate that maintenance relearning may be a crucial aspect of preserving overlapping neural representations of visual objects in long-term memory. (C) 2009 Elsevier Inc. All rights reserved. C1 [Marsolek, Chad J.; Deason, Rebecca G.; Ketz, Nicholas A.; Ramanathan, Pradeep; Bernat, Edward M.; Steele, Vaughn R.; Patrick, Christopher J.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Verfaellie, Mieke] Boston VA Healthcare Syst, Boston, MA USA. [Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02215 USA. [Schnyer, David M.] Univ Texas Austin, Austin, TX 78712 USA. RP Marsolek, CJ (reprint author), Univ Minnesota, Dept Psychol, 75 E River Rd, Minneapolis, MN 55455 USA. EM chad.j.marsolek-1@umn.edu FU Medical Research Service of the Department of Veterans Affairs; Center for Cognitive Sciences in conjunction with the National Institute of Health and Human Development; University of Minnesota FX We thank Chris Azorson, Steve Engel, and Yuhong Jiang for valuable comments on a previous version of the manuscript; Susan Park Anderson, Sarah Davis, Sarah Fitch, Luke Kane, Alvina Kittur, Rachel LaNasa, Mithra Sathishkumar, and Benjamin Spear for help with data collection and analysis; and Randy O'Reilly for help with the simulation models. The research was supported by the National Institute of Mental Health (D.M.S., M.V., and C.J.M.). It was also supported by the Medical Research Service of the Department of Veterans Affairs and the Center for Cognitive Sciences in conjunction with the National Institute of Health and Human Development and the Office of the Vice President for Research and Dean of the Graduate School of the University of Minnesota. NR 56 TC 7 Z9 8 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2010 VL 49 IS 2 BP 1919 EP 1932 DI 10.1016/j.neuroimage.2009.08.063 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400076 PM 19744565 ER PT J AU Kang, JW Kim, P Alonzo, CA Park, H Yun, SH AF Kang, Jeon Woong Kim, Pilhan Alonzo, Carlo Amadeo Park, Hyunsung Yun, Seok H. TI Two-photon microscopy by wavelength-swept pulses delivered through single-mode fiber SO OPTICS LETTERS LA English DT Article ID ENCODED CONFOCAL MICROSCOPY; OPTICAL MICROSCOPY; IN-VIVO; FLUORESCENCE; LASER AB Nonlinear microscopy through flexible fiber-optic catheters has potential in clinical diagnostic applications. Here, we demonstrate a new approach based on wavelength-swept narrowband pulses that permits simple fiber-optic delivery without need of the dispersion management and allows nonmechanical beam scanning. Using 0.86 ps pulses rapidly tuned from 789 nm to 822 nm at a sweep rate of 200 Hz, we demonstrate two-photon fluorescence and second-harmonic generation imaging through a 5-m-long standard single-mode fiber. (C) 2010 Optical Society of America C1 [Kang, Jeon Woong; Kim, Pilhan; Alonzo, Carlo Amadeo; Park, Hyunsung; Yun, Seok H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kang, Jeon Woong; Kim, Pilhan; Alonzo, Carlo Amadeo; Park, Hyunsung; Yun, Seok H.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Park, Hyunsung; Yun, Seok H.] Korea Adv Inst Sci & Technol, Grad Sch Nanosci & Technol, Taejon 305701, South Korea. [Park, Hyunsung; Yun, Seok H.] Korea Adv Inst Sci & Technol, WCU Program, Taejon 305701, South Korea. RP Yun, SH (reprint author), Harvard Univ, Sch Med, 50 Blossom St,BAR 8, Boston, MA 02114 USA. EM syun@hms.harvard.edu RI Kim, Pilhan/C-1836-2011 OI Kim, Pilhan/0000-0001-8388-1840 FU National Science Foundation (NSF) [ECCS-0801412]; National Research Foundation of Korea [R312008-000-10071-0, KRF-2007-357C00036]; Human Frontier Science Program FX The authors acknowledge the support by the National Science Foundation (NSF) (ECCS-0801412), the National Research Foundation of Korea (R312008-000-10071-0 and fellowship KRF-2007-357C00036 to J. W. K.), and Human Frontier Science Program (Cross Disciplinary Fellowship to P. K.). NR 15 TC 4 Z9 4 U1 0 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD JAN 15 PY 2010 VL 35 IS 2 BP 181 EP 183 PG 3 WC Optics SC Optics GA 547IA UT WOS:000273879200030 PM 20081961 ER PT J AU Reichmann, WM Losina, E Seage, GR Arbelaez, C Safren, SA Katz, JN Hetland, A Walensky, RP AF Reichmann, William M. Losina, Elena Seage, George R., III Arbelaez, Christian Safren, Steven A. Katz, Jeffrey N. Hetland, Adam Walensky, Rochelle P. TI Does Modality of Survey Administration Impact Data Quality: Audio Computer Assisted Self Interview (ACASI) Versus Self-Administered Pen and Paper? SO PLOS ONE LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASE; EMERGENCY SEVERITY INDEX; RANDOMIZED-TRIAL; RISK BEHAVIORS; DRUG-USERS; HIV RISK; IMPLEMENTATION; MODE; BIAS AB Background: In the context of a randomized controlled trial (RCT) on HIV testing in the emergency department (ED) setting, we evaluated preferences for survey modality and data quality arising from each modality. Methods: Enrolled participants were offered the choice of answering a survey via audio computer assisted self-interview (ACASI) or pen and paper self-administered questionnaire (SAQ). We evaluated factors influencing choice of survey modality. We defined unusable data for a particular survey domain as answering fewer than 75% of the questions in the domain. We then compared ACASI and SAQ with respect to unusable data for domains that address sensitive topics. Results: Of 758 enrolled ED patients, 218 (29%) chose ACASI, 343 chose SAQ (45%) and 197 (26%) opted not to complete either. Results of the log-binomial regression indicated that older (RR = 1.08 per decade) and less educated participants (RR = 1.25) were more likely to choose SAQ over ACASI. ACASI yielded substantially less unusable data than SAQ. Conclusions: In the ED setting there may be a tradeoff between increased participation with SAQ versus better data quality with ACASI. Future studies of novel approaches to maximize the use of ACASI in the ED setting are needed. C1 [Reichmann, William M.; Losina, Elena; Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Reichmann, William M.; Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, Elena; Walensky, Rochelle P.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. [Seage, George R., III; Katz, Jeffrey N.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Arbelaez, Christian; Hetland, Adam] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Safren, Steven A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Reichmann, WM (reprint author), Brigham & Womens Hosp, Dept Orthoped Surg, 75 Francis St, Boston, MA 02115 USA. EM wreichmann@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU National Institute of Mental Health [R01 MH073445, R01 MH65869] FX Funding: This work was supported by the National Institute of Mental Health [R01 MH073445, R01 MH65869]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 16 Z9 17 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 15 PY 2010 VL 5 IS 1 AR e8728 DI 10.1371/journal.pone.0008728 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 545EI UT WOS:000273714900009 PM 20090953 ER PT J AU Rihel, J Prober, DA Arvanites, A Lam, K Zimmerman, S Jang, S Haggarty, SJ Kokel, D Rubin, LL Peterson, RT Schier, AF AF Rihel, Jason Prober, David A. Arvanites, Anthony Lam, Kelvin Zimmerman, Steven Jang, Sumin Haggarty, Stephen J. Kokel, David Rubin, Lee L. Peterson, Randall T. Schier, Alexander F. TI Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation SO SCIENCE LA English DT Article ID SLEEP; STRATEGIES; INHIBITORS; DISORDERS; DISCOVERY; EMBRYOS; HERG; MICE; QT AB A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. In addition, behavioral profiling implicated new factors such as ether-a-go-go-related gene ( ERG) potassium channels and immunomodulators in the control of rest and locomotor activity. These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors. C1 [Rihel, Jason; Prober, David A.; Zimmerman, Steven; Jang, Sumin; Schier, Alexander F.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Arvanites, Anthony; Lam, Kelvin; Rubin, Lee L.; Schier, Alexander F.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Haggarty, Stephen J.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kokel, David; Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Dev Biol Lab, Charlestown, MA 02129 USA. [Peterson, Randall T.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Schier, Alexander F.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA 02215 USA. [Schier, Alexander F.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. RP Rihel, J (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. EM rihel@fas.harvard.edu; schier@fas.harvard.edu RI Rihel, Jason/G-7106-2011; OI Rihel, Jason/0000-0003-4067-2066; Haggarty, Stephen J./0000-0002-7872-168X FU Life Sciences Research Foundation; Helen Hay Whitney Foundation; NIH [MH086867, MH085205]; Stanley Medical Research Institute; Harvard Stem Cell Institute; McKnight Endowment Fund for Neuroscience FX We thank J. Dowling, D. Milan, and G. Vanderlaan for suggestions and reagents and D. Schoppik, G. Uhl, and I. Woods for critical reading of the manuscript. Supported by a Bristol-Myers Squibb postdoctoral fellowship of the Life Sciences Research Foundation (J. R.), a Helen Hay Whitney Foundation postdoctoral fellowship (D. A. P.), a NIH Pathway to Independence grant (D. A. P.), the Stanley Medical Research Institute (S. J. H.), the Harvard Stem Cell Institute (L. L. R.), NIH grants MH086867 and MH085205 (R. T. P.), and grants from NIH and the McKnight Endowment Fund for Neuroscience (A. F. S.). L. L. R. is a founder of iPierian Inc., a biotechnology company, and is a member of its scientific advisory board. NR 19 TC 290 Z9 295 U1 4 U2 51 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 JAN 15 PY 2010 VL 327 IS 5963 BP 348 EP 351 DI 10.1126/science.1183090 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 544CM UT WOS:000273629700048 PM 20075256 ER PT J AU Bose-O'Reilly, S Drasch, G Beinhoff, C Rodrigues-Filho, S Roider, G Lettmeier, B Maydl, A Maydl, S Siebert, U AF Bose-O'Reilly, Stephan Drasch, Gustav Beinhoff, Christian Rodrigues-Filho, Saulo Roider, Gabriele Lettmeier, Beate Maydl, Alexandra Maydl, Stefan Siebert, Uwe TI Health assessment of artisanal gold miners in Indonesia SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Mercury; Neurotoxic; Artisanal gold mining; Indonesia; Environment; Health; Amalgam smelting; Mercury vapor ID BIOLOGICAL MONITORING VALUES; SEYCHELLES CHILD-DEVELOPMENT; 1998 GERES-III; MINING AREAS; ENVIRONMENTAL-POLLUTANTS; MERCURY CONTAMINATION; GERMAN POPULATION; PRENATAL EXPOSURE; METHYLMERCURY; PHILIPPINES AB Small scale miners use mercury to extract gold from ore in many countries. An environmental and health assessment was performed in Indonesia in two regions, Galangan in Central Kalimantan and Talawaan in Northern Sulawesi. The environmental assessment showed severe mercury contamination of the sediments, and increased mercury levels in local fish. For the health investigation 281 volunteers were recruited and examined by a standardized questionnaire, a neurological examination and neuro-psychological tests. A medical score was used consisting of significant factors of mercury intoxication. Mercury exposed workers showed typical symptoms of mercury intoxication, such as movement 'disorders (ataxia, tremor, dyschadochokinesia, etc.). Blood, urine and hair samples were taken from any participant and analyzed for mercury. The mercury concentration in the biomonitors was high, partly extreme high in the working population, increased in the population living in the same habitat and low in the control group. By a standard protocol which includes a combination of threshold values of mercury in the biomonitors and a medical sum score the diagnosis of chronic mercury intoxication was made for highly burdened workers (amalgam smelters) in 55% in Sulawesi and in 62% in Kalimantan. Less exposed mineral processors and the general population in the mining areas were also intoxicated to a high percentage. (C) 2009 Elsevier B.V. All rights reserved. C1 [Bose-O'Reilly, Stephan; Lettmeier, Beate; Siebert, Uwe] 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. [Drasch, Gustav; Roider, Gabriele; Lettmeier, Beate; Maydl, Alexandra; Maydl, Stefan] Univ Munich, Inst Forens Med, D-80336 Munich, Germany. [Rodrigues-Filho, Saulo] Univ Brasilia, CDS, BR-70910900 Brasilia, DF, Brazil. [Rodrigues-Filho, Saulo] Ctr Mineral Technol, Rio De Janeiro, Brazil. [Siebert, Uwe] Harvard Univ, Sch Med, Cardiovasc Res Program, Inst Technol Assessment, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. RP Bose-O'Reilly, S (reprint author), 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 stephan.boeseoreilly@umit.at RI Banks, Tamara/G-3007-2012 NR 35 TC 33 Z9 33 U1 5 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD JAN 15 PY 2010 VL 408 IS 4 BP 713 EP 725 DI 10.1016/j.scitotenv.2009.10.070 PG 13 WC Environmental Sciences SC Environmental Sciences & Ecology GA 547ZI UT WOS:000273928000004 PM 19945736 ER PT J AU Bose-O'Reilly, S Drasch, G Beinhoff, C Tesha, A Drasch, K Roider, G Taylor, H Appleton, D Siebert, U AF Bose-O'Reilly, Stephan Drasch, Gustav Beinhoff, Christian Tesha, Aloyce Drasch, Katalin Roider, Gabriele Taylor, Helen Appleton, Don Siebert, Uwe TI Health assessment of artisanal gold miners in Tanzania SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Mercury; Neurotoxic; Artisanal gold mining; Tanzania; Environment; Health; Amalgam smelting; Mercury vapor ID 1998 GERES-III; MERCURY CONTAMINATION; MINING AREAS; ENVIRONMENTAL-POLLUTANTS; GERMAN POPULATION; PHILIPPINES; EXPOSURE; FISH; METHYLMERCURY; MINDANAO AB In 2003 UNIDO (United Nations Industrial Development Organization) conducted an environmental and health assessment in a small-scale mining area in Tanzania. BGS (British Geological Survey) per-formed the environmental assessment. The Institute of Forensic Medicine - University of Munich performed the health assessment. The results of the medical, neurological and neuro-psychological examination of 180 participants from the affected area of Rwamagasa and 31 controls were analyzed. Urine. blood and hair samples were analyzed to detect the level of mercury body burden. Mercury concentrations in the bio-monitors urine, blood and hair were statistically significantly higher in the exposed population from Rwamagasa compared to the control group from Katoro. Only amalgam burners showed mercury levels above the toxicological threshold limits. A speciation of mercury in hair indicated that mainly elemental mercury vapor contributed to the high body burden of the artisanal miners. 104 amalgam-burners, the most exposed population group, were examined. 25 of these workers were found to be intoxicated. Small-scale mining is a serious health hazard for amalgam burners. Reduction of the exposure is essential to prevent further damage. (C) 2009 Elsevier B.V. All rights reserved. C1 [Bose-O'Reilly, Stephan; Siebert, Uwe] 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. [Drasch, Gustav; Drasch, Katalin; Roider, Gabriele] Univ Munich, Inst Forens Med, D-80636 Munich, Germany. [Tesha, Aloyce] Minist Energy & Minerals, Dar Es Salaam, Tanzania. [Tesha, Aloyce] UNIDO, Dar Es Salaam, Tanzania. [Taylor, Helen; Appleton, Don] British Geol Survey, Kingsley Dunham Ctr, Keyworth NG12 5GG, Notts, England. [Siebert, Uwe] Harvard Univ, Sch Med, Inst Technol Assessment, Cardiovasc Res Program, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. RP Bose-O'Reilly, S (reprint author), 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 stephan.boeseoreilly@umit.at RI Banks, Tamara/G-3007-2012 NR 34 TC 31 Z9 32 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD JAN 15 PY 2010 VL 408 IS 4 BP 796 EP 805 DI 10.1016/j.scitotenv.2009.10.051 PG 10 WC Environmental Sciences SC Environmental Sciences & Ecology GA 547ZI UT WOS:000273928000014 PM 19945738 ER PT J AU Nikolic, B Onoe, T Takeuchi, Y Khalpey, Z Primo, V Leykin, I Smith, RN Sykes, M AF Nikolic, Boris Onoe, Takashi Takeuchi, Yasuo Khalpey, Zain Primo, Valeria Leykin, Igor Smith, R. Neal Sykes, Megan TI Distinct Requirements for Achievement of Allotolerance Versus Reversal of Autoimmunity via Nonmyeloablative Mixed Chimerism Induction in NOD Mice SO TRANSPLANTATION LA English DT Article DE Tolerance; Immunology; Transplantation ID BONE-MARROW-TRANSPLANTATION; NONOBESE DIABETIC MICE; STEM-CELL TRANSPLANTATION; WHOLE-BODY IRRADIATION; HEMATOPOIETIC CHIMERISM; MONOCLONAL-ANTIBODIES; TOLERANCE INDUCTION; COSTIMULATORY BLOCKADE; ISLET TRANSPLANTATION; CONDITIONING REGIMEN AB Objectives. Mixed hematopoietic chimerism is associated with islet allograft tolerance and may reverse auto immunity, We developed low intensity regimens for the induction of mixed chimerism and examined the effects on autoimmunity in prediabetic nonobese diabetic (NOD) mice. Research Design and Methods. NOD mice received various combinations of total body irradiation, anti-CD154, anti-CD8 alpha, anti-CD4, and anti-Thy1.2 monoclonal antibodies, with or without transplantation of C57BL/6 bone marrow cells and were followed up for development of diabetes, chimerism, and donor skin graft survival. Autoimmunity was assessed by histologic examination of salivary glands and pancreata. Results. Although conditioning alone prevented or delayed the onset of diabetes, stable mixed chimerism was required for the reversal of isletitis. Mixed chimerism and skin graft tolerance were achieved in NOD mice receiving anti-CD154 with bone marrow transplantation as the means of tolerizing peripheral CD4(+) T cells to alloantigens. However, isletitis was not reversed in allotolerant mixed chimeras prepared with this regimen. Conclusions. Partial depletion of peripheral autoreactive NOD CD4(+) T cells is needed to achieve full reversal of isletitis by mixed chimerism induction from a protective donor strain, but it is not required for induction of specific tolerance to donor alloantigens. Thus, the requirements for tolerizing alloreactive and autoreactive NOD CD4 cells are distinct. C1 [Sykes, Megan] Harvard Univ, Bone Marrow Transplantat Sect, Sch Med, Massachusetts Gen Hosp,Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Nikolic, Boris; Primo, Valeria] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA 02129 USA. [Smith, R. Neal] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, Bone Marrow Transplantat Sect, Sch Med, Massachusetts Gen Hosp,Transplantat Biol Res Ctr, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. EM megan.sykes@tbrc.mgh.harvard.edu FU Juvenile Diabetes Foundation Center for Islet Transplantation at Harvard Medical School; JDRF Center on Immunological Tolerance in Type I Diabetes; NIH/NHLBI [R01 HL049915]; NIH/NIDDK [R03 DK067940]; National Kidney Foundation; Uehara Memorial Foundation FX This work was supported in part by the Juvenile Diabetes Foundation Center for Islet Transplantation at Harvard Medical School, the JDRF Center on Immunological Tolerance in Type I Diabetes, the NIH/NHLBI R01 HL049915, the NIH/NIDDK R03 DK067940, The Patricia Welder Robinson Young Investigator Grant of the National Kidney Foundation (B.N.), and a Postdoctoral Fellowship for study abroad from the Uehara Memorial Foundation (T.O.). NR 45 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2010 VL 89 IS 1 BP 23 EP 32 DI 10.1097/TP.0b013e3181c4692e PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 543DQ UT WOS:000273551000003 PM 20061915 ER PT J AU Osawa, R Alexander, BD Lortholary, O Dromer, F Forrest, GN Lyon, GM Somani, J Gupta, KL del Busto, R Pruett, TL Sifri, CD Limaye, AP John, GT Klintmalm, GB Pursell, K Stosor, V Morris, MI Dowdy, LA Munoz, P Kalil, AC Garcia-Diaz, J Orloff, S House, AA Houston, S Wray, D Huprikar, S Johnson, LB Humar, A Razonable, RR Fisher, RA Husain, S Wagener, MM Singh, N AF Osawa, Ryosuke Alexander, Barbara D. Lortholary, Olivier Dromer, Francoise Forrest, Graeme N. Lyon, G. Marshall Somani, Jyoti Gupta, Krishan L. del Busto, Ramon Pruett, Timothy L. Sifri, Costi D. Limaye, Ajit P. John, George T. Klintmalm, Goran B. Pursell, Kenneth Stosor, Valentina Morris, Michele I. Dowdy, Lorraine A. Munoz, Patricia Kalil, Andre C. Garcia-Diaz, Julia Orloff, Susan House, Andrew A. Houston, Sally Wray, Dannah Huprikar, Shirish Johnson, Leonard B. Humar, Atul Razonable, Raymund R. Fisher, Robert A. Husain, Shahid Wagener, Marilyn M. Singh, Nina TI Identifying Predictors of Central Nervous System Disease in Solid Organ Transplant Recipients With Cryptococcosis SO TRANSPLANTATION LA English DT Article DE Cryptococcosis; Solid organ transplant; Central nervous system disease ID HEMATOPOIETIC STEM-CELL; NEOFORMANS INFECTION; PRACTICE GUIDELINES; MENINGITIS; MANAGEMENT AB Background. Cerebrospinal fluid (CSF) analysis is often deferred in patients with cryptococcal disease, particularly in the absence of neurologic manifestations. We sought to determine whether a subset of solid organ transplant (SOT) recipients with high likelihood of central nervous system (CNS) disease could be identified in whom CSF analysis must be performed. Methods. Patients comprised a multicenter cohort of SOT recipients with cryptococcosis. Results. Of 129 (88%) of 146 SOT recipients with cryptococcosis who underwent CSF analysis, 80 (62%) had CNS disease. In the overall study population, abnormal mental status, time to onset of cryptococcosis more than 24 months posttransplantation (late-onset disease), serum cryptococcal antigen titer more than 1:64, and fungemia were independently associated with an increased risk of CNS disease. Of patients with abnormal mental status, 95% had CNS cryptococcosis. When only patients with normal mental status were considered, three predictors (serum antigen titer >1:64, fungemia, and late-onset disease) independently identified patients with CNS cryptococcosis; the risk of CNS disease was 14% if none, 39% if one, and 94% if two of the aforementioned predictors existed (chi(2) for trend P<0.001). Conclusions. CSF analysis should be strongly considered in SOT recipients with cryptococcosis who have late-onset disease, fungemia, or serum cryptococcal antigen titer more than 1:64 even in the presence of normal mental status. C1 [Osawa, Ryosuke; Singh, Nina] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Osawa, Ryosuke; Husain, Shahid; Wagener, Marilyn M.; Singh, Nina] Univ Pittsburgh, Pittsburgh, PA USA. [Alexander, Barbara D.] Duke Univ, Med Ctr, Durham, NC USA. [Lortholary, Olivier] Hop Necker Enfants Malad, Fac Med Paris Descartes, Paris, France. [Lortholary, Olivier; Dromer, Francoise] Inst Pasteur, Paris, France. [Lyon, G. Marshall; Somani, Jyoti] Emory Univ, Atlanta, GA 30322 USA. [Gupta, Krishan L.] Postgrad Inst Med Educ & Res, Chandigarh 160012, Punjab, India. [del Busto, Ramon] Henry Ford Hosp, Detroit, MI 48202 USA. [Pruett, Timothy L.; Sifri, Costi D.] Univ Virginia, Charlottesville, VA USA. [Pruett, Timothy L.; Sifri, Costi D.] Univ Minnesota, Minneapolis, MN USA. [Limaye, Ajit P.] Univ Washington, Seattle, WA 98195 USA. [John, George T.] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Klintmalm, Goran B.] Baylor Univ, Med Ctr, Dallas, TX USA. [Pursell, Kenneth] Univ Chicago, Chicago, IL 60637 USA. [Stosor, Valentina] Northwestern Univ, Chicago, IL 60611 USA. [Morris, Michele I.; Dowdy, Lorraine A.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Munoz, Patricia] Hosp Gen Univ Gregorio Maranon, CIBER Enfermedades Resp CIBERES, Madrid, Spain. [Kalil, Andre C.] Univ Nebraska, Omaha, NE 68182 USA. [Garcia-Diaz, Julia] Ochsner Clin & Alton Ochsner Med Fdn, New Orleans, LA USA. [Orloff, Susan] Oregon Hlth & Sci Univ, Portland, OR USA. [House, Andrew A.] Univ Western Ontario, London, ON, Canada. [Houston, Sally] Tampa Gen Hosp, Tampa, FL 33606 USA. [Wray, Dannah] Med Univ S Carolina, Charleston, SC 29425 USA. [Huprikar, Shirish] Mt Sinai Med Ctr, New York, NY 10029 USA. [Johnson, Leonard B.] St Johns Hosp, Detroit, MI USA. [Humar, Atul] Toronto Gen Hosp, Univ Hlth Network, Toronto, ON, Canada. [Forrest, Graeme N.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Razonable, Raymund R.] Mayo Clin, Rochester, MN USA. [Fisher, Robert A.] Virginia Commonwealth Univ, Richmond, VA USA. RP Singh, N (reprint author), Vet Adm Med Ctr, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu RI Garcia-Diaz, Julia/D-3555-2011; OI Munoz Garcia, Patricia Carmen/0000-0001-5706-5583 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01 AI 054719-01]; Astellas; Enzon; Pfizer; Merck; Basilea; Schering-Plough FX This work was Supported by National Institutes of Health, National Institute of Allergy and infectious Diseases (R01 AI 054719-01; N.S.).; B.D.A. has served on advisory board for Enzon, Basilea, Abbott, and Schering-Plough, served on the speaker's bureau of Astellas and Pfizer, and received grant from Astellas, Enzon, and Pfizer; G.N.F. has received grant from Astellas. G.M.L. has served on advisory board for and received grant front Merck and Astellas and served on speaker's bureau of Astellas, Schering-Plough, and Wyeth; K.P. has served on speaker's bureau of Merck; M.I.M. has served on advisory board for Astellas, Pfizer, and Merck, received grant from Astellas, Basilea, and Pfizer, and served on speaker's bureau of Astellas and Pfizer; P.M. has served on the speaker's bureau of Merck and Novartis and served on advisory board for Pfizer; L.B.J. has served on speaker's bureau of Pfizer; and S. Husain has served on consultant board for and received grant from Pfizer, Astellas, and Schering-Plough; N.S. has received grant from Pfizer; and the other authors have no conflict of interests. NR 22 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2010 VL 89 IS 1 BP 69 EP 74 DI 10.1097/TP.0b013e3181bcda41 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 543DQ UT WOS:000273551000009 PM 20061921 ER PT J AU Provan, D Stasi, R Newland, AC Blanchette, VS Bolton-Maggs, P Bussel, JB Chong, BH Cines, DB Gernsheimer, TB Godeau, B Grainger, J Greer, I Hunt, BJ Imbach, PA Lyons, G McMillan, R Rodeghiero, F Sanz, MA Tarantino, M Watson, S Young, J Kuter, DJ AF Provan, Drew Stasi, Roberto Newland, Adrian C. Blanchette, Victor S. Bolton-Maggs, Paula Bussel, James B. Chong, Beng H. Cines, Douglas B. Gernsheimer, Terry B. Godeau, Bertrand Grainger, John Greer, Ian Hunt, Beverley J. Imbach, Paul A. Lyons, Gordon McMillan, Robert Rodeghiero, Francesco Sanz, Miguel A. Tarantino, Michael Watson, Shirley Young, Joan Kuter, David J. TI International consensus report on the investigation and management of primary immune thrombocytopenia SO BLOOD LA English DT Review ID INTRAVENOUS ANTI-D; HIGH-DOSE DEXAMETHASONE; QUALITY-OF-LIFE; ITP-STUDY-GROUP; THROMBOPOIESIS-STIMULATING PEPTIBODY; NEONATAL ALLOIMMUNE THROMBOCYTOPENIA; REFRACTORY AUTOIMMUNE CYTOPENIAS; ANTI-CD20 MONOCLONAL-ANTIBODY; RANDOMIZED CONTROLLED-TRIAL; INFLAMMATORY-BOWEL-DISEASE AB Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making. (Blood. 2010; 115:168-186) C1 [Provan, Drew; Newland, Adrian C.] Barts & London Queen Marys Sch Med & Dent, Dept Haematol, London E1 2ES, England. [Stasi, Roberto] NHS Trust, St Georges Healthcare, Dept Haematol, London, England. [Blanchette, Victor S.] Univ Toronto, Hosp Sick Children, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada. [Bolton-Maggs, Paula] Manchester Royal Infirm, Dept Clin Haematol, Manchester M13 9WL, Lancs, England. [Bussel, James B.] New York Hosp, Dept Pediat, New York, NY 10021 USA. [Chong, Beng H.] Univ New S Wales, St George Clin Sch, Sydney, NSW, Australia. [Cines, Douglas B.] Hosp Univ Penn, Dept Pathol & Lab, Philadelphia, PA 19104 USA. [Gernsheimer, Terry B.] Puget Sound Blood Ctr, Seattle, WA 98104 USA. [Gernsheimer, Terry B.] Univ Washington, Seattle, WA 98195 USA. [Godeau, Bertrand] Assistance Publ Hop Paris, Serv Med Interne, Paris, France. [Grainger, John] Royal Manchester Childrens Hosp, Manchester M27 1HA, Lancs, England. [Greer, Ian] Univ York, Hull York Med Sch, York YO10 5DD, N Yorkshire, England. [Hunt, Beverley J.] Kings Coll London, London WC2R 2LS, England. [Hunt, Beverley J.] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Dept Haematol, London, England. [Hunt, Beverley J.] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Dept Pathol, London, England. [Hunt, Beverley J.] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Dept Rheumatol, London, England. [Imbach, Paul A.] Univ Childrens Hosp, Basel, Switzerland. [Lyons, Gordon] St James Univ Hosp, Leeds LS9 7TF, W Yorkshire, England. [McMillan, Robert] Scripps Res Inst, La Jolla, CA 92037 USA. [Rodeghiero, Francesco] San Bortolo Hosp, Dept Cell Therapy & Hematol, Vicenza, Italy. [Sanz, Miguel A.] Hosp Univ La Fe, Dept Haematol, Valencia, Spain. [Tarantino, Michael] Comprehens Bleeding Disorders Ctr, Peoria, IL USA. [Watson, Shirley] ITP Support Assoc, Bedford, England. [Young, Joan] Platelet Disorder Support Assoc, Rockville, MD USA. [Kuter, David J.] Massachusetts Gen Hosp, Dept Hematol, Boston, MA 02114 USA. [Kuter, David J.] Harvard Univ, Sch Med, Boston, MA USA. RP Provan, D (reprint author), Barts & London Queen Marys Sch Med & Dent, Dept Haematol, 80 Newark St, London E1 2ES, England. EM a.b.provan@qmul.ac.uk FU Amgen Ltd; Baxter Ltd; GlaxoSmithKline Ltd FX The writing and project management of this consensus document were supported by an unrestricted grant provided by Amgen Ltd, Baxter Ltd, and GlaxoSmithKline Ltd. Frances Essex, MSc, Senior Medical Writer, ScopeMedical Ltd, provided writing assistance throughout the project; Rebecca Hunt, Account Director, ScopeMedical Ltd, provided project management; and Keely Jennings BA, Editorial Services Manager, ScopeMedical Ltd, provided editorial assistance throughout the project. NR 206 TC 630 Z9 702 U1 5 U2 40 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 JAN 14 PY 2010 VL 115 IS 2 BP 168 EP 186 DI 10.1182/blood-2009-06-225565 PG 19 WC Hematology SC Hematology GA 544AE UT WOS:000273622600006 PM 19846889 ER PT J AU Schlett, CL Doll, H Dahmen, J Polacsek, O Federkeil, G Fischer, MR Bamberg, F Butzlaff, M AF Schlett, Christopher L. Doll, Hinnerk Dahmen, Janosch Polacsek, Ole Federkeil, Gero Fischer, Martin R. Bamberg, Fabian Butzlaff, Martin TI Job requirements compared to medical school education: differences between graduates from problem-based learning and conventional curricula SO BMC MEDICAL EDUCATION LA English DT Article ID GENERAL COMPETENCES; PHYSICIAN; OUTCOMES AB Background: Problem-based Learning (PBL) has been suggested as a key educational method of knowledge acquisition to improve medical education. We sought to evaluate the differences in medical school education between graduates from PBL-based and conventional curricula and to what extent these curricula fit job requirements. Methods: Graduates from all German medical schools who graduated between 1996 and 2002 were eligible for this study. Graduates self-assessed nine competencies as required at their day-to-day work and as taught in medical school on a 6-point Likert scale. Results were compared between graduates from a PBL-based curriculum (University Witten/Herdecke) and conventional curricula. Results: Three schools were excluded because of low response rates. Baseline demographics between graduates of the PBL-based curriculum (n = 101, 49% female) and the conventional curricula (n = 4720, 49% female) were similar. No major differences were observed regarding job requirements with priorities for "Independent learning/working" and "Practical medical skills". All competencies were rated to be better taught in PBL-based curriculum compared to the conventional curricula (all p < 0.001), except for "Medical knowledge" and "Research competence". Comparing competencies required at work and taught in medical school, PBL was associated with benefits in "Interdisciplinary thinking" (Delta + 0.88), "Independent learning/working" (Delta + 0.57), "Psycho-social competence" (Delta + 0.56), "Teamwork" (Delta + 0.39) and "Problem-solving skills" (Delta + 0.36), whereas "Research competence" (Delta - 1.23) and "Business competence" (Delta - 1.44) in the PBL-based curriculum needed improvement. Conclusion: Among medical graduates in Germany, PBL demonstrated benefits with regard to competencies which were highly required in the job of physicians. Research and business competence deserve closer attention in future curricular development. C1 [Butzlaff, Martin] Private Univ Witten Herdecke, Board Directors, Witten, Germany. [Schlett, Christopher L.; Doll, Hinnerk; Dahmen, Janosch; Polacsek, Ole; Fischer, Martin R.] Private Univ Witten Herdecke, Inst Teaching & Educ Res Hlth Sci, Witten, Germany. [Schlett, Christopher L.; Bamberg, Fabian] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Schlett, Christopher L.; Bamberg, Fabian] Harvard Univ, Sch Med, Boston, MA USA. [Federkeil, Gero] Ctr Higher Educ Dev, Gutersloh, Germany. [Bamberg, Fabian] Univ Munich, Univ Hosp Munich, Dept Clin Radiol, Munich, Germany. RP Butzlaff, M (reprint author), Private Univ Witten Herdecke, Board Directors, Witten, Germany. EM butzlaff@uni-wh.de NR 29 TC 6 Z9 8 U1 3 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6920 J9 BMC MED EDUC JI BMC Med. Educ. PD JAN 14 PY 2010 VL 10 AR 1 DI 10.1186/1472-6920-10-1 PG 8 WC Education & Educational Research; Education, Scientific Disciplines SC Education & Educational Research GA 688GO UT WOS:000284838000001 PM 20074350 ER PT J AU Kajiwara, Y Franciosi, S Takahashi, N Krug, L Schmeidler, J Taddei, K Haroutunian, V Fried, U Ehrlich, M Martins, RN Gandy, S Buxbaum, JD AF Kajiwara, Yuji Franciosi, Sonia Takahashi, Nagahide Krug, Lisa Schmeidler, James Taddei, Kevin Haroutunian, Vahram Fried, Ulrik Ehrlich, Michelle Martins, Ralph N. Gandy, Samuel Buxbaum, Joseph D. TI Extensive proteomic screening identifies the obesity-related NYGGF4 protein as a novel LRP1-interactor, showing reduced expression in early Alzheimer's disease SO MOLECULAR NEURODEGENERATION LA English DT Article ID RECEPTOR-RELATED PROTEIN; AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN-E RECEPTOR; ISOFORM-SPECIFIC MANNER; CYTOPLASMIC DOMAIN; E GENE; LIPOPROTEIN; LRP; BINDING; MICE AB Background: The low-density lipoprotein receptor related protein 1 (LRP1) has been implicated in Alzheimer's disease (AD) but its signalling has not been fully evaluated. There is good evidence that the cytoplasmic domain of LRP1 is involved in protein-protein interactions, important in the cell biology of LRP1. Results: We carried out three yeast two-hybrid screens to identify proteins that interact with the cytoplasmic domain of LRP1. The screens included both conventional screens as well as a novel, split-ubiquitin-based screen in which an LRP1 construct was expressed and screened as a transmembrane protein. The split-ubiquitin screen was validated in a screen using full-length amyloid protein precursor (APP), which successfully identified FE65 and FE65L2, as well as novel interactors (Rab3a, Napg, and ubiquitin b). Using both a conventional screen as well as the split-ubiquitin screen, we identified NYGGF4 as a novel LRP1 interactor. The interaction between LRP1 and NYGGF4 was validated using two-hybrid assays, coprecipitation and colocalization in mammalian cells. Mutation analysis demonstrated a specific interaction of NYGGF4 with an NPXY motif that required an intact tyrosine residue. Interestingly, while we confirmed that other LRP1 interactors we identified, including JIP1B and EB-1, were also able to bind to APP, NYGGF4 was unique in that it showed specific binding with LRP1. Expression of NYGGF4 decreased significantly in patients with AD as compared to age-matched controls, and showed decreasing expression with AD disease progression. Examination of Nyggf4 expression in mice with different alleles of the human APOE4 gene showed significant differences in Nyggf4 expression. Conclusions: These results implicate NYGGF4 as a novel and specific interactor of LRP1. Decreased expression of LRP1 and NYGGF4 over disease, evident with the presence of even moderate numbers of neuritic plaques, suggests that LRP1-NYGGF4 is a system altered early in disease. Genetic and functional studies have implicated both LRP1 and NYGGF4 in obesity and cardiovascular disease and the physical association of these proteins may reflect a common mechanism. This is particularly interesting in light of the dual role of ApoE in both cardiovascular risk and AD. The results support further studies on the functional relationship between NYGGF4 and LRP1. C1 [Kajiwara, Yuji; Franciosi, Sonia; Takahashi, Nagahide; Krug, Lisa; Fried, Ulrik; Buxbaum, Joseph D.] Mt Sinai Sch Med, Lab Mol Neuropsychiat, New York, NY 10029 USA. [Kajiwara, Yuji; Franciosi, Sonia; Takahashi, Nagahide; Krug, Lisa; Schmeidler, James; Haroutunian, Vahram; Fried, Ulrik; Gandy, Samuel; Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Kajiwara, Yuji; Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Taddei, Kevin; Martins, Ralph N.] Edith Cowan Univ, Sch Exercise Biomed & Hlth Sci, Ctr Excellence Alzheimers Dis Res Care, Joondalup, WA, Australia. [Taddei, Kevin] Hollywood Private Hosp, Sir James McCusker Alzheimers Dis Res Unit, Perth, WA, Australia. [Haroutunian, Vahram] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [Ehrlich, Michelle; Gandy, Samuel] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Buxbaum, JD (reprint author), Mt Sinai Sch Med, Lab Mol Neuropsychiat, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM joseph.buxbaum@mssm.edu OI Buxbaum, Joseph/0000-0001-8898-8313 FU National Institute of Aging of the National Institutes of Health [AG010491, AG005138, AG002219, AG21792] FX A part of this work was carried out at the Marine Biological Laboratory, Woods Hole, MA. We thank Dr. Guojun Bu for the mLRP4 construct, Dr. Eddie Koo for anti-LRP1, and Rebecca Vitale for her help with this study. This work was supported by grants from the National Institute of Aging of the National Institutes of Health [AG010491 (SEG, PI; JDB, PL), AG005138 (Mary Sano, PI; JDB, PL), AG002219 (VH, PI; JDB, PL), and AG21792 (JDB, PI)]. JDB is the G. Harold and Leila Y. Mathers Professor of Geriatrics and Adult Development. NR 51 TC 7 Z9 8 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD JAN 14 PY 2010 VL 5 AR 1 DI 10.1186/1750-1326-5-1 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 559QA UT WOS:000274839800001 PM 20205790 ER PT J AU Pleasance, ED Cheetham, RK Stephens, PJ McBride, DJ Humphray, SJ Greenman, CD Varela, I Lin, ML Ordonez, GR Bignell, GR Ye, K Alipaz, J Bauer, MJ Beare, D Butler, A Carter, RJ Chen, LN Cox, AJ Edkins, S Kokko-Gonzales, PI Gormley, NA Grocock, RJ Haudenschild, CD Hims, MM James, T Jia, MM Kingsbury, Z Leroy, C Marshall, J Menzies, A Mudie, LJ Ning, ZM Royce, T Schulz-Trieglaff, OB Spiridou, A Stebbings, LA Szajkowski, L Teague, J Williamson, D Chin, L Ross, MT Campbell, PJ Bentley, DR Futreal, PA Stratton, MR AF Pleasance, Erin D. Cheetham, R. Keira Stephens, Philip J. McBride, David J. Humphray, Sean J. Greenman, Chris D. Varela, Ignacio Lin, Meng-Lay Ordonez, Gonzalo R. Bignell, Graham R. Ye, Kai Alipaz, Julie Bauer, Markus J. Beare, David Butler, Adam Carter, Richard J. Chen, Lina Cox, Anthony J. Edkins, Sarah Kokko-Gonzales, Paula I. Gormley, Niall A. Grocock, Russell J. Haudenschild, Christian D. Hims, Matthew M. James, Terena Jia, Mingming Kingsbury, Zoya Leroy, Catherine Marshall, John Menzies, Andrew Mudie, Laura J. Ning, Zemin Royce, Tom Schulz-Trieglaff, Ole B. Spiridou, Anastassia Stebbings, Lucy A. Szajkowski, Lukasz Teague, Jon Williamson, David Chin, Lynda Ross, Mark T. Campbell, Peter J. Bentley, David R. Futreal, P. Andrew Stratton, Michael R. TI A comprehensive catalogue of somatic mutations from a human cancer genome SO NATURE LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; ETS TRANSCRIPTION FACTOR; MYELOID-LEUKEMIA GENOME; SKIN-CANCER; PATHWAYS; MELANOMA; CARCINOGENESIS; EPIDEMIOLOGY; MECHANISMS; EXPRESSION AB All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic. C1 [Pleasance, Erin D.; Stephens, Philip J.; McBride, David J.; Greenman, Chris D.; Varela, Ignacio; Lin, Meng-Lay; Ordonez, Gonzalo R.; Bignell, Graham R.; Beare, David; Butler, Adam; Chen, Lina; Edkins, Sarah; Jia, Mingming; Leroy, Catherine; Marshall, John; Menzies, Andrew; Mudie, Laura J.; Ning, Zemin; Stebbings, Lucy A.; Teague, Jon; Campbell, Peter J.; Futreal, P. Andrew; Stratton, Michael R.] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Cheetham, R. Keira; Humphray, Sean J.; Bauer, Markus J.; Carter, Richard J.; Cox, Anthony J.; Kokko-Gonzales, Paula I.; Gormley, Niall A.; Grocock, Russell J.; Hims, Matthew M.; James, Terena; Kingsbury, Zoya; Schulz-Trieglaff, Ole B.; Spiridou, Anastassia; Szajkowski, Lukasz; Ross, Mark T.; Bentley, David R.] Illumina Cambridge Ltd, Saffron Walden CB10 1XL, Essex, England. [Ye, Kai] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2333 ZC Leiden, Netherlands. [Ye, Kai] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, NL-2333 ZC Leiden, Netherlands. [Alipaz, Julie; Royce, Tom] Illumina Inc, Corp Headquarters, San Diego, CA 92121 USA. [Haudenschild, Christian D.; Williamson, David] Illumina Hayward, Hayward, CA 94545 USA. [Chin, Lynda] Dana Farber Canc Inst, Boston, MA 02115 USA. [Stratton, Michael R.] Inst Canc Res, Sutton SM2 5NG, Surrey, England. RP Stratton, MR (reprint author), Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. EM paf@sanger.ac.uk; mrs@sanger.ac.uk RI Bell, Tiffany/F-4403-2010; Ye, Kai/B-3640-2012; Ning, Zemin/D-2411-2013; Tang, Macy/B-9798-2014; Varela, Ignacio/G-1699-2016; OI Varela, Ignacio/0000-0002-0969-506X; Ning, Zemin/0000-0003-4359-776X FU Wellcome Trust [077012/Z/05/Z] FX The authors acknowledge the support of C. Henry, S. Kahn, D. Evers, G. Smith, K. Hall and the technical and administrative support staff at Illumina. I. V. is supported by the Human Frontiers Science Program and P.J.C. by the Kay Kendall Leukaemia Fund. We would like to acknowledge the Wellcome Trust for support under grant reference 077012/Z/05/Z. NR 41 TC 781 Z9 803 U1 9 U2 103 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 14 PY 2010 VL 463 IS 7278 BP 191 EP U73 DI 10.1038/nature08658 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543MQ UT WOS:000273582700027 PM 20016485 ER PT J AU McMahon, GT Blake, MA Wu, CL AF McMahon, Graham T. Blake, Michael A. Wu, Chin-Lee TI A Man with Hypertension, Hyperglycemia, and Edema Secondary Cushing's syndrome due to metastatic small-cell carcinoma of prostatic origin SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ECTOPIC ACTH; ADENOCARCINOMA; THERAPY; MANAGEMENT; CANCER C1 [McMahon, Graham T.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Dept Med, Boston, MA 02115 USA. [Blake, Michael A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [McMahon, Graham T.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Blake, Michael A.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Wu, Chin-Lee] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP McMahon, GT (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Dept Med, Boston, MA 02115 USA. RI McMahon, Graham/D-3740-2009 OI McMahon, Graham/0000-0003-4288-6535 NR 31 TC 4 Z9 5 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 JAN 14 PY 2010 VL 362 IS 2 BP 156 EP 166 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 543FU UT WOS:000273558500015 PM 20071706 ER PT J AU Sykes, M AF Sykes, Megan TI Immune Evasion by Chimeric Trachea SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TRANSPLANTATION; TOLERANCE; ALLOGRAFTS; RESPONSES; MICE C1 [Sykes, Megan] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sykes, Megan] Massachusetts Gen Hosp, Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Sykes, M (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. FU NHLBI NIH HHS [R01 HL063474, P01 HL018646]; NIAID NIH HHS [R01 AI055581] NR 12 TC 8 Z9 9 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 JAN 14 PY 2010 VL 362 IS 2 BP 172 EP 174 DI 10.1056/NEJMe0908366 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 543FU UT WOS:000273558500018 PM 20071709 ER PT J AU Li, JF Li, L Sheen, J AF Li, Jian-Feng Li, Li Sheen, Jen TI Protocol: a rapid and economical procedure for purification of plasmid or plant DNA with diverse applications in plant biology SO PLANT METHODS LA English DT Article ID GENE-EXPRESSION ANALYSIS; TRANSFORMATION; ARABIDOPSIS; EXTRACTION; VECTORS AB Research in plant molecular biology involves DNA purification on a daily basis. Although different commercial kits enable convenient extraction of high-quality DNA from E. coli cells, PCR and agarose gel samples as well as plant tissues, each kit is designed for a particular type of DNA extraction work, and the cost of purchasing these kits over a long run can be considerable. Furthermore, a simple method for the isolation of binary plasmid from Agrobacterium tumefaciens cells with satisfactory yield is lacking. Here we describe an easy protocol using homemade silicon dioxide matrix and seven simple solutions for DNA extraction from E. coli and A. tumefaciens cells, PCR and restriction digests, agarose gel slices, and plant tissues. Compared with the commercial kits, this protocol allows rapid DNA purification from diverse sources with comparable yield and purity at negligible cost. Following this protocol, we have demonstrated: (1) DNA fragments as small as a MYC-epitope tag coding sequence can be successfully recovered from an agarose gel slice; (2) Miniprep DNA from E. coli can be eluted with as little as 5 mu l water, leading to high DNA concentrations (> 1 mu g/mu l) for efficient biolistic bombardment of Arabidopsis seedlings, polyethylene glycol (PEG)-mediated Arabidopsis protoplast transfection and maize protoplast electroporation; (3) Binary plasmid DNA prepared from A. tumefaciens is suitable for verification by restriction analysis without the need for large scale propagation; (4) High-quality genomic DNA is readily isolated from several plant species including Arabidopsis, tobacco and maize. Thus, the silicon dioxide matrix-based DNA purification protocol offers an easy, efficient and economical way to extract DNA for various purposes in plant research. C1 [Li, Jian-Feng; Li, Li; Sheen, Jen] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Li, Jian-Feng; Li, Li; Sheen, Jen] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Li, JF (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM jli@molbio.mgh.harvard.edu RI Li, Jian-Feng/H-4307-2011 FU NIH R01 [GM070567, GM060493] FX We are grateful to Dr. Andreas Nebenfuh (University of Tennessee) for the generous gifts of pAN-GFP and pPZP222 vectors. This work was sponsored by NIH R01 grants GM070567 and GM060493 to J. S. NR 12 TC 7 Z9 7 U1 5 U2 37 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-4811 J9 PLANT METHODS JI Plant Methods PD JAN 14 PY 2010 VL 6 AR 1 DI 10.1186/1746-4811-6-1 PG 8 WC Biochemical Research Methods; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA 562HB UT WOS:000275039700001 ER PT J AU Hui, KKS Marina, O Claunch, JD Nixon, EE Fang, JL Liu, J Li, M Napadow, V Vangel, M Makris, N Chan, ST Kwong, KK Rosen, BR AF Hui, Kathleen K. S. Marina, Ovidiu Claunch, Joshua D. NiXon, Erika E. Fang, Jiliang Liu, Jing Li, Ming Napadow, Vitaly Vangel, Mark Makris, Nikos Chan, Suk-Tak Kwong, Kenneth K. Rosen, Bruce R. TI Acupuncture mobilizes the brain's default mode and its anti-correlated network in healthy subjects (vol 1287, pg 84, 2009) SO BRAIN RESEARCH LA English DT Correction C1 [Hui, Kathleen K. S.; Marina, Ovidiu; Claunch, Joshua D.; NiXon, Erika E.; Fang, Jiliang; Liu, Jing; Li, Ming; Napadow, Vitaly; Vangel, Mark; Chan, Suk-Tak; Kwong, Kenneth K.; Rosen, Bruce R.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hui, Kathleen K. S.; Marina, Ovidiu; Claunch, Joshua D.; NiXon, Erika E.; Fang, Jiliang; Liu, Jing; Li, Ming; Napadow, Vitaly; Vangel, Mark; Makris, Nikos; Chan, Suk-Tak; Kwong, Kenneth K.; Rosen, Bruce R.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Marina, Ovidiu] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Fang, Jiliang] China Acad Tradit Chinese Med, Dept Radiol, Guang An Men Hosp, Beijing, Peoples R China. [Makris, Nikos] Massachusetts Gen Hosp, Dept Neurol, Ctr Morphometr Anal, Charlestown, MA 02129 USA. [Chan, Suk-Tak] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. RP Hui, KKS (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM hui@nmr.mgh.harvard.edu RI Chan, Suk-tak/G-5846-2015 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 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 13 PY 2010 VL 1308 BP 185 EP 185 DI 10.1016/j.brainres.2009.10.017 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 555LT UT WOS:000274513000019 ER PT J AU Goldstein, JM Jerram, M Abbs, B Whitfield-Gabrieli, S Makris, N AF Goldstein, Jill M. Jerram, Matthew Abbs, Brandon Whitfield-Gabrieli, Susan Makris, Nikos TI Sex Differences in Stress Response Circuitry Activation Dependent on Female Hormonal Cycle SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; ESTROGEN-RECEPTOR-BETA; GENDER-DIFFERENCES; PARAVENTRICULAR NUCLEUS; MENSTRUAL-CYCLE; VISUAL-STIMULI; WOMEN; FMRI; HYPOTHALAMUS; ESTRADIOL AB Understanding sex differences in stress regulation has important implications for understanding basic physiological differences in the male and female brain and their impact on vulnerability to sex differences in chronic medical disorders associated with stress response circuitry. In this functional magnetic resonance imaging study, we demonstrated that significant sex differences in brain activity in stress response circuitry were dependent on women's menstrual cycle phase. Twelve healthy Caucasian premenopausal women were compared to a group of healthy men from the same population, based on age, ethnicity, education, and right handedness. Subjects were scanned using negative valence/high arousal versus neutral visual stimuli that we demonstrated activated stress response circuitry [amygdala, hypothalamus, hippocampus, brainstem, orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and anterior cingulate gyrus (ACG)]. Women were scanned twice based on normal variation in menstrual cycle hormones [i. e., early follicular (EF) compared with late follicular-midcycle (LF/MC) menstrual phases]. Using SPM8b, there were few significant differences in blood oxygenation level-dependent (BOLD) signal changes in men compared to EF women, except ventromedial nucleus (VMN), lateral hypothalamic area (LHA), left amygdala, and ACG. In contrast, men exhibited significantly greater BOLD signal changes compared to LF/MC women on bilateral ACG and OFC, mPFC, LHA, VMN, hippocampus, and periaqueductal gray, with largest effect sizes in mPFC and OFC. Findings suggest that sex differences in stress response circuitry are hormonally regulated via the impact of subcortical brain activity on the cortical control of arousal, and demonstrate that females have been endowed with a natural hormonal capacity to regulate the stress response that differs from males. C1 [Goldstein, Jill M.; Jerram, Matthew; Abbs, Brandon] Brigham & Womens Hosp, Div Womens Hlth, Boston, MA 02120 USA. [Goldstein, Jill M.; Jerram, Matthew; Abbs, Brandon] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02120 USA. [Goldstein, Jill M.; Jerram, Matthew; Abbs, Brandon] Brigham & Womens Hosp, Dept Med, Boston, MA 02120 USA. [Goldstein, Jill M.; Jerram, Matthew; Abbs, Brandon] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02120 USA. Harvard Univ, Sch Med, Boston, MA 02120 USA. [Goldstein, Jill M.; Abbs, Brandon] Massachusetts Gen Hosp, Dept Psychiat, Div Psychiat Neurosci, Charlestown, MA 02129 USA. [Goldstein, Jill M.; Abbs, Brandon] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Goldstein, Jill M.; Jerram, Matthew; Makris, Nikos] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Goldstein, Jill M.; Jerram, Matthew; Makris, Nikos] MIT, Charlestown, MA 02129 USA. [Jerram, Matthew] Suffolk Univ, Dept Psychol, Boston, MA 02108 USA. [Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Makris, Nikos] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Charlestown, MA 02129 USA. RP Goldstein, JM (reprint author), Brigham & Womens Hosp, Div Womens Hlth, 1 Brigham Circle,1620 Tremont St, Boston, MA 02120 USA. EM jill_goldstein@hms.harvard.edu FU National Institute of Mental Health [NIMH-ORWH P50MH082679, NIMH R01MH56956]; Athinoula Martinos Center for Biomedical Imaging at Massachusetts General Hospital Collaborative Start-up Award FX This work was supported by grants from the National Institute of Mental Health to J. M. G. (NIMH-ORWH P50MH082679, NIMH R01MH56956) and the Athinoula Martinos Center for Biomedical Imaging at Massachusetts General Hospital Collaborative Start-up Award. Wealso thank Dr. Bernard Harlow for access to the female population sample, Dr. Russell Poldrack for statistical help on the design of earlier versions of this study, Dr. Deborah Walder and Gabe Daly for help on some earlier stages of data analyses, Sarah Spaeth for help with data acquisition and analysis, George Papadimitriou for help in image production, Drs. Anne Klibanski and Stuart Tobet for comments on earlier aspects of the study, and Lisa Cushman-Daly for manuscript preparation. NR 48 TC 120 Z9 126 U1 4 U2 15 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 JAN 13 PY 2010 VL 30 IS 2 BP 431 EP 438 DI 10.1523/JNEUROSCI.3021-09.2010 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 543OC UT WOS:000273586900003 PM 20071507 ER PT J AU Rodriguez, E Nilges, M Weissleder, R Chen, JW AF Rodriguez, Elisenda Nilges, Mark Weissleder, Ralph Chen, John W. TI Activatable Magnetic Resonance Imaging Agents for Myeloperoxidase Sensing: Mechanism of Activation, Stability, and Toxicity SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PARAMAGNETIC CONTRAST AGENTS; CORONARY-ARTERY-DISEASE; ENZYME MYELOPEROXIDASE; ROTATIONAL-DYNAMICS; MULTIPLE-SCLEROSIS; PEROXIDASE; OXIDATION; MEDIA; EXPRESSION; LESIONS AB Myeloperoxidase (MPO) is increasingly being recognized as an important factor in many inflammatory diseases, particularly cardiovascular and neurological diseases. MPO-specific imaging agents would thus be highly useful to diagnose early disease, monitor disease progression, and quantify treatment effects. This study reports in vitro and in vivo characterizations of the mechanism of interaction between MPO and paramagnetic enzyme substrates based on physical and biological measurements. We show that these agents are activated through a radical mechanism, which can combine to form oligomers and, in the presence of tyrosine-containing peptide, bind to proteins. We further identified two new imaging agents, which represent the near extremes in either oligomerization (mono-5HT-DTPA-Gd) or protein-binding in their activation mechanism (bis-o-dianisidine-DTPA-Gd). On the other hand, we found that the agent bis-5HT-DTPA-Gd utilizes both mechanisms when activated. These properties yield distinct in vivo pharmacokinetics profiles for each of these agents that may be exploited for different applications. Specificity studies show that only MPO, but not eosinophil peroxidase, can highly activate these agents, and that MPO activity as low as 0.005 U/mg of tissue can be detected. Gd kinetic lability and cytotoxicity studies further confirm stability of the Gd ion and low toxicity for the 5HT-based agents, suggesting that these agents are suitable for translational in vivo studies. C1 [Rodriguez, Elisenda; Weissleder, Ralph; Chen, John W.] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Dept Radiol, Boston, MA 02114 USA. [Nilges, Mark] Univ Illinois, Illinois EPR Res Ctr, Urbana, IL 61801 USA. [Weissleder, Ralph; Chen, John W.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Chen, JW (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Dept Radiol, Boston, MA 02114 USA. EM jwchen@mgh.harvard.edu FU EC-Marie Curie [39639]; National Institutes of Health [K08HL081170, ROI-HL078641] FX We thank Ben Bautz, Alexy Chudnovsky, Martin Etzrodt, and Christopher N. LaFratta for experimental assistance and Brian Rutt for helpful discussions. We also acknowledge Alexei Bogdanov and Manel Querol for early contributions to the development of MPO sensing agents. E.R. was supported by the EC-Marie Curie grant OIF (Molecular Imaging 39639). This work was supported in part by National Institutes of Health Grants K08HL081170 (J.W.C.) and ROI-HL078641 (R.W.). NR 43 TC 41 Z9 44 U1 1 U2 18 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 JAN 13 PY 2010 VL 132 IS 1 BP 168 EP 177 DI 10.1021/ja905274f PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 562VW UT WOS:000275084400047 PM 19968300 ER PT J AU Yamodo, IH Chiara, DC Cohen, JB Miller, KW AF Yamodo, Innocent H. Chiara, David C. Cohen, Jonathan B. Miller, Keith W. TI Conformational Changes in the Nicotinic Acetylcholine Receptor during Gating and Desensitization SO BIOCHEMISTRY LA English DT Article ID GATED ION-CHANNEL; LIPID-PROTEIN INTERFACE; X-RAY-STRUCTURE; BINDING-SITES; NONCOMPETITIVE INHIBITOR; HYDROPHOBIC INHIBITOR; GLYCINE RECEPTORS; RESTING STATE; TORPEDO; MECHANISM AB The nicotinic acetylcholine receptor (nAChR) is a member of the important Cys loop ligand-gated ion channel superfamily that modulates neuronal excitability. After they respond to their agonists, their actions are terminated either by removal of ligand or by fast and slow desensitization, processes that play ail important role in modulating the duration of conducting states and hence of integrated neuronal behavior. We monitored structural changes Occurring during fast and slow desensitization in the transmembrane domain of the Torpedo nAChR using time-resolved photolabeling with the hydrophobic probe 3-(trifluoromethyl)-3-(m-iodophenyl)diazirine (TID). After channel opening, TID photolabels a residue oil the delta-subunit's M2-M3 loop and a cluster of four residues on delta M1 and delta M2, defining all open state pocket [Arevalo, E., et al. (2005) J. Biol. Chem. 280, 13631-13640]. We now find that photolabeling of this pocket persists during the transition to the fact desensitized state, the extent of photoincorporation decreasing only with the transition to the slow desensitized state. In contrast, the extent of photoincorporation in the channel lumen at the conserved 9'-leucines oil the second transmembrane helix (M2-9') decreased successively during the resting to open and open to fast desensitized state transitions, implying that the local conformation is different in each state, a Conclusion consistent with the hypothesis that there are separate gates for channel opening and desensitization. Thus, although during Cast desensitization there is a conformation change in the channel lumen at the level of M2-9', there is none in the regions of the delta-subunit's M2-M3 loop and the interior of its M1-M4 helix bundle until slow desensitization occurs. C1 [Yamodo, Innocent H.; Miller, Keith W.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Miller, Keith W.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02116 USA. [Chiara, David C.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02116 USA. RP Miller, KW (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 32 Fruit St, Boston, MA 02114 USA. EM k_miller@helix.mgh.harvard.edu FU National Institutes of Health [GM-58448]; Department of Anesthesia and Critical Care; Massachusetts General Hospital; Howard Hughes Biomedical Research Support Program FX This research was supported by a grant from the National Institutes of Health (GM-58448), by the Department of Anesthesia and Critical Care, Massachusetts General Hospital, and by an award to the Harvard Medical School from the Howard Hughes Biomedical Research Support Program. NR 47 TC 23 Z9 23 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 12 PY 2010 VL 49 IS 1 BP 156 EP 165 DI 10.1021/bi901550p PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539PE UT WOS:000273267300018 PM 19961216 ER PT J AU Li, NC Lee, A Whitmer, RA Kivipelto, M Lawler, E Kazis, LE Wolozin, B AF Li, Nien-Chen Lee, Austin Whitmer, Rachel A. Kivipelto, Miia Lawler, Elizabeth Kazis, Lewis E. Wolozin, Benjamin TI Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis SO BRITISH MEDICAL JOURNAL LA English DT Article ID ALZHEIMER-DISEASE PROGRESSION; MILD COGNITIVE IMPAIRMENT; ENZYME ACE INHIBITORS; QUALITY-OF-LIFE; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; HYPERTENSIVE PATIENTS; HEART-FAILURE; SYSTEM; LOSARTAN AB Objective To investigate whether angiotensin receptor blockers protect against Alzheimer's disease and dementia or reduce the progression of both diseases. Design Prospective cohort analysis. Setting Administrative database of the US Veteran Affairs, 2002-6. Population 819 491 predominantly male participants (98%) aged 65 or more with cardiovascular disease. Main outcome measures Time to incident Alzheimer's disease or dementia in three cohorts (angiotensin receptor blockers, lisinopril, and other cardiovascular drugs, the "cardiovascular comparator") over a four year period (fiscal years 2003-6) using Cox proportional hazard models with adjustments for age, diabetes, stroke, and cardiovascular disease. Disease progression was the time to admission to a nursing home or death among participants with pre-existing Alzheimer's disease or dementia. Results Hazard rates for incident dementia in the angiotensin receptor blocker group were 0.76 (95% confidence interval 0.69 to 0.84) compared with the cardiovascular comparator and 0.81 (0.73 to 0.90) compared with the lisinopril group. Compared with the cardiovascular comparator, angiotensin receptor blockers in patients with pre-existing Alzheimer's disease were associated with a significantly lower risk of admission to a nursing home (0.51, 0.36 to 0.72) and death (0.83, 0.71 to 0.97). Angiotensin receptor blockers exhibited a dose-response as well as additive effects in combination with angiotensin converting enzyme inhibitors. This combination compared with angiotensin converting enzyme inhibitors alone was associated with a reduced risk of incident dementia (0.54, 0.51 to 0.57) and admission to a nursing home (0.33, 0.22 to 0.49). Minor differences were shown in mean systolic and diastolic blood pressures between the groups. Similar results were observed for Alzheimer's disease. Conclusions Angiotensin receptor blockers are associated with a significant reduction in the incidence and progression of Alzheimer's disease and dementia compared with angiotensin converting enzyme inhibitors or other cardiovascular drugs in a predominantly male population. C1 [Li, Nien-Chen; Lee, Austin; Kazis, Lewis E.; Wolozin, Benjamin] Vet Affairs Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Li, Nien-Chen; Kazis, Lewis E.] Boston Univ, Sch Publ Hlth,Management & Policy Program, Ctr Assessment Pharmaceut Practices & Pharmaceut, Dept Hlth Policy & Management, Boston, MA USA. [Lee, Austin] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Whitmer, Rachel A.] Kaiser Permanente, Div Res Epidemiol Etiol & Prevent, Oakland, CA USA. [Kivipelto, Miia] Karolinska Inst, Aging Res Ctr, Stockholm, Sweden. [Lawler, Elizabeth] VA Cooperat Studies Program, MAVERIC, Boston, MA USA. [Wolozin, Benjamin] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA. [Wolozin, Benjamin] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Wolozin, B (reprint author), Vet Affairs Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. EM bwolozin@bu.edu OI Kazis, Lewis/0000-0003-1800-5849; Kivipelto, Miia/0000-0003-0992-3875 FU Retirement Research Foundation; Casten Foundation FX This work was supported by a grant award to BW from the Retirement Research Foundation and a donation from the Casten Foundation. The researchers operate independently of the funders of the study.; BW and RAW received a grant award from the Retirement Research Foundation to fund this research. BW received a donation from the Casten Foundation to fund this research. NR 61 TC 192 Z9 197 U1 3 U2 17 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JAN 12 PY 2010 VL 340 AR b5465 DI 10.1136/bmj.b5465 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 545CZ UT WOS:000273711400005 PM 20068258 ER PT J AU Ay, H Gungor, L Arsava, EM Rosand, J Vangel, M Benner, T Schwamm, LH Furie, KL Koroshetz, WJ Sorensen, AG AF Ay, H. Gungor, L. Arsava, E. M. Rosand, J. Vangel, M. Benner, T. Schwamm, L. H. Furie, K. L. Koroshetz, W. J. Sorensen, A. G. TI A score to predict early risk of recurrence after ischemic stroke SO NEUROLOGY LA English DT Article ID LONG-TERM RISK; CEREBRAL INFARCTION; SUBTYPE DIAGNOSIS; COMMUNITY STROKE; ATTACK; SEVERITY; SURVIVAL; LEUKOARAIOSIS; PROGNOSIS; PATTERNS AB Background: There is currently no instrument to stratify patients presenting with ischemic stroke according to early risk of recurrent stroke. We sought to develop a comprehensive prognostic score to predict 90-day risk of recurrent stroke. Methods: We analyzed data on 1,458 consecutive ischemic stroke patients using a Cox regression model with time to recurrent stroke as the response and clinical and imaging features typically available to physician at admission as covariates. The 90-day risk of recurrent stroke was calculated by summing up the number of independent predictors weighted by their corresponding beta-coefficients. The resultant score was called recurrence risk estimator at 90 days or RRE-90 score (available at: http://www.nmr.mgh.harvard.edu/RRE-90/). Results: Sixty recurrent strokes (54 had baseline imaging) occurred during the follow-up period. The risk adjusted for time to follow-up was 6.0%. Predictors of recurrence included admission etiologic stroke subtype, prior history of TIA/stroke, and topography, age, and distribution of brain infarcts. The RRE-90 score demonstrated adequate calibration and good discrimination (area under the ROC curve [AUC] = 0.70-0.80), which was maintained when applied to a separate cohort of 433 patients (AUC = 0.70-0.76). The model's performance was also maintained for predicting early (14-day) risk of recurrence (AUC = 0.80). Conclusions: The RRE-90 is a Web-based, easy-to-use prognostic score that integrates clinical and imaging information available in the acute setting to quantify early risk of recurrent stroke. The RRE-90 demonstrates good predictive performance, suggesting that, if validated externally, it has promise for use in creating individualized patient management algorithms and improving clinical practice in acute stroke care. Neurology (R) 2010;74:128-135 C1 [Ay, H.; Rosand, J.; Schwamm, L. H.; Furie, K. L.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Stroke Serv, Boston, MA 02115 USA. [Ay, H.; Gungor, L.; Arsava, E. M.; Vangel, M.; Benner, T.; Sorensen, A. G.] Harvard Univ, Sch Med, Dept Radiol, AA Martinos Ctr Biomed Imaging,Massachusetts Gen, Boston, MA 02115 USA. [Rosand, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Rosand, J.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Koroshetz, W. J.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Ay, H (reprint author), Harvard Univ, AA Martinos Ctr Biomed Imaging, Sch Med, Massachusetts Gen Hosp, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013; OI Arsava, Ethem Murat/0000-0002-6527-4139; Schwamm, Lee/0000-0003-0592-9145 FU NIH [R01-NS059710, R01-NS059727, NINDS P50 NS051343-01, NINDS U01 NS052220 IMS-3, NCRR 1 UL 1 RR025758-01, DHHS/CDC [5 U13 DP001176-02], NINDS NS38477, NCI CA137254, NINDS NS063925, NINDS NS061119]; American Heart Association; Forest Laboratories, Inc; Deane Institute; Millennium Pharmaceuticals, Inc.; Siemens Medical Solutions; AstraZeneca; Genentech Inc; Novartis; Merck Serono; Schering Plough Corp FX Dr. Ay receives research support from the NIH [R01-NS059710 (PI)]. Dr. Gungor and Dr. Arsava report no disclosures. Dr. Rosand receives research support from the NIH [R01-NS059727 (PI)] and from the American Heart Association. Dr. Vangel reports no disclosures. Dr. Benner serves as a consultant for Siemens Medical Solutions and Bayer Schering Pharma. Dr. Schwamm serves on scientific advisory boards for CoAxia, Inc. and Phreesia; has received honoraria and funding for travel for lectures or educational activities not funded by industry; serves on the editorial board of Neurocritical Care; may accrue revenue on US Patent 6,542,769 (filed 2003): Imaging system for obtaining quantitative perfusion indices; his spouse receives royalties from publishing Obstetric Anesthesia (Cambridge Pocket Clinicians, 2007-2009); serves as a consultant to Medtronic, Inc./CryoCath, Research Triangle Inc., and the Massachusetts Department of Public Health; serves on an external scientific review committee for the Canadian Stroke Network; and receives research support from Forest Laboratories, Inc., the NIH [NINDS P50 NS051343-01 (Co-I), NINDS U01 NS052220 IMS-3 (Site PI), and NCRR 1 UL 1 RR025758-01 (CRC Staff)] and the DHHS/CDC [5 U13 DP001176-02 (PI)]. Dr. Furie has served on scientific advisory boards for Novartis and GE Healthcare and receives research support from the NIH/NINDS [R01-HS011392 (PI) and P50-NS051343 (PI)], the American Heart Association, and the Deane Institute. Dr. Koroshetz is a full-time employee of the NIH and holds stock in NeuroLogica. Dr. Sorensen has served on scientific advisory boards for Olea Medical and Breakaway Imaging; has received funding for travel from Genentech, Inc., Siemens Medical Solutions, Millennium Pharmaceuticals, Inc., AstraZeneca, and for speaking and educational activities not funded by industry; serves as a Section Editor of Stroke and on the editorial boards of The Oncologist and the Journal of Clinical Oncology; may accrue revenue on US Patent 7020578 (issued 2001): Method for evaluating novel, stroke treatments using a tissue risk map, US Patent 6542769 (issued 2000): Imaging system for obtaining quantitative perfusion indices, US Patent 10558343 (issued 2004): Delay-compensated calculation of tissue blood flow, US Patent 11075990 (issued: 2005): High-flow oxygen delivery system and methods of use thereof, and US Patent 11417769 (issued: 2006): Magnetic resonance spatial risk map for tissue outcome prediction; receives royalties from publishing Cerebral MR Perfusion Imaging (Thieme, 2000); has received honoraria from Siemens Medical Solutions, Novartis, GE Healthcare, and for speaking and educational activities not funded by industry; has served as a consultant to Mitsubishi Tanabe Pharma Corporation, AstraZeneca, and Genentech, Inc.; receives research support from Millennium Pharmaceuticals, Inc., Siemens Medical Solutions, AstraZeneca, Genentech Inc., Novartis, Merck Serono, Schering Plough Corp, the NIH [NINDS NS38477 (PI), NCI CA137254 (PI), NINDS NS063925 (PI), and NINDS NS061119 (PI)]; and holds stock and stock options in Epix Pharmaceuticals. NR 38 TC 44 Z9 46 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 12 PY 2010 VL 74 IS 2 BP 128 EP 135 DI 10.1212/WNL.0b013e3181ca9cff PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 543HC UT WOS:000273563600007 PM 20018608 ER PT J AU VanCott, AC Cramer, JA Copeland, LA Zeber, JE Steinman, MA Dersh, JJ Glickman, ME Mortensen, EM Amuan, ME Pugh, MJ AF VanCott, Anne C. Cramer, Joyce A. Copeland, Laurel A. Zeber, John E. Steinman, Michael A. Dersh, Jeffrey J. Glickman, Mark E. Mortensen, Eric M. Amuan, Megan E. Pugh, Mary Jo TI Suicide-related behaviors in older patients with new anti-epileptic drug use: data from the VA hospital system SO BMC MEDICINE LA English DT Article ID LEVETIRACETAM THERAPY; CLINICAL-TRIALS; RISK-FACTORS; FOLLOW-UP; EPILEPSY; DEPRESSION; VETERANS; AGE; DISORDERS; DEMENTIA AB Background: The U. S. Food and Drug Administration (FDA) recently linked antiepileptic drug (AED) exposure to suicide-related behaviors based on meta-analysis of randomized clinical trials. We examined the relationship between suicide-related behaviors and different AEDs in older veterans receiving new AED monotherapy from the Veterans Health Administration (VA), controlling for potential confounders. Methods: VA and Medicare databases were used to identify veterans 66 years and older, who received a) care from the VA between 1999 and 2004, and b) an incident AED ( monotherapy) prescription. Previously validated ICD-9-CM codes were used to identify suicidal ideation or behavior (suicide-related behaviors cases), epilepsy, and other conditions previously associated with suicide-related behaviors. Each case was matched to controls based on prior history of suicide-related behaviors, year of AED prescription, and epilepsy status. Results: The strongest predictor of suicide-related behaviors (N = 64; Controls N = 768) based on conditional logistic regression analysis was affective disorder ( depression, anxiety, or post-traumatic stress disorder (PTSD); Odds Ratio 4.42, 95% CI 2.30 to 8.49) diagnosed before AED treatment. Increased suicide-related behaviors were not associated with individual AEDs, including the most commonly prescribed AED in the US - phenytoin. Conclusion: Our extensive diagnostic and treatment data demonstrated that the strongest predictor of suicide-related behaviors for older patients newly treated with AED monotherapy was a previous diagnosis of affective disorder. Additional, research using a larger sample is needed to clearly determine the risk of suicide-related behaviors among less commonly used AEDs. C1 [VanCott, Anne C.] VA Pittsburgh Healthcare Syst, Div Neurol, Pittsburgh, PA USA. [VanCott, Anne C.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Cramer, Joyce A.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Cramer, Joyce A.] Epilepsy Therapy Project, Orange, CT USA. [Copeland, Laurel A.; Zeber, John E.; Dersh, Jeffrey J.; Mortensen, Eric M.; Pugh, Mary Jo] S Texas Vet Hlth Care Syst VERDICT, Vet Affairs HSR&D, San Antonio, TX USA. [Copeland, Laurel A.; Zeber, John E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Steinman, Michael A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Steinman, Michael A.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Glickman, Mark E.; Amuan, Megan E.] Edith Nourse Rogers Mem Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Glickman, Mark E.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Pugh, Mary Jo] Univ Texas Hlth Sci Ctr San Antonio, Dept Gen Med, San Antonio, TX 78229 USA. RP VanCott, AC (reprint author), VA Pittsburgh Healthcare Syst, Div Neurol, Pittsburgh, PA USA. EM Anne.VanCott@va.gov OI Glickman, Mark/0000-0003-3993-2801; Pugh, Mary Jo/0000-0003-4196-7763; Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 FU Department of Veterans Affairs, Health Services Research and Development Service [IIR-02-274]; VA Health Services Research and Development Service Merit Review Entry [MRP-05-145]; South Texas Veterans Healthcare System/Audie L. Murphy Division; VERDICT FX This study was funded by the Department of Veterans Affairs, Health Services Research and Development Service (IIR-02-274). Dr. Copeland received funding from VA Health Services Research and Development Service Merit Review Entry Program Award (MRP-05-145). The authors acknowledge and appreciate support from the South Texas Veterans Healthcare System/Audie L. Murphy Division and the VERDICT research program. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. We thank Alan Ettinger, MD for reviewing and providing comments regarding this manuscript. We also acknowledge contributions of other members of the TIGER research team: Dan R. Berlowitz MD, MPH, Janice E. Knoefel MD, Jeffrey Tabares BA, Francesca Cunningham PharmD, Omotola Hope MD, Nancy Kressin PhD, Barbara Bokhour PhD, and Marcos Restrepo MD. NR 31 TC 40 Z9 41 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD JAN 11 PY 2010 VL 8 AR 4 DI 10.1186/1741-7015-8-4 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 557OG UT WOS:000274678200001 PM 20064226 ER PT J AU Lee, BJ Egi, Y van Leyen, K Lo, EH Arai, K AF Lee, Brian J. Egi, Yasuhiro van Leyen, Klaus Lo, Eng H. Arai, Ken TI Edaravone, a free radical scavenger, protects components of the neurovascular unit against oxidative stress in vitro SO BRAIN RESEARCH LA English DT Article DE Oxidative stress; Neuron; Astrocyte; Endothelial cell; Neurovascular unit; Stroke ID PRIMARY-CULTURED ASTROCYTES; CEREBRAL ENDOTHELIAL-CELLS; PEROXIDE-INDUCED APOPTOSIS; ACUTE ISCHEMIC-STROKE; MITOCHONDRIAL DYSFUNCTION; ARTERY OCCLUSION; NEURONAL DEATH; BRAIN EDEMA; MCI-186; NEUROPROTECTION AB The concept of the neurovascular unit suggests that to be successful, stroke therapies must protect all neuronal, glial and endothelial components in brain. in this study, we tested the efficacy of the free radical scavenger edaravone in three cellular models of oxidative stress. HT22 neuronal cells were subjected to oxidative stress using the standard glutamate-induced glutathione depletion model. Primary rat astrocytes were exposed to H(2)O(2). Oxidative stress was induced in human brain endothelial cells with sodium nitroprusside (SNP). Edaravone significantly reduced oxidative cell death in both HT22 neuronal cells and primary rat astrocytes in a dose-dependent manner. SNP did not kill brain endothelial cells but instead reduced their production of brain-derived neurotrophic factor (BDNF). Edaravone significantly ameliorated this response. These data suggest that free radical scavengers are effective in all cell types of the neurovascular unit, and should still be considered as a potential therapeutic approach for stroke. (C) 2009 Elsevier B.V. All rights reserved. C1 [Arai, Ken] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Arai, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, MGH E 149-2401, Charlestown, MA 02129 USA. EM karai@partners.org RI van Leyen, Klaus/C-9126-2013 FU Deane Foundation; American Heart Association; NIH FX Supported in part by the Deane Foundation, American Heart Association and NIH. NR 44 TC 31 Z9 36 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 11 PY 2010 VL 1307 BP 22 EP 27 DI 10.1016/j.brainres.2009.10.026 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 554QZ UT WOS:000274450800003 PM 19840779 ER PT J AU Mehta, DD Deliyski, DD Zeitels, SM Quatieri, TF Hillman, RE AF Mehta, Daryush D. Deliyski, Dimitar D. Zeitels, Steven M. Quatieri, Thomas F. Hillman, Robert E. TI Voice Production Mechanisms Following Phonosurgical Treatment of Early Glottic Cancer SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article; Proceedings Paper CT 89th Annual Meeting of the American-Broncho-Esophagological-Association CY MAY 28-29, 2009 CL Phoenix, AZ SP Amer Broncho Esophagol Assoc DE acoustic perturbation; glottic cancer; high-speed videoendoscopy; vocal fold asymmetry; voice production ID HIGH-SPEED VIDEOENDOSCOPY; VOCAL FOLD; VIDEOKYMOGRAPHY; EVOLUTION AB Objectives: Although near-normal conversational voices can be achieved with the phonosurgical management of early glottic cancer, there are still acoustic and aerodynamic deficits in vocal function that Must be better understood to help further optimize phonosurgical interventions. Stroboscopic assessment is inadequate for this purpose. Methods: A newly developed color high-speed videoendoscopy (HSV) system that included time-synchronized recordings of the acoustic signal Was used to perform a detailed examination of voice production mechanisms in 14 Subjects. Digital image processing techniques were used to quantify glottal phonatory function and to delineate relationships between vocal fold vibratory properties and acoustic perturbation measures. Results: The results for multiple measurements of vibratory asymmetry showed that 31% to 62% of subjects displayed higher-than-normal average values, whereas the mean values for glottal Closure duration (open quotient) and periodicity of vibration fell within normal limits. The average HSV-based measures did not correlate significantly with the acoustic perturbation Measures, but moderate correlations were exhibited between the acoustic measures and the SDs of the HSV-based parameters. Conclusions: The use of simultaneous, time-synchronized HSV and acoustic recordings can provide new insights into postoperative voice production mechanisms that cannot be obtained with stroboscopic assessment. C1 [Mehta, Daryush D.; Zeitels, Steven M.; Hillman, Robert E.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Mehta, Daryush D.; Quatieri, Thomas F.; Hillman, Robert E.] MIT, Harvard Mit Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol Program, Cambridge, MA 02139 USA. [Mehta, Daryush D.; Quatieri, Thomas F.] MIT, Lincoln Lab, Lexington, MA 02173 USA. [Zeitels, Steven M.; Hillman, Robert E.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Deliyski, Dimitar D.] Univ S Carolina, Dept Commun Sci & Disorders, Columbia, SC 29208 USA. RP Hillman, RE (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. FU NIDCD NIH HHS [R01 DC007640, R01 DC007640-01A2, R01 DC007640-02, R01 DC007640-03, T32 DC000038, T32 DC00038]; NIEHS NIH HHS [27304C0002, 27306C0002] NR 20 TC 40 Z9 41 U1 0 U2 5 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JAN 10 PY 2010 VL 119 IS 1 BP 1 EP 9 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA 544SW UT WOS:000273680600001 PM 20128179 ER PT J AU Scott, AR Chong, PST Hartnick, CJ Randolph, GW AF Scott, Andrew R. Chong, Peter Siao Tick Hartnick, Christopher J. Randolph, Gregory W. TI Spontaneous and Evoked Laryngeal Electromyography of the Thyroarytenoid Muscles: A Canine Model for Intraoperative Recurrent Laryngeal Nerve Monitoring SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article; Proceedings Paper CT 88th Annual Meeting of the American-Broncho-Esophagological-Association CY MAY 01-02, 2008 CL Orlando, FL SP Amer Broncho Esophagol Assoc DE canine recurrent laryngeal nerve model; laryngeal electromyography; recurrent laryngeal nerve monitoring ID VOCAL FOLD PARALYSIS AB Objectives: We sought to determine the feasibility of performing spontaneous and evoked intraoperative laryngeal electromyography (L-EMG) using nerve monitoring equipment and to compare recording electrode configurations and methods of recurrent laryngeal nerve (RLN) stimulation in dogs. Methods: Four beagles underwent crush injury of the left RLN, and 2 beagles underwent left RLN transection. Serial spontaneous and evoked L-EMG was recorded with the NIM-Response nerve monitoring system under sedation. Transesophageal, percutaneous, and direct open RLN stimulation was performed. Recordings of spontaneous and evoked responses were made with endotracheal tube surface electrodes and bipolar vocal fold needle electrodes. The L-EMG procedures were repeated every 1 to 2 weeks after injury, and intersubject and intertrial differences were evaluated. Results: Low-amplitude motor unit action potentials, polyphasic potentials, fasciculations, and fibrillations were detected in injured animals with bipolar needle recording electrodes with this system of spontaneous L-EMG. The surface recording electrodes did not detect pathologic waveforms. Percutaneous needle stimulation of the RLN is possible at Currents slightly higher than those used for direct stimulation. Consistent, discrete, transesophageal stimulation of the RLN could not be reliably performed. Recording evoked responses with needle electrodes generated sharper waveforms, facilitating calculation of latency and wave duration. Evoked L-EMG utilizing surface recording electrodes limited the intertrial and intersubject variability of evoked amplitude. Conclusions: Typical patterns of nerve injury can be detected with this system of intraoperative L-EMG in a canine model. Quantitative measures of amplitude, latency, and wave duration in healthy and injured canine RLNs may be determined with this system. C1 [Randolph, Gregory W.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Div Thyroid & Parathyroid Surg, Boston, MA 02114 USA. [Scott, Andrew R.; Hartnick, Christopher J.; Randolph, Gregory W.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Div Pediat, Boston, MA 02114 USA. [Chong, Peter Siao Tick] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Randolph, Gregory W.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp,Div Surg Oncol, Boston, MA 02115 USA. [Randolph, Gregory W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Surg Serv, Boston, MA 02115 USA. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Div Thyroid & Parathyroid Surg, 243 Charles St, Boston, MA 02114 USA. NR 12 TC 15 Z9 16 U1 0 U2 2 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JAN 10 PY 2010 VL 119 IS 1 BP 54 EP 63 PG 10 WC Otorhinolaryngology SC Otorhinolaryngology GA 544SW UT WOS:000273680600011 PM 20128189 ER PT J AU Maron, BA Goldhaber, SZ Sturzu, AC Rhee, DK Ali, BS Shah, PB Kirshenbaum, JM AF Maron, Bradley A. Goldhaber, Samuel Z. Sturzu, Anthony C. Rhee, David K. Ali, Bilal S. Shah, Pinak Bipin Kirshenbaum, James M. TI Catheter-Directed Thrombolysis for Giant Right Atrial Thrombus SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Editorial Material C1 [Maron, Bradley A.] Brigham & Womens Hosp, Div Cardiovasc Med, PBB G, Dept Internal Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Sturzu, Anthony C.] Massachusetts Gen Hosp, Dept Internal Med, Div Cardiol, Boston, MA 02114 USA. RP Maron, BA (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, PBB G, Dept Internal Med, 75 Francis St, Boston, MA 02115 USA. EM bmaron@partners.org NR 4 TC 2 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD JAN 10 PY 2010 VL 3 IS 1 BP 126 EP 127 DI 10.1161/CIRCIMAGING.109.906487 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 545MI UT WOS:000273736000016 PM 20086226 ER PT J AU Duda, DG Ancukiewicz, M Jain, RK AF Duda, Dan G. Ancukiewicz, Marek Jain, Rakesh K. TI Biomarkers of Antiangiogenic Therapy: How Do We Move From Candidate Biomarkers to Valid Biomarkers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; VASCULAR NORMALIZATION; GLIOBLASTOMA PATIENTS; TUMOR ANGIOGENESIS; KINASE INHIBITOR; BEVACIZUMAB; PACLITAXEL; FLUOROURACIL; CARBOPLATIN C1 [Duda, Dan G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Duda, DG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. FU NCI NIH HHS [P01 CA080124] NR 24 TC 31 Z9 31 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2010 VL 28 IS 2 BP 183 EP 185 DI 10.1200/JCO.2009.24.8021 PG 3 WC Oncology SC Oncology GA 541LU UT WOS:000273418000001 PM 19949009 ER PT J AU Hanrahan, EO Lin, HY Kim, ES Yan, SY Du, DZ McKee, KS Tran, HT Lee, JJ Ryan, AJ Langmuir, P Johnson, BE Heymach, JV AF Hanrahan, Emer O. Lin, Heather Y. Kim, Edward S. Yan, Shaoyu Du, Danny Z. McKee, Kathryn S. Tran, Hai T. Lee, J. Jack Ryan, Anderson J. Langmuir, Peter Johnson, Bruce E. Heymach, John V. TI Distinct Patterns of Cytokine and Angiogenic Factor Modulation and Markers of Benefit for Vandetanib and/or Chemotherapy in Patients With Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; METASTATIC COLORECTAL-CANCER; COOPERATIVE-ONCOLOGY-GROUP; RANDOMIZED PHASE-II; FACTOR RECEPTOR; THERAPEUTIC IMPLICATIONS; TUMOR ANGIOGENESIS; BREAST-CANCER; BEVACIZUMAB AB Purpose There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit. Methods Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non-small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk. Results VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk. Conclusion Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit. C1 [Heymach, John V.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol & Canc Biol, Unit 432, Houston, TX 77030 USA. AstraZeneca, Wilmington, DE USA. Dana Farber Canc Inst, Boston, MA 02115 USA. AstraZeneca, Macclesfield, Cheshire, England. RP Heymach, JV (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol & Canc Biol, Unit 432, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM jheymach@mdanderson.org RI Ryan, Anderson/O-7701-2015 OI Ryan, Anderson/0000-0001-6241-7969 FU American Society of Clinical Oncology (ASCO) Young Investigator Award; Research Excellence [P50 CA70907]; AstraZeneca; Damon Runyon Cancer Research Foundation [CI 24-04] FX Supported in part by an American Society of Clinical Oncology (ASCO) Young Investigator Award (E.O.H.), ASCO Career Development Award (J.V.H.), Specialized Programs of Research Excellence Grant No. P50 CA70907, and AstraZeneca. J.V.H. is a Damon Runyon-Lilly Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (Grant No. CI 24-04). NR 44 TC 89 Z9 89 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2010 VL 28 IS 2 BP 193 EP 201 DI 10.1200/JCO.2009.22.4279 PG 9 WC Oncology SC Oncology GA 541LU UT WOS:000273418000006 PM 19949019 ER PT J AU Lamont, EB Landrum, MB Keating, NL Archer, L Lan, L Strauss, GM Lilenbaum, R Niell, HB Maurer, LH Kosty, MP Miller, AA Clamon, GH Elias, AD McClay, EF Vokes, EE McNeil, BJ AF Lamont, Elizabeth B. Landrum, Mary Beth Keating, Nancy L. Archer, Laura Lan, Lan Strauss, Gary M. Lilenbaum, Rogerio Niell, Harvey B. Maurer, L. Herbert Kosty, Michael P. Miller, Antonius A. Clamon, Gerald H. Elias, Anthony D. McClay, Edward F. Vokes, Everett E. McNeil, Barbara J. TI Differences in Clinical Trial Patient Attributes and Outcomes According to Enrollment Setting SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; LEUKEMIA GROUP-B; COOPERATIVE-ONCOLOGY-GROUP; RANDOMIZED PHASE-III; RADIATION-THERAPY; SOCIOECONOMIC-STATUS; PARTICIPATION; CHEMOTHERAPY; MULTICENTER; CISPLATIN AB Purpose During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration (VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings. Patients and Methods Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting. Results Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted. Conclusion Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons. C1 [Lamont, Elizabeth B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Duke Univ, Canc & Leukemia Grp B, Ctr Stat, Durham, NC 27706 USA. Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. Tufts Univ New England Med Ctr, Boston, MA USA. Mt Sinai Canc Ctr, Miami Beach, FL USA. Univ Tennessee, Inst Canc, Memphis, TN USA. SW Vermont Hlth Care Oncol Associates, Bennington, VT USA. Scripps Green Hosp, Scripps Clin, Div Hematol & Oncol, La Jolla, CA USA. San Diego Pacific Oncol & Hematol Associates, Vista, CA USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. Univ Colorado, Ctr Canc, Aurora, CO USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. RP Lamont, EB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180A Longwood Ave, Boston, MA 02115 USA. EM lamont@hcp.med.harvard.edu FU National Cancer Institute [CA31946, CA33601]; Massachusetts General Hospital 2006 Claflin Award; Department of Veterans Affairs Office of Policy and Planning [RFQ 101-35-04] FX Supported in part by National Cancer Institute Grants No. CA31946 to the Cancer and Leukemia Group B (CALGB) for CALGB 70602 ( R. L. S.) and CA33601 to the CALGB Statistical Center ( S. G.); by a Massachusetts General Hospital 2006 Claflin Award; and by Department of Veterans Affairs Office of Policy and Planning Contract No. RFQ 101-35-04 to Abt Associates and Harvard Medical School. NR 42 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2010 VL 28 IS 2 BP 215 EP 221 DI 10.1200/JCO.2008.21.3652 PG 7 WC Oncology SC Oncology GA 541LU UT WOS:000273418000009 PM 19933919 ER PT J AU Dow, LA Matsuyama, RK Ramakrishnan, V Kuhn, L Lamont, EB Lyckholm, L Smith, TJ AF Dow, Lindsay A. Matsuyama, Robin K. Ramakrishnan, V. Kuhn, Laura Lamont, Elizabeth B. Lyckholm, Laurel Smith, Thomas J. TI Paradoxes in Advance Care Planning: The Complex Relationship of Oncology Patients, Their Physicians, and Advance Medical Directives SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OF-LIFE CARE; CANCER-PATIENTS; END; COMMUNICATION; DISCUSSIONS; PREFERENCES; DEATH; ASSOCIATIONS; HEALTH; ILL AB Purpose Many seriously ill patients with cancer do not discuss prognosis or advance directives (ADs), which may lead to inappropriate and/or unwanted aggressive care at the end of life. Ten years ago, patients with cancer said they would not like to discuss ADs with their oncologist but would be willing to discuss them with an admitting physician. We assessed whether this point of view still held. Patients and Methods Semi-structured interviews were conducted with 75 consecutively admitted patients with cancer in the cancer inpatient service. Results Of those enrolled, 41% (31 of 75) had an AD. Nearly all (87%, 65 of 75) thought it acceptable to discuss ADs with the admitting physician with whom they had no prior relationship, and 95% (62 of 65) thought that discussing AD issues was very or somewhat important. Only 7% (5 of 75) had discussed ADs with their oncologist, and only 23% (16 of 70) would like to discuss ADs with their oncologist. When specifically asked which physician they would choose, 48% (36 of 75) of patients would prefer their oncologist, and 35% (26 of 75) would prefer their primary care physician. Conclusion Fewer than half of seriously ill patients with cancer admitted to an oncology service have an AD. Only 23% (16 of 70) would like to discuss their ADs with their oncologist but nearly all supported a policy of discussing ADs with their admitting physician. However, fully 48% (36 of 75) actually preferred to discuss advance directives with their oncologist if AD discussion was necessary. We must educate patients on why communicating their ADs is beneficial and train primary care physicians, house staff, hospitalists, and oncologists to initiate these difficult discussions. C1 [Smith, Thomas J.] Virginia Commonwealth Univ, Div Hematol Oncol & Palliat Care, Sch Med, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Smith, TJ (reprint author), Virginia Commonwealth Univ, Div Hematol Oncol & Palliat Care, Sch Med, MCV Box 980230, Richmond, VA 23298 USA. EM tsmith5@mcvh.vcu.edu FU Virginia Commonwealth University School of Medicine Research; National Library of Medicine [GO8 LM0095259]; National Cancer Institute [R01CA116227-01] FX Supported by a Virginia Commonwealth University School of Medicine Research year-out scholarship and Grants No. GO8 LM0095259 from the National Library of Medicine (T.J.S.) and R01CA116227-01 from the National Cancer Institute (T.J.S.). NR 27 TC 55 Z9 55 U1 4 U2 10 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 JAN 10 PY 2010 VL 28 IS 2 BP 299 EP 304 DI 10.1200/JCO.2009.24.6397 PG 6 WC Oncology SC Oncology GA 541LU UT WOS:000273418000020 PM 19933909 ER PT J AU El-Jawahri, A Podgurski, LM Eichler, AF Plotkin, SR Temel, JS Mitchell, SL Chang, YC Barry, MJ Volandes, AE AF El-Jawahri, Areej Podgurski, Lisa M. Eichler, April F. Plotkin, Scott R. Temel, Jennifer S. Mitchell, Susan L. Chang, Yuchiao Barry, Michael J. Volandes, Angelo E. TI Use of Video to Facilitate End-of-Life Discussions With Patients With Cancer: A Randomized Controlled Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADVANCE DIRECTIVES; DECISION-MAKING; MEDICAL-CARE; COMMUNICATION; PREFERENCES; SUPPORT; DEATH; PHYSICIANS; DEMENTIA AB Purpose To determine whether the use of a goals-of-care video to supplement a verbal description can improve end-of-life decision making for patients with cancer. Methods Fifty participants with malignant glioma were randomly assigned to either a verbal narrative of goals-of-care options at the end of life (control), or a video after the same verbal narrative (intervention) in this randomized controlled trial. The video depicts three levels of medical care: life-prolonging care (cardiopulmonary resuscitation [CPR], ventilation), basic care (hospitalization, no CPR), and comfort care (symptom relief). The primary study outcome was participants' preferences for end-of-life care. The secondary outcome was participants' uncertainty regarding decision making (score range, 3 to 15; higher score indicating less uncertainty). Participants' comfort level with the video was also measured. Results Fifty participants were randomly assigned to either the verbal narrative (n = 27) or video (n = 23). After the verbal description, 25.9% of participants preferred life-prolonging care, 51.9% basic care, and 22.2% comfort care. In the video arm, no participants preferred life-prolonging care, 4.4% preferred basic care, 91.3% preferred comfort care, and 4.4% were uncertain (P < .0001). The mean uncertainty score was higher in the video group than in the verbal group (13.7 v 11.5, respectively; P < .002). In the intervention arm, 82.6% of participants reported being very comfortable watching the video. Conclusion Compared with participants who only heard a verbal description, participants who viewed a goals-of-care video were more likely to prefer comfort care and avoid CPR, and were more certain of their end-of-life decision making. Participants reported feeling comfortable watching the video. C1 [Volandes, Angelo E.] Massachusetts Gen Hosp, Gen Med Unit, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Hebrew Senior Life, Boston, MA USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Univ Pittsburgh, Dept Med, Med Ctr, Pittsburgh, PA USA. RP Volandes, AE (reprint author), Massachusetts Gen Hosp, Gen Med Unit, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM avolandes@partners.org FU Foundation for Informed Medical Decision Making; NIH-NIA [K24AG033640] FX Supported by the Foundation for Informed Medical Decision Making and NIH-NIA K24AG033640. The funding agencies had no role in the design or conduct of the study; the collection, analysis, or interpretation of the data; or the preparation, review, or approval of the article. NR 27 TC 70 Z9 70 U1 7 U2 17 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 JAN 10 PY 2010 VL 28 IS 2 BP 305 EP 310 DI 10.1200/JCO.2009.24.7502 PG 6 WC Oncology SC Oncology GA 541LU UT WOS:000273418000021 PM 19949010 ER PT J AU Jackman, D Pao, W Riely, GJ Engelman, JA Kris, MG Janne, PA Lynch, T Johnson, BE Miller, VA AF Jackman, David Pao, William Riely, Gregory J. Engelman, Jeffrey A. Kris, Mark G. Jaenne, Pasi A. Lynch, Thomas Johnson, Bruce E. Miller, Vincent A. TI Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID T790M MUTATIONS; GEFITINIB; ERLOTINIB; TRIALS; TUMORS; ADENOCARCINOMAS; IMATINIB; COMMON AB Ten percent of North American patients with non-small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib. C1 [Miller, Vincent A.] Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, New York, NY 10021 USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med,Dept Med, Boston, MA 02114 USA. Yale Univ, Yale Canc Ctr, New Haven, CT USA. RP Miller, VA (reprint author), Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, Box 437,1275 York Ave, New York, NY 10021 USA. EM millerv@mskcc.org OI Kris, Mark/0000-0002-7317-5341 FU Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA FX Supported by the Memorial Sloan-Kettering Cancer Center, New York, NY, and Dana-Farber Cancer Institute, Boston, MA. NR 16 TC 310 Z9 345 U1 2 U2 18 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 JAN 10 PY 2010 VL 28 IS 2 BP 357 EP 360 DI 10.1200/JCO.2009.24.7049 PG 4 WC Oncology SC Oncology GA 541LU UT WOS:000273418000028 PM 19949011 ER PT J AU Wen, PY AF Wen, Patrick Y. TI Cerebral spinal fluid abnormalities in patients with paraneoplastic syndromes of the nervous system SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Editorial Material C1 Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, SW430D,44 Binney St, Boston, MA 02115 USA. EM pwen@partners.org NR 4 TC 0 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JAN 10 PY 2010 VL 81 IS 1 BP 3 EP 3 DI 10.1136/jnnp.2008.161646 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 533WF UT WOS:000272855400003 PM 20019217 ER PT J AU Zhou, YH Rideout, WM Zi, T Bressel, A Reddypalli, S Rancourt, R Woo, JK Horner, JW Chin, L Chiu, MI Bosenberg, M Jacks, T Clark, SC DePinho, RA Robinson, MO Heyer, J AF Zhou, Yinghui Rideout, William M., III Zi, Tong Bressel, Angela Reddypalli, Shailaja Rancourt, Rebecca Woo, Jin-Kyeung Horner, James W. Chin, Lynda Chiu, M. Isabel Bosenberg, Marcus Jacks, Tyler Clark, Steven C. DePinho, Ronald A. Robinson, Murray O. Heyer, Joerg TI Chimeric mouse tumor models reveal differences in pathway activation between ERBB family- and KRAS-dependent lung adenocarcinomas SO NATURE BIOTECHNOLOGY LA English DT Article ID GROWTH-FACTOR-RECEPTOR; TYROSINE KINASE INHIBITOR; GENE-EXPRESSION; MAMMARY EPITHELIUM; CANCER; RESISTANCE; MUTATION; GEFITINIB; EGFR; ERLOTINIB AB To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFR(L858R) and KRAS(G12V) chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category. C1 [Zhou, Yinghui; Rideout, William M., III; Zi, Tong; Bressel, Angela; Reddypalli, Shailaja; Rancourt, Rebecca; Woo, Jin-Kyeung; Chiu, M. Isabel; Clark, Steven C.; Robinson, Murray O.; Heyer, Joerg] AVEO Pharmaceut, Cambridge, MA USA. [Chin, Lynda] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Belfer Inst Appl Canc Sci,Dept Dermatol, Boston, MA 02115 USA. [Horner, James W.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Horner, James W.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA. [Horner, James W.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA. [Bosenberg, Marcus] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. [Jacks, Tyler] MIT, Koch Inst, Cambridge, MA 02139 USA. [Jacks, Tyler] MIT, Dept Biol, Cambridge, MA 02139 USA. [Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Heyer, J (reprint author), AVEO Pharmaceut, Cambridge, MA USA. EM jheyer@aveopharma.com OI Robinson, Murray/0000-0003-4462-0685 NR 42 TC 43 Z9 44 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JAN 10 PY 2010 VL 28 IS 1 BP 71 EP U102 DI 10.1038/nbt.1595 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 541PP UT WOS:000273430400023 PM 20023657 ER PT J AU Wu, HC Wang, TW Bohn, MC Lin, FH Spector, M AF Wu, Hsi-Chin Wang, Tzu-Wei Bohn, Martha C. Lin, Feng-Huei Spector, Myron TI Novel Magnetic Hydroxyapatite Nanoparticles as Non-Viral Vectors for the Glial Cell Line-Derived Neurotrophic Factor Gene SO ADVANCED FUNCTIONAL MATERIALS LA English DT Article ID CALCIUM-PHOSPHATE NANOPARTICLES; NEURONS IN-VITRO; AMYOTROPHIC-LATERAL-SCLEROSIS; DRUG-DELIVERY; DOPAMINERGIC-NEURONS; POLYMERIC NANOPARTICLES; BIOMEDICAL APPLICATIONS; PARKINSON-DISEASE; CANCER-TREATMENT; BRAIN-TUMORS AB Nanoparticles (NPs) of synthetic hydroxyapatite (Hap) and natural bone mineral (NBM) are rendered magnetic by treatment with iron ions using a wet-chemical process. The magnetic NPs (mNPs), which are about 300 nm in 1 diameter, display superparamagnetic properties in a superconducting quantum interference device, with a saturation magnetization of about 30 emu g(-1). X-ray diffraction and transmission electron microscopy reveal that the magnetic properties of the NPs are the result of the hetero-epitaxial 1 growth of magnetite on the Hap and NBM crystallites. The mNPs display a high binding affinity for plasmid DNA in contrast to magnetite NPs which do not bind the plasmid well. The mHap and mNBM NPs result in substantial increases in the transfection of rat marrow-derived mesenchymal stem cells with the gene for glial cell line-derived neurotrophic factor (GDNF), with magnetofection compared to transfection in the absence of a magnet. The : amount of GDNF recovered in the medium approaches therapeutic levels despite the small amount of plasmid delivered by the NPs. C1 [Wu, Hsi-Chin; Wang, Tzu-Wei; Spector, Myron] VA Boston Healthcare Syst, Tissue Engn Labs, Boston, MA 02130 USA. [Wang, Tzu-Wei; Spector, Myron] Harvard Univ, Dept Orthopaed Surg, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Wu, Hsi-Chin; Lin, Feng-Huei] Natl Taiwan Univ, Inst Biomed Engn, Taipei 100, Taiwan. [Wu, Hsi-Chin] Harvard Univ, Sch Med, Div Med Sci, Visiting Fellows Program, Boston, MA 02115 USA. [Wang, Tzu-Wei] Natl Tsing Hua Univ, Dept Mat Sci & Engn, Hsinchu 30013, Taiwan. [Bohn, Martha C.] Northwestern Univ, Childrens Mem Res Ctr, Chicago, IL 60614 USA. RP Wu, HC (reprint author), VA Boston Healthcare Syst, Tissue Engn Labs, 150 S Huntington Ave, Boston, MA 02130 USA. EM double@ntu.edu.tw; mspector@rics.bwh.harvard.edu RI Lin, Feng-Huei /E-3970-2010; WU, HSI-CHIN/A-2306-2013 FU Department of Veterans Affairs; Department of Defense; National Science Council of Taiwan; College of Engineering of the National Taiwan University FX Funding for this work was provided by the Department of Veterans Affairs and the Department of Defense. H.C. Wu also acknowledges the graduate student study abroad program (GSSAP) of the National Science Council of Taiwan and a scholarship from the College of Engineering of the National Taiwan University. M. Spector is a Veterans Affairs Research Career Scientist. The technical assistance of Alix Weaver is gratefully acknowledged. NR 62 TC 40 Z9 40 U1 3 U2 41 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1616-301X J9 ADV FUNCT MATER JI Adv. Funct. Mater. PD JAN 8 PY 2010 VL 20 IS 1 BP 67 EP 77 DI 10.1002/adfm.200901108 PG 11 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 549JR UT WOS:000274044900008 ER PT J AU Liu, XZ Han, DY Li, JZ Han, B Ouyang, XM Cheng, J Li, X Jin, ZG Wang, YQ Bitner-Glindzicz, M Kong, XY Xu, H Kantardzhieva, A Eavey, RD Seidman, CE Seidman, JG Du, LL Chen, ZY Dai, P Teng, MK Yan, D Yuan, HJ AF Liu, Xuezhong Han, Dongyi Li, Jianzhong Han, Bing Ouyang, Xiaomei Cheng, Jing Li, Xu Jin, Zhanguo Wang, Youqin Bitner-Glindzicz, Maria Kong, Xiangyin Xu, Heng Kantardzhieva, Albena Eavey, Roland D. Seidman, Christine E. Seidman, Jonathan G. Du, Li L. Chen, Zheng-Yi Dai, Pu Teng, Maikun Yan, Denise Yuan, Huijun TI Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic X-linked Sensorineural Deafness, DFN2 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY; PURINE METABOLISM; HEARING-LOSS; OVERPRODUCTION; ASSOCIATION AB We report a large Chinese family with X-linked postlingual nonsyndromic hearing impairment in which the critical linkage interval spans a genetic distance of 5.41 cM and a physical distance of 15.1 Mb that overlaps the DFN2 locus. Mutation screening of the PRPS1 gene in this family and in the three previously reported DFN2 families identified four different missense mutations in PRPS1. These Mutations result in a loss of phosphoribosyl pyrophosphate (PRPP) synthetase I activity, as was shown in silico by structural analysis and was shown in vitro by enzymatic activity assays in erythrocytes and fibroblasts from patients. By ill Situ hybridization, we demonstrate expression of Prps1 in murine vestibular and cochlea hair cells, with Continuous expression in hair cells and postnatal expression in the spiral ganglion. Being the second identified gene associated with X-linked nonsyndromic deafness, PRPS1 will be a good candidate gene for genetic testing for X-linked nonsyndromic hearing loss. C1 [Liu, Xuezhong; Han, Dongyi; Li, Jianzhong; Han, Bing; Cheng, Jing; Jin, Zhanguo; Dai, Pu; Yuan, Huijun] Chinese Peoples Liberat Army Gen Hosp, Inst Otolaryngol, Beijing 100853, Peoples R China. [Liu, Xuezhong; Ouyang, Xiaomei; Du, Li L.; Yan, Denise] Univ Miami, Dept Otolaryngol, Miami, FL 33136 USA. [Li, Xu; Teng, Maikun] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Peoples R China. [Li, Xu; Teng, Maikun] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China. [Li, Xu; Teng, Maikun] Chinese Acad Sci, Key Lab Struct Biol, Hefei 230026, Peoples R China. [Wang, Youqin] Guizhou Prov Peoples Hosp, Hearing Ctr, Guiyang 550002, Peoples R China. [Bitner-Glindzicz, Maria] UCL Inst Child Hlth, London WC1N 1EH, England. [Kong, Xiangyin; Xu, Heng] Chinese Acad Sci, Shanghai Inst Biol Sci, Hlth Sci Ctr, Shanghai 200025, Peoples R China. [Kong, Xiangyin; Xu, Heng] Shanghai Med Univ 2, Shanghai 200025, Peoples R China. [Kantardzhieva, Albena; Eavey, Roland D.; Chen, Zheng-Yi] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otolaryngol,Easton Peabody Lab, Boston, MA 02114 USA. [Seidman, Christine E.; Seidman, Jonathan G.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Seidman, Christine E.; Seidman, Jonathan G.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Yuan, HJ (reprint author), Chinese Peoples Liberat Army Gen Hosp, Inst Otolaryngol, Beijing 100853, Peoples R China. EM yuanhj301@yahoo.com.cn RI Bitner-Glindzicz, Maria/A-4231-2009 FU NIDCD NIH HHS [R01 DC005575, R01 DC006908, R01DC005575] NR 19 TC 36 Z9 50 U1 0 U2 8 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 JAN 8 PY 2010 VL 86 IS 1 BP 65 EP 71 DI 10.1016/j.ajhg.2009.11.015 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 554XZ UT WOS:000274471200006 PM 20021999 ER PT J AU Tischfield, MA Baris, HN Wu, C Rudolph, G Van Maldergem, L He, W Chan, WM Andrews, C Demer, JL Robertson, RL Mackey, DA Ruddle, JB Bird, TD Gottlob, I Pieh, C Traboulsi, EI Pomeroy, SL Hunter, DG Soul, JS Newlin, A Sabol, LJ Doherty, EJ de Uzcategui, CE de Uzcategui, N Collins, MLZ Sener, EC Wabbels, B Hellebrand, H Meitinger, T de Berardinis, T Magli, A Schiavi, C Pastore-Trossello, M Koc, F Wong, AM Levin, AV Geraghty, MT Descartes, M Flaherty, M Jamieson, RV Moller, HU Meuthen, I Callen, DF Kerwin, J Lindsay, S Meindl, A Gupta, ML Pellman, D Engle, EC AF Tischfield, Max A. Baris, Hagit N. Wu, Chen Rudolph, Guenther Van Maldergem, Lionel He, Wei Chan, Wai-Man Andrews, Caroline Demer, Joseph L. Robertson, Richard L. Mackey, David A. Ruddle, Jonathan B. Bird, Thomas D. Gottlob, Irene Pieh, Christina Traboulsi, Elias I. Pomeroy, Scott L. Hunter, David G. Soul, Janet S. Newlin, Anna Sabol, Louise J. Doherty, Edward J. de Uzcategui, Clara E. de Uzcategui, Nicolas Collins, Mary Louise Z. Sener, Emin C. Wabbels, Bettina Hellebrand, Heide Meitinger, Thomas de Berardinis, Teresa Magli, Adriano Schiavi, Costantino Pastore-Trossello, Marco Koc, Feray Wong, Agnes M. Levin, Alex V. Geraghty, Michael T. Descartes, Maria Flaherty, Maree Jamieson, Robyn V. Moller, H. U. Meuthen, Ingo Callen, David F. Kerwin, Janet Lindsay, Susan Meindl, Alfons Gupta, Mohan L., Jr. Pellman, David Engle, Elizabeth C. TI Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance SO CELL LA English DT Article ID BETA-TUBULIN GENE; CONGENITAL FIBROSIS; EXTRAOCULAR-MUSCLES; MITOTIC SPINDLE; ALPHA-TUBULIN; IN-VITRO; ISOTYPE; KIF21A; YEAST; IDENTIFICATION AB We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals. C1 [Tischfield, Max A.; Wu, Chen; He, Wei; Chan, Wai-Man; Andrews, Caroline; Pomeroy, Scott L.; Soul, Janet S.; Engle, Elizabeth C.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Tischfield, Max A.; Wu, Chen; He, Wei; Chan, Wai-Man; Andrews, Caroline; Pomeroy, Scott L.; Engle, Elizabeth C.] Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Tischfield, Max A.; Baris, Hagit N.; He, Wei; Chan, Wai-Man; Andrews, Caroline; Engle, Elizabeth C.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Tischfield, Max A.; Engle, Elizabeth C.] Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Baris, Hagit N.; Engle, Elizabeth C.] Childrens Hosp, Dept Med Genet, Boston, MA 02115 USA. [Pellman, David] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Hunter, David G.; Engle, Elizabeth C.] Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. [Robertson, Richard L.] Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. [Tischfield, Max A.; Wu, Chen; Pomeroy, Scott L.; Engle, Elizabeth C.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Gupta, Mohan L., Jr.; Pellman, David] Harvard Univ, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. [Pomeroy, Scott L.; Soul, Janet S.; Engle, Elizabeth C.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Gupta, Mohan L., Jr.; Pellman, David] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Rudolph, Guenther] Univ Munich, Univ Eye Hosp, D-80539 Munich, Germany. [Van Maldergem, Lionel] Univ Liege, Ctr Genet Humaine, B-4000 Liege, Belgium. [Wu, Chen; Chan, Wai-Man; Andrews, Caroline; Pellman, David; Engle, Elizabeth C.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Demer, Joseph L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Demer, Joseph L.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Demer, Joseph L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Demer, Joseph L.] Univ Calif Los Angeles, David Geffen Sch Med, Neurosci Interdepartmental Program, Los Angeles, CA 90095 USA. [Demer, Joseph L.] Univ Calif Los Angeles, David Geffen Sch Med, Bioengn Interdepartmental Program, Los Angeles, CA 90095 USA. [Mackey, David A.; Ruddle, Jonathan B.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Dept Ophthalmol, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia. [Mackey, David A.] Univ Tasmania, Royal Hobart Hosp, Dept Ophthalmol, Hobart, Tas 7000, Australia. [Bird, Thomas D.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA. [Bird, Thomas D.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Bird, Thomas D.] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98195 USA. [Gottlob, Irene] Univ Leicester, Ophthalmol Grp, Leicester LE2 7LX, Leics, England. [Pieh, Christina] Univ Freiburg, Univ Eye Hosp, D-79106 Freiburg, Germany. [Traboulsi, Elias I.] Cleveland Clin i32, Cole Eye Inst, Cleveland, OH 44195 USA. [Newlin, Anna] NorthShore Univ HealthSyst, Ctr Genet Med, Evanston, IL 60201 USA. [Sabol, Louise J.] Geisinger Med Inst, Dept Ophthalmol, Danville, PA 17822 USA. [Doherty, Edward J.] St Johns Hosp, Atlantic Hlth Sci Ctr, St John, NB E2L 4L2, Canada. [de Uzcategui, Clara E.] Inst Oftalmol, Caracas 1010, Venezuela. [de Uzcategui, Nicolas] Upstate Med Univ SUNY, Dept Ophthalmol, Syracuse, NY 13210 USA. [Collins, Mary Louise Z.] Greater Baltimore Med Ctr, Dept Ophthalmol, Baltimore, MD 21204 USA. [Sener, Emin C.] Hacettepe Univ Hosp, Dept Ophthalmol, TR-06100 Ankara, Turkey. [Wabbels, Bettina] Univ Bonn, Dept Ophthalmol, D-53127 Bonn, Germany. [Hellebrand, Heide; Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, D-81675 Munich, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-81675 Munich, Germany. [Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany. [de Berardinis, Teresa; Magli, Adriano] Univ Naples Federico II, Dept Ophthalmol Sci, Fac Med & Surg, I-80138 Naples, Italy. [Schiavi, Costantino] Univ Bologna, Dept Ophthalmol, I-40126 Bologna, Italy. [Pastore-Trossello, Marco] St Orsola Marcello Malpighi Hosp, Dept Neuroradiol, I-40138 Bologna, Italy. [Koc, Feray] Acibadem Univ, Kocaeli Hosp, Dept Ophthalmol & Strabismus & Neuroophthalmol, TR-41100 Kocaeli, Turkey. [Wong, Agnes M.] Hosp Sick Children, Dept Ophthalmol & Vis Sci, Toronto, ON M5G 1X8, Canada. [Levin, Alex V.] Wills Eye Inst, Philadelphia, PA 19107 USA. [Geraghty, Michael T.] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada. [Descartes, Maria] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA. [Flaherty, Maree] Childrens Hosp Westmead, Dept Ophthalmol, Sydney, NSW 2145, Australia. [Jamieson, Robyn V.] Childrens Hosp Westmead, Dept Clin Genet, Sydney, NSW 2145, Australia. [Jamieson, Robyn V.] Univ Sydney, Sydney, NSW 2008, Australia. [Moller, H. U.] Viborg Hosp, Dept Ophthalmol, DK-8000 Viborg, Denmark. [Meuthen, Ingo] Kliniken Stadt Koln, Dept Hematol Oncol, D-51067 Cologne, Germany. [Callen, David F.] Univ Adelaide, Sch Med, Breast Canc Genet Grp, Adelaide, SA 5005, Australia. [Kerwin, Janet; Lindsay, Susan] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Lindsay, Susan] Newcastle Univ, MRC Wellcome Trust Human Dev Biol Resource Newcas, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. RP Gupta, ML (reprint author), Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA. EM mlgupta@uchicago.edu; elizabeth.engle@childrens.harvard.edu RI Callen, David/G-1975-2012; Lindsay, Susan/B-3828-2013; Wu, Chen/B-3932-2010; Meitinger, Thomas/O-1318-2015; Mackey, David/H-5340-2014; OI Lindsay, Susan/0000-0003-2980-4582; Mackey, David/0000-0001-7914-4709; DE BERARDINIS, Teresa/0000-0001-6872-0432; schiavi, costantino/0000-0002-5753-6987; Magli, Adriano/0000-0002-6490-2068; Callen, David/0000-0002-6189-9991; Hunter, David/0000-0002-4587-4794; Robertson, Richard/0000-0001-8811-4405 FU NIH [R01 EY012498, R01 EY013583, HD18655, F32 EY016306, R01 GM061345-08] FX We thank the families for their participation; Michelle DeLisle and Carrie Wu for technical assistance and members of the Engle lab for their thoughtful comments; A. Nurten Akarsu, Peter Kang, Lisa S Kearns, James Hoekel, Marijean Miller, Marilyn Miller, Peter Roggenkamper, and Sandra Staffieri for pedigree referrals and/or clinical exam data. This work was supported by NIH R01 EY012498, R01 EY013583, HD18655 (E. C. E.), F32 EY016306 (H. B.), R01 GM061345-08 (D. P.), and VA Research Funds (T. D. B.). E. C. E. and D. P. are investigators of the Howard Hughes Medical Institute. NR 36 TC 208 Z9 214 U1 2 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JAN 8 PY 2010 VL 140 IS 1 BP 74 EP 87 DI 10.1016/j.cell.2009.12.011 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 541CY UT WOS:000273391900016 PM 20074521 ER PT J AU Ryan, DP da Silva, MRD Soong, TW Fontaine, B Donaldson, MR Kung, AWC Jongjaroenprasert, W Liang, MC Khoo, DHC Cheah, JS Ho, SC Bernstein, HS Maciel, RMB Brown, RH Ptacek, LJ AF Ryan, Devon P. da Silva, Magnus R. Dias Soong, Tuck Wah Fontaine, Bertrand Donaldson, Matt R. Kung, Annie W. C. Jongjaroenprasert, Wallaya Liang, Mui Cheng Khoo, Daphne H. C. Cheah, Jin Seng Ho, Su Chin Bernstein, Harold S. Maciel, Rui M. B. Brown, Robert H., Jr. Ptacek, Louis J. TI Mutations in Potassium Channel Kir2.6 Cause Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis SO CELL LA English DT Article ID RECTIFYING K+ CHANNEL; FUNCTIONAL EXPRESSION; ANDERSENS-SYNDROME; THYROID-HORMONE; HUMAN-GENOME; CHANNELOPATHIES; CARDIOMYOCYTES; TRAFFICKING; REVEALS; CLONING AB Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clearly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis. C1 [Ryan, Devon P.; Ptacek, Louis J.] Univ Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94158 USA. [Ryan, Devon P.; da Silva, Magnus R. Dias; Donaldson, Matt R.; Ptacek, Louis J.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Ptacek, Louis J.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA. [Soong, Tuck Wah] Natl Inst Neurosci, Ion Channel & Transporter Lab, Singapore 308433, Singapore. [Fontaine, Bertrand] Univ Paris 06, INSERM, UMRS 546, F-75013 Paris, France. [Fontaine, Bertrand] Grp Hosp Pitie Salpetriere, AP HP, Ctr Reference Canalopathies Musculaires, F-75013 Paris, France. [Kung, Annie W. C.] Univ Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Jongjaroenprasert, Wallaya] Mahidol Univ, Ramathibodi Hosp, Dept Med, Bangkok 10400, Thailand. [Soong, Tuck Wah; Liang, Mui Cheng] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 308433, Singapore. [Cheah, Jin Seng] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 308433, Singapore. [Khoo, Daphne H. C.; Ho, Su Chin] Singapore Gen Hosp, Dept Clin Res, Singapore 169608, Singapore. [Bernstein, Harold S.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Maciel, Rui M. B.] Univ Fed Sao Paulo, Div Endocrinol, Dept Med, BR-04039032 Sao Paulo, Brazil. [Brown, Robert H., Jr.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Ptacek, LJ (reprint author), Univ Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94158 USA. EM ljp@ucsf.edu RI Dias da Silva, Magnus/B-9132-2012; OI Dias da Silva, Magnus/0000-0002-8516-966X; Maciel, Rui/0000-0002-6123-6098; Ryan, Devon/0000-0002-8549-0971 FU Muscular Dystrophy Association; National Institutes of Health [U54 RR19481]; CAPES Foundation [2284/01-4]; FAPESP (Sao Paulo State Research Foundation) [2000/03442-4, 1999/03688-4]; INSERM; AFM; C.B. Day Foundation; NINDS FX We thank Lily Jan, Friederike Haas, and Carol Vandenburg for helpful discussions and advice and all the patients for their participation. We also thank Kathleen Giacomini for additional DNA controls. This work was supported by the Muscular Dystrophy Association, National Institutes of Health grant U54 RR19481, CAPES Foundation grant 2284/01-4 (MRDS), and FAPESP (Sao Paulo State Research Foundation) grants 2000/03442-4 (MRDS) and 1999/03688-4 (RMBM). B. F. is supported by INSERM, AFM, and ANR Maladies Rares and acknowledges patient referral and fruitful discussions of members of the clinical and research French network Resocanaux. R. Brown received generous support from the C.B. Day Foundation and the NINDS L.J.P. is an Investigator of the Howard Hughes Medical Institute. NR 35 TC 98 Z9 106 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 8 PY 2010 VL 140 IS 1 BP 88 EP 98 DI 10.1016/j.cell.2009.12.024 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 541CY UT WOS:000273391900017 PM 20074522 ER PT J AU Woo, CJ Kharchenko, PV Daheron, L Park, PJ Kingston, RE AF Woo, Caroline J. Kharchenko, Peter V. Daheron, Laurence Park, Peter J. Kingston, Robert E. TI A Region of the Human HOXD Cluster that Confers Polycomb-Group Responsiveness SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; POLYCOMB/TRITHORAX RESPONSE ELEMENTS; TRANSCRIPTION FACTOR YY1; DNA-BINDING PROTEIN; DROSOPHILA-MELANOGASTER; DEVELOPMENTAL REGULATORS; PCG PROTEINS; GROUP GENES; IN-VIVO; COMPLEXES AB Polycomb group (PcG) proteins are essential for accurate axial body patterning during embryonic development. PcG-mediated repression is conserved in metazoans and is targeted in Drosophila by Polycomb response elements (PREs). However, targeting sequences in humans have not been described. While analyzing chromatin architecture in the context of human embryonic stem cell (hESC) differentiation, we discovered a 1.8kb region between HOXD11 and HOXD12(D11.12) that is associated with PcG proteins, becomes nuclease hypersensitive, and then shows alteration in nuclease sensitivity as hESCs differentiate. The D11.12 element repressed luciferase expression from a reporter construct and full repression required a highly conserved region and YY1 binding sites. Furthermore, repression was dependent on the PcG proteins BMI1 and EED and a YY1-interacting partner, RYBP. We conclude that D11.12 is a Polycomb-dependent regulatory region with similarities to Drosophila PREs, indicating conservation in the mechanisms that target PcG function in mammals and flies. C1 [Woo, Caroline J.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Kharchenko, Peter V.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Kharchenko, Peter V.; Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Daheron, Laurence] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Daheron, Laurence] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu FU NIH [GM43901, HG003141, GM082798]; NRSA [GM072265] FX We thank S. K. Bowman and M. D. Simon for discussions and critical reading of the manuscript. Funding for this work for R. E. K. and C. J. W. was provided by NIH (GM43901 and HG003141). C. J. W. was supported by NRSA GM072265. P. J. K. and P. V. K. were supported by NIH grant GM082798. NR 53 TC 197 Z9 202 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 8 PY 2010 VL 140 IS 1 BP 99 EP 110 DI 10.1016/j.cell.2009.12.022 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 541CY UT WOS:000273391900018 PM 20085705 ER PT J AU Kakkar, R Lee, RT AF Kakkar, Rahul Lee, Richard T. TI Intramyocardial Fibroblast Myocyte Communication SO CIRCULATION RESEARCH LA English DT Review DE cardiac failure; fibroblasts; cardiac differentiation; cytokines; growth factors ID GROWTH-FACTOR-BETA; RAT CARDIAC FIBROBLASTS; MATRIX-METALLOPROTEINASE INHIBITION; SPONTANEOUSLY HYPERTENSIVE-RATS; RABBIT VENTRICULAR MYOCYTES; ANGIOTENSIN-II RECEPTORS; CONGESTIVE-HEART-FAILURE; HIGH-MOLECULAR-WEIGHT; GAP JUNCTION PROTEIN; MYOCARDIAL-INFARCTION AB Cardiac fibroblasts are emerging as key components of normal cardiac function, as well as the response to stressors and injury. These most numerous cells of the heart interact with myocytes via paracrine mechanisms, alterations in extracellular matrix homeostasis, and direct cell-cell interactions. It is possible that they are a contributor to the inability of adult myocytes to proliferate and may influence cardiac progenitor biology. Furthering our understanding of how cardiac fibroblasts and myocytes interact may provide an avenue to novel treatments for heart failure prevention. This review discusses the most recent concepts in cardiac fibroblast-myocyte communication and areas of potential future research. (Circ Res. 2010;106:47-57.) C1 [Lee, Richard T.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Partners Res Facil,Dept Med,Cardiovasc Div, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Cambridge, MA 02139 USA. RP Lee, RT (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Partners Res Facil,Dept Med,Cardiovasc Div, Room 279,65 Landsdowne St, Cambridge, MA 02139 USA. EM rlee@partners.org FU National Institutes of Health [HL092930, AG032977] FX This work was supported by grants from the National Institutes of Health (HL092930 and AG032977). NR 163 TC 138 Z9 142 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 8 PY 2010 VL 106 IS 1 BP 47 EP 57 DI 10.1161/CIRCRESAHA.109.207456 PG 11 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 541GP UT WOS:000273403600012 PM 20056945 ER PT J AU Qi, Y Spong, MC Nam, K Karplus, M Verdine, GL AF Qi, Yan Spong, Marie C. Nam, Kwangho Karplus, Martin Verdine, Gregory L. TI Entrapment and Structure of an Extrahelical Guanine Attempting to Enter the Active Site of a Bacterial DNA Glycosylase, MutM SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FREE R-VALUE; MOLECULAR-DYNAMICS; REPAIR ENZYME; SUBSTRATE-SPECIFICITY; INTRAHELICAL LESION; CROSS-VALIDATION; DAMAGED DNA; DUPLEX DNA; RECOGNITION; PROTEIN AB MutM, a bacterial DNA glycosylase, protects genome integrity by catalyzing glycosidic bond cleavage of 8-oxoguanine (oxoG) lesions, thereby initiating base excision DNA repair. The process of searching for and locating oxoG lesions is especially challenging, because of the close structural resemblance of oxoG to its million-fold more abundant progenitor, G. Extrusion of the target nucleobase from the DNA double helix to an extrahelical position is an essential step in lesion recognition and catalysis by MutM. Although the interactions between the extruded oxoG and the active site of MutM have been well characterized, little is known in structural detail regarding the interrogation of extruded normal DNA bases by MutM. Here we report the capture and structural elucidation of a complex in which MutM is attempting to present an undamaged G to its active site. The structure of this MutM-extrahelical G complex provides insights into the mechanism MutM employs to discriminate against extrahelical normal DNA bases and into the base extrusion process in general. C1 [Qi, Yan; Verdine, Gregory L.] Harvard Univ, Sch Med, Grad Program Biophys, Boston, MA 02115 USA. [Spong, Marie C.; Nam, Kwangho; Karplus, Martin; Verdine, Gregory L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Chem Biol Initiat, Boston, MA 02115 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. [Karplus, Martin] Univ Strasbourg, Inst Sci & Ingn Supramol, F-67000 Strasbourg, France. RP Verdine, GL (reprint author), 12 Oxford St, Cambridge, MA 02138 USA. EM gregory_verdine@harvard.edu FU National Institutes of Health [GM044853, GM047467, CA100742, GM030804]; National Science Foundation; Howard Hughes Medical Institute; National Cancer Center FX This work was supported, in whole or in part, by National Institutes of Health Grants GM044853, GM047467, and CA100742 (to G.L.V.) and GM030804 (to M.K.).; Supported by a predoctoral fellowship from the National Science Foundation.; Supported by a predoctoral fellowship from the Howard Hughes Medical Institute.; Supported by a postdoctoral fellowship from the National Cancer Center. NR 49 TC 29 Z9 29 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 8 PY 2010 VL 285 IS 2 BP 1468 EP 1478 DI 10.1074/jbc.M109.069799 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539MH UT WOS:000273258200066 PM 19889642 ER PT J AU Ugai, H Wang, MH Le, LP Matthews, DA Yamamoto, M Curiel, DT AF Ugai, Hideyo Wang, Minghui Le, Long P. Matthews, David A. Yamamoto, Masato Curiel, David T. TI In Vitro Dynamic Visualization Analysis of Fluorescently Labeled Minor Capsid Protein IX and Core Protein V by Simultaneous Detection SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE adenovirus, fluorescent protein; pV; pIX; imaging ID HUMAN ADENOVIRUS TYPE-5; ONCOLYTIC VIRUSES; DNA-REPLICATION; RECOMBINANT ADENOVIRUS; GENE-THERAPY; SUBSTRATE-SPECIFICITY; NUCLEOPROTEIN CORES; CELLS; PROMOTER; CANCER AB Oncolytic adenoviruses represent a promising therapeutic medicine for human cancer therapy, but successful translation into human clinical trials requires careful evaluation of their viral characteristics. While the function of adenovirus proteins has been analyzed in detail, the dynamics of adenovirus infection remain largely unknown due to technological constraints that prevent adequate tracking of adenovirus particles after infection. Fluorescence labeling of adenoviral particles is one new strategy designed to directly analyze the dynamic processes of viral infection in virus-host cell interactions. We hypothesized that the double labeling of an adenovirus with fluorescent proteins would allow us to properly analyze intracellular viruses and the fate of viral proteins in a live analysis of an adenovirus as compared to single labeling. Thus, we generated a fluorescently labeled adenovirus with both a red fluorescent minor capsid protein IX (pIX) [pIX monomeric red fluorescent protein 1 (mLRFP1)] and a green fluorescent minor core protein V (pV) [pV enhanced green fluorescent protein (EGFP)], resulting in Ad5-IX-mRFP1-E3-V-EGFP. The fluorescent signals for pIX-n-LRFP1 and pV-EGFP were detected within 10 min in living cells. However, a growth curve analysis of Ad5-IX-mRFP1-E3-V-EGFP showed an approximately 150-fold reduced production of the viral progeny at 48 h postinfection as compared to adenovirus type 5. Interestingly, pIX-mRFP1 and pV-EGFP were initially localized in the cytoplasm and nucleolus, respectively, at 18 h postinfection. These proteins were observed in the nucleus during the late stage of infection, and relocalization of the proteins was observed in an adenoviral-replication-dependent manner These results indicate that simultaneous detection of adenoviruses using dual-fluorescent proteins is Suitable for real-time analysis, including identification of infected cells and monitoring of viral spread, which will be required for a complete evaluation of oncolytic adenoviruses. (C) 2009 Elsevier Ltd All rights reserved. C1 [Ugai, Hideyo; Wang, Minghui; Curiel, David T.] Univ Alabama, Dept Med, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Ugai, Hideyo; Wang, Minghui; Curiel, David T.] Univ Alabama, Dept Obstet & Gynecol, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Ugai, Hideyo; Wang, Minghui; Curiel, David T.] Univ Alabama, Dept Pathol, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Ugai, Hideyo; Wang, Minghui; Curiel, David T.] Univ Alabama, Dept Surg, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Le, Long P.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Matthews, David A.] Univ Bristol, Sch Med Sci, Dept Cellular & Mol Med, Bristol BS8 1TD, Avon, England. [Yamamoto, Masato] Univ Minnesota, Dept Surg, Div Basic & Translat Res, Minneapolis, MN 55455 USA. [Curiel, David T.] Univ Alabama, Gene Therapy Ctr, Birmingham, AL 35294 USA. RP Curiel, DT (reprint author), Univ Alabama, Dept Med, Div Human Gene Therapy, 901 19th St S,BMR2-R502, Birmingham, AL 35294 USA. EM curiel@uab.edu RI Matthews, David/H-5311-2011; OI Matthews, David/0000-0003-4611-8795 FU National Institutes of Health [5R01CA111569, 5R56CA094084]; Susan G. Komen for the Cure [PDF0707736] FX We thank Dr. Roger Y. Tsien (University of California at San Diego) for providing the mRFP1 construct and Dr. Igor P. Dmitriev (University of Alabama at Birmingham) for providing a rabbit polyclonal pIX antibody. We also thank Drs. Anton V. Borovjagin, Erin E. Thacker, George C. Dobbins, Joel N. Glasgow, Matthew S. Beatty, Qiana L. Matthews, and Yizhe Tang for useful advice and fruitful discussions We are grateful to Cynthia M.. Rodenburg for technical support with TEM at the High Resolution Imaging Facility of the University of Alabama at Birmingham. This work was supported by grants from the National Institutes of Health (grant 5R01CA111569 to Dr. David T. Curiel and grant 5R56CA094084 to Drs. Masato Yamamoto and David T Curiel) and by a grant from Susan G. Komen for the Cure (grant PDF0707736 to Dr. Hideyo Ugai). NR 73 TC 10 Z9 12 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 8 PY 2010 VL 395 IS 1 BP 55 EP 78 DI 10.1016/j.jmb.2009.10.034 PG 24 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553FP UT WOS:000274351900006 PM 19853616 ER PT J AU Maze, I Covington, HE Dietz, DM LaPlant, Q Renthal, W Russo, SJ Mechanic, M Mouzon, E Neve, RL Haggarty, SJ Ren, YH Sampath, SC Hurd, YL Greengard, P Tarakhovsky, A Schaefer, A Nestler, EJ AF Maze, Ian Covington, Herbert E., III Dietz, David M. LaPlant, Quincey Renthal, William Russo, Scott J. Mechanic, Max Mouzon, Ezekiell Neve, Rachael L. Haggarty, Stephen J. Ren, Yanhua Sampath, Srihari C. Hurd, Yasmin L. Greengard, Paul Tarakhovsky, Alexander Schaefer, Anne Nestler, Eric J. TI Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity SO SCIENCE LA English DT Article ID NUCLEUS-ACCUMBENS; DELTA-FOSB; GENE-EXPRESSION; EXPOSURE; PROTEIN; NEURONS; REWARD; AMPHETAMINE; MECHANISMS; ADDICTION AB Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. In mice, we identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor Delta FosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine. C1 [Maze, Ian; Covington, Herbert E., III; Dietz, David M.; LaPlant, Quincey; Russo, Scott J.; Mouzon, Ezekiell; Ren, Yanhua; Hurd, Yasmin L.; Nestler, Eric J.] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY 10029 USA. [LaPlant, Quincey; Renthal, William; Mechanic, Max] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [LaPlant, Quincey; Renthal, William; Mechanic, Max] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. [Neve, Rachael L.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Haggarty, Stephen J.] Harvard & Massachusetts Inst Technol, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Sampath, Srihari C.; Tarakhovsky, Alexander] Rockefeller Univ, Lab Lymphocyte Signaling, New York, NY 10021 USA. [Greengard, Paul; Schaefer, Anne] Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. RP Nestler, EJ (reprint author), Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY 10029 USA. EM eric.nestler@mssm.edu RI Dietz, David/J-9458-2015; OI Dietz, David/0000-0002-6927-9236; Maze, Ian/0000-0003-1490-7781; Haggarty, Stephen J./0000-0002-7872-168X FU National Institute on Drug Abuse [P01 DA08227, R01 DA07359, P0110044] FX This work was supported by grants from the National Institute on Drug Abuse: P01 DA08227 and R01 DA07359 (E. J. N.) and P0110044 (P. G.). E. J. N. certifies that none of the materials included in the manuscript have been previously published or are under consideration elsewhere, including on the Internet. All work involving the use of animals was conducted in accordance with institutional and Institutional Animal Care and Use Committee guidelines at both the University of Texas Southwestern Medical Center and Mount Sinai School of Medicine. NR 27 TC 274 Z9 286 U1 7 U2 38 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 JAN 8 PY 2010 VL 327 IS 5962 BP 213 EP 216 DI 10.1126/science.1179438 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 541DQ UT WOS:000273394000038 PM 20056891 ER PT J AU Quirk, GJ Milad, MR AF Quirk, Gregory J. Milad, Mohammed R. TI NEUROSCIENCE Editing out fear SO NATURE LA English DT Editorial Material ID RECONSOLIDATION; EXTINCTION; MEMORY; CONSOLIDATION; RETRIEVAL C1 [Quirk, Gregory J.] Univ Puerto Rico, Sch Med, Dept Psychiat, San Juan, PR 00936 USA. [Milad, Mohammed R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. RP Quirk, GJ (reprint author), Univ Puerto Rico, Sch Med, Dept Psychiat, San Juan, PR 00936 USA. EM gjquirk@yahoo.com; milad@nmr.mgh.harvard.edu NR 10 TC 15 Z9 15 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 7 PY 2010 VL 463 IS 7277 BP 36 EP 37 DI 10.1038/463036a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 540OV UT WOS:000273344900020 PM 20054384 ER PT J AU Darouiche, RO Wall, MJ Itani, KMF Otterson, MF Webb, AL Carrick, MM Miller, HJ Awad, SS Crosby, CT Mosier, MC AlSharif, A Berger, DH AF Darouiche, Rabih O. Wall, Matthew J., Jr. Itani, Kamal M. F. Otterson, Mary F. Webb, Alexandra L. Carrick, Matthew M. Miller, Harold J. Awad, Samir S. Crosby, Cynthia T. Mosier, Michael C. AlSharif, Atef Berger, David H. TI Chlorhexidine-Alcohol versus Povidone-Iodine for Surgical-Site Antisepsis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ELECTIVE COLORECTAL SURGERY; SUPPLEMENTAL PERIOPERATIVE OXYGEN; WOUND-INFECTION; ANTIMICROBIAL PROPHYLAXIS; PREVENTION; TRIAL; CEFOTETAN; HOSPITALIZATION; ANTIBIOTICS; MULTICENTER AB BACKGROUND Since the patient's skin is a major source of pathogens that cause surgical-site infection, optimization of preoperative skin antisepsis may decrease postoperative infections. We hypothesized that preoperative skin cleansing with chlorhexidine-alcohol is more protective against infection than is povidone-iodine. METHODS We randomly assigned adults undergoing clean-contaminated surgery in six hospitals to preoperative skin preparation with either chlorhexidine-alcohol scrub or povidone-iodine scrub and paint. The primary outcome was any surgical-site infection within 30 days after surgery. Secondary outcomes included individual types of surgical-site infections. RESULTS A total of 849 subjects (409 in the chlorhexidine-alcohol group and 440 in the povidone-iodine group) qualified for the intention-to-treat analysis. The overall rate of surgical-site infection was significantly lower in the chlorhexidine-alcohol group than in the povidone-iodine group (9.5% vs. 16.1%; P = 0.004; relative risk, 0.59; 95% confidence interval, 0.41 to 0.85). Chlorhexidine-alcohol was significantly more protective than povidone-iodine against both superficial incisional infections (4.2% vs. 8.6%, P = 0.008) and deep incisional infections (1% vs. 3%, P = 0.05) but not against organ-space infections (4.4% vs. 4.5%). Similar results were observed in the per-protocol analysis of the 813 patients who remained in the study during the 30-day follow-up period. Adverse events were similar in the two study groups. CONCLUSIONS Preoperative cleansing of the patient's skin with chlorhexidine-alcohol is superior to cleansing with povidone-iodine for preventing surgical-site infection after clean-contaminated surgery. (ClinicalTrials.gov number, NCT00290290.) C1 [Darouiche, Rabih O.] Baylor Coll Med, Ctr Prostheses Infect, Houston, TX 77030 USA. [Darouiche, Rabih O.; Awad, Samir S.; AlSharif, Atef; Berger, David H.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Wall, Matthew J., Jr.; Carrick, Matthew M.; Miller, Harold J.] Ben Taub Gen Hosp, Houston, TX 77030 USA. [Itani, Kamal M. F.] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Itani, Kamal M. F.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Otterson, Mary F.] Vet Affairs Med Ctr, Milwaukee, WI USA. [Otterson, Mary F.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Webb, Alexandra L.] Vet Affairs Med Ctr, Atlanta, GA 30033 USA. [Crosby, Cynthia T.] Cardinal Hlth, Leawood, KS USA. [Mosier, Michael C.] Washburn Univ, Topeka, KS 66621 USA. RP Darouiche, RO (reprint author), Baylor Coll Med, Ctr Prostheses Infect, 1333 Moursund Ave,Suite A221, Houston, TX 77030 USA. EM rdarouiche@aol.com NR 27 TC 417 Z9 431 U1 0 U2 46 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 JAN 7 PY 2010 VL 362 IS 1 BP 18 EP 26 DI 10.1056/NEJMoa0810988 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 540PA UT WOS:000273345500005 PM 20054046 ER PT J AU Bortfeld, T AF Bortfeld, Thomas TI The number of beams in IMRT-theoretical investigations and implications for single-arc IMRT SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MODULATED ARC; CONFORMAL RADIOTHERAPY; MULTILEAF COLLIMATOR; ROTATION THERAPY; X-RAYS; IMPLEMENTATION AB The first purpose of this paper is to shed some new light on the old question of selecting the number of beams in intensity-modulated radiation therapy (IMRT). The second purpose is to illuminate the related issue of discrete static beam angles versus rotational techniques, which has recently re-surfaced due to the advancement of volumetric modulated arc therapy (VMAT). A specific objective is to find analytical expressions that allow one to address the points raised above. To make the problem mathematically tractable, it is assumed that the depth dose is flat and that the lateral dose profile can be approximated by polynomials, specifically Chebyshev polynomials of the first kind, of finite degree. The application of methods known from image reconstruction then allows one to answer the first question above as follows: the required number of beams is determined by the maximum degree of the polynomials used in the approximation of the beam profiles, which is a measure of the dose variability. There is nothing to be gained by using more beams. In realistic cases, in which the variability of the lateral dose profile is restricted in several ways, the required number of beams is of the order of 10-20. The consequence of delivering the beams with a 'leaf sweep' technique during continuous rotation of the gantry, as in VMAT, is also derived in an analytical form. The main effect is that the beams fan out, but the effect near the axis of rotation is small. This result can serve as a theoretical justification of VMAT. Overall the analytical derivations in this paper, albeit based on strong simplifications, provide new insights into, and a deeper understanding of, the beam angle problem in IMRT. The decomposition of the beam profiles into well-behaved and easily deliverable smooth functions, such as Chebyshev polynomials, could be of general interest in IMRT treatment planning. C1 [Bortfeld, Thomas] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bortfeld, Thomas] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. RP Bortfeld, T (reprint author), Massachusetts Gen Hosp, 30 Fruit St, Boston, MA 02114 USA. EM tbortfeld@partners.org FU NCI NIH HHS [R01 CA103904-07, R01 CA103904, R01 CA118200, R01 CA118200-04] NR 18 TC 30 Z9 30 U1 3 U2 6 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 JAN 7 PY 2010 VL 55 IS 1 BP 83 EP 97 DI 10.1088/0031-9155/55/1/006 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 531BN UT WOS:000272637800006 PM 19949256 ER PT J AU Brooks-Pollock, E Cohen, T Murray, M AF Brooks-Pollock, Ellen Cohen, Ted Murray, Megan TI The Impact of Realistic Age Structure in Simple Models of Tuberculosis Transmission SO PLOS ONE LA English DT Article ID DRUG-RESISTANT TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; INFECTIOUS-DISEASES; EPIDEMIC MODELS; PERSISTENCE; DYNAMICS; RISKS; DISTRIBUTIONS; POPULATIONS; PATTERNS AB Background: Mathematical models of tuberculosis (TB) transmission have been used to characterize disease dynamics, investigate the potential effects of public health interventions, and prioritize control measures. While previous work has addressed the mathematical description of TB natural history, the impact of demography on the behaviour of TB models has not been assessed. Methods: A simple model of TB transmission, with alternative assumptions about survivorship, is used to explore the effect of age structure on the prevalence of infection, disease, basic reproductive ratio and the projected impact of control interventions. We focus our analytic arguments on the differences between constant and exponentially distributed lifespans and use an individual-based model to investigate the range of behaviour arising from realistic distributions of survivorship. Results: The choice of age structure and natural (non-disease related) mortality strongly affects steady-state dynamics, parameter estimation and predictions about the effectiveness of control interventions. Since most individuals infected with TB develop an asymptomatic latent infection and never progress to active disease, we find that assuming a constant mortality rate results in a larger reproductive ratio and an overestimation of the effort required for disease control in comparison to using more realistic age-specific mortality rates. Conclusions: Demographic modelling assumptions should be considered in the interpretation of models of chronic infectious diseases such as TB. For simple models, we find that assuming constant lifetimes, rather than exponential lifetimes, produces dynamics more representative of models with realistic age structure. C1 [Brooks-Pollock, Ellen; Cohen, Ted; Murray, Megan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cohen, Ted; Murray, Megan] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Murray, Megan] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Brooks-Pollock, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM ebrooks@hsph.harvard.edu RI Cohen, Ted/G-8101-2011 FU National Institutes of Health (NIH) [U19 AI076217] FX EBP, TC and MM are funded by National Institutes of Health (NIH) grant U19 AI076217. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 15 Z9 15 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 7 PY 2010 VL 5 IS 1 AR e8479 DI 10.1371/journal.pone.0008479 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 541KN UT WOS:000273414100002 ER PT J AU Leergaard, TB White, NS de Crespigny, A Bolstad, I D'Arceuil, H Bjaalie, JG Dale, AM AF Leergaard, Trygve B. White, Nathan S. de Crespigny, Alex Bolstad, Ingeborg D'Arceuil, Helen Bjaalie, Jan G. Dale, Anders M. TI Quantitative Histological Validation of Diffusion MRI Fiber Orientation Distributions in the Rat Brain SO PLOS ONE LA English DT Article ID AXON DIAMETER DISTRIBUTION; SPHERICAL DECONVOLUTION; TENSOR MRI; SUPERIOR COLLICULUS; ANGULAR RESOLUTION; OPTIC TRACTS; WEIGHTED MRI; TRACTOGRAPHY; NMR; RECONSTRUCTION AB Diffusion MRI (dMRI) is widely used to measure microstructural features of brain white matter, but commonly used dMRI measures have limited capacity to resolve the orientation structure of complex fiber architectures. While several promising new approaches have been proposed, direct quantitative validation of these methods against relevant histological architectures remains missing. In this study, we quantitatively compare neuronal fiber orientation distributions (FODs) derived from ex vivo dMRI data against histological measurements of rat brain myeloarchitecture using manual recordings of individual myelin stained fiber orientations. We show that accurate FOD estimates can be obtained from dMRI data, even in regions with complex architectures of crossing fibers with an intrinsic orientation error of approximately 5-6 degrees in these regions. The reported findings have implications for both clinical and research studies based on dMRI FOD measures, and provide an important biological benchmark for improved FOD reconstruction and fiber tracking methods. C1 [Leergaard, Trygve B.; Bolstad, Ingeborg; Bjaalie, Jan G.] Univ Oslo, Inst Basic Med Sci, Ctr Mol Biol & Neurosci, Oslo, Norway. [White, Nathan S.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA. [de Crespigny, Alex; D'Arceuil, Helen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, Boston, MA USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. RP Leergaard, TB (reprint author), Univ Oslo, Inst Basic Med Sci, Ctr Mol Biol & Neurosci, Oslo, Norway. EM amdale@ucsd.edu RI Dale, Anders/A-5180-2010; OI Leergaard, Trygve B./0000-0001-5965-8470 FU Research Council of Norway; NIH [R01-EB00790, U24-RR021382]; Martinos Center for Biomedical imaging; American Heart Association FX This project was funded by grants from The Research Council of Norway (to TBL and JGB), the NIH (R01-EB00790, U24-RR021382 to AMD), The Martinos Center for Biomedical imaging, and The American Heart Association (to AdC and HD'A). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 70 Z9 70 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 7 PY 2010 VL 5 IS 1 AR e8595 DI 10.1371/journal.pone.0008595 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 541KN UT WOS:000273414100005 PM 20062822 ER PT J AU Kushner, JA Weir, GC Bonner-Weir, S AF Kushner, Jake A. Weir, Gordon C. Bonner-Weir, Susan TI Ductal Origin Hypothesis of Pancreatic Regeneration under Attack SO CELL METABOLISM LA English DT Editorial Material ID BETA-CELL REGENERATION; PROGENITORS; GROWTH; MICE AB Although pancreatic beta cells are known to expand by self-renewal in postnatal life, contribution by ductal progenitors remains vigorously debated. In a recent issue of Developmental Cell, Jorge Ferrer and colleagues report lineage tracing studies that challenge the ductal origin hypothesis (Solar et al., 2010). C1 [Kushner, Jake A.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Kushner, Jake A.] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Kushner, Jake A.] Univ Penn, Sch Med, Inst Regenerat Med, Philadelphia, PA 19104 USA. [Kushner, Jake A.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Weir, Gordon C.; Bonner-Weir, Susan] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Kushner, JA (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. OI Bonner-Weir, Susan/0000-0003-4682-0656 FU NIDDK NIH HHS [P30 DK036836, R01 DK044523, R01 DK081469, R01 DK066056] NR 10 TC 40 Z9 40 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JAN 6 PY 2010 VL 11 IS 1 BP 2 EP 3 DI 10.1016/j.cmet.2009.12.005 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 543YJ UT WOS:000273617000002 PM 20085728 ER PT J AU Rodgers, JT Haas, W Gygi, SP Puigserver, P AF Rodgers, Joseph T. Haas, Wilhelm Gygi, Steven P. Puigserver, Pere TI Cdc2-like Kinase 2 Is an Insulin-Regulated Suppressor of Hepatic Gluconeogenesis SO CELL METABOLISM LA English DT Article ID TRANSCRIPTION FACTOR FOXO1; LAMMER PROTEIN-KINASES; COACTIVATOR PGC-1; INTRANUCLEAR DISTRIBUTION; SPLICING FACTORS; GLUCOSE; CLK/STY; METABOLISM; PHOSPHORYLATION; SPECIFICITY AB Dynamic regulation of insulin signaling and metabolic gene expression is critical to nutrient homeostasis; dysregulation of these pathways is widely implicated in insulin resistance and other disease states. Though the metabolic effects of insulin are well established, the components linking insulin signal transduction to a metabolic response are not as well understood. Here, we show that Cdc2-like kinase 2 (Clk2) is an insulin-regulated suppressor of hepatic gluconeogenesis and glucose output. Clk2 protein levels and kinase activity are induced as part of the hepatic refeeding response by the insulin/Akt pathway. Clk2 directly phosphorylates the SR domain on PGC-1 alpha, resulting in repression of gluconeogenic gene expression and hepatic glucose output. In addition, Clk2 is downregulated in db/db mice, and reintroduction of Clk2 largely corrects glycemia. Thus, we have identified a role for and regulation of the Clk2 kinase as a component of hepatic insulin signaling and glucose metabolism. C1 [Rodgers, Joseph T.; Puigserver, Pere] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Rodgers, Joseph T.; Haas, Wilhelm; Gygi, Steven P.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Puigserver, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. FU American Heart Association; Ellison Medical Foundation; American Diabetes Association; US Department of Defense; NIH [RO1 DK069966] FX We would like to thank Axel Ulrich, Marc Montminy, Morris Birnbaum, and Alexander Banks for their donation of reagents, which were of critical importance to this work, Susan Keezer and Qingyuan Ge at Cell Signaling for development of Clk2 and P-Clk2 antibodies, and Roderick Bronson, Bruce M Spiegelman, Lewis C Cantley, and Nathanael S Gray and members of their labs for discussion Special thanks are given to all members of the Puigserver lab. Christine Chin for technical assistance and Timothy Kelly, John Dominy, John Tom Cunningham, and Francisca Vazquez for their critical reading of this manuscript A portion of this work was funded by an American Heart Association Pre-Doctoral Fellowship Q T R) W H is a Charles A King Trust and Bank of America Co-Trustee These studies were supported, in part, by an Ellison Medical Foundation New Scholar Award, American Diabetes Association, US Department of Defense, and NIH RO1 DK069966 (to P.P) J.T.R designed and performed experiments, analyzed data, and wrote the manuscript W H and S P G performed M S experiments and analyzed M S data P P designed experiments. analyzed data, and wrote the manuscript A portion of this work appears in a patent in collaboration with Sirtris Pharmaceuticals, J T R and P P NR 44 TC 56 Z9 60 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JAN 6 PY 2010 VL 11 IS 1 BP 23 EP 34 DI 10.1016/j.cmet.2009.11.006 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 543YJ UT WOS:000273617000007 PM 20074525 ER PT J AU Keating, NL O'Malley, AJ Freedland, SJ Smith, MR AF Keating, Nancy L. O'Malley, A. James Freedland, Stephen J. Smith, Matthew R. TI Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy: Observational Study of Veterans With Prostate Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; QUALITY-OF-CARE; ADMINISTRATIVE DATA; RADIATION-THERAPY; HORMONE AGONISTS; BODY-COMPOSITION; SUPPRESSION; MEDICARE; TRIAL; RADIOTHERAPY AB Previous studies indicate that androgen deprivation therapy for prostate cancer is associated with diabetes and cardiovascular disease among older men. We evaluated the relationship between androgen deprivation therapy and incident diabetes and cardiovascular disease in men of all ages with prostate cancer. We conducted an observational study of 37 443 population-based men who were diagnosed with local or regional prostate cancer in the Veterans Healthcare Administration from January 1, 2001, through December 31, 2004, with follow-up through December 31, 2005. Cox proportional hazards models were used to assess whether androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonists, oral antiandrogens, the combination of the two (ie, combined androgen blockade), or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, sudden cardiac death, or stroke, after adjustment for patient and tumor characteristics. All statistical tests were two-sided. Overall, 14 597 (39%) of the 37 443 patients were treated with androgen deprivation therapy. Treatment with GnRH agonists was associated with statistically significantly increased risks of incident diabetes (for GnRH agonist therapy, 159.4 events per 1000 person-years vs 87.5 events for no androgen deprivation therapy, difference = 71.9, 95% confidence interval [CI] = 71.6 to 72.2; adjusted hazard ratio [aHR] = 1.28, 95% CI = 1.19 to 1.38), incident coronary heart disease (aHR = 1.19, 95% CI = 1.10 to 1.28), myocardial infarction (12.8 events per 1000 person-years for GnRH agonist therapy vs 7.3 for no androgen deprivation therapy, difference = 5.5, 95% CI = 5.4 to 5.6; aHR = 1.28, 95% CI = 1.08 to 1.52), sudden cardiac death (aHR = 1.35, 95% CI = 1.18 to 1.54), and stroke (aHR = 1.22, 95% CI = 1.10 to 1.36). Combined androgen blockade was statistically significantly associated with an increased risk of incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53), and orchiectomy was associated with coronary heart disease (aHR = 1.40, 95% CI = 1.04 to 1.87) and myocardial infarction (aHR = 2.11, 95% CI = 1.27 to 3.50). Oral antiandrogen monotherapy was not associated with any outcome studied. Androgen deprivation therapy with GnRH agonists was associated with an increased risk of diabetes and cardiovascular disease. C1 [Keating, Nancy L.; O'Malley, A. James] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02115 USA. Duke Univ, Sch Med, Dept Surg, Durham Vet Affairs Med Ctr, Durham, NC USA. Duke Univ, Sch Med, Div Urol, Duke Prostate Ctr, Durham, NC USA. [Freedland, Stephen J.] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27706 USA. [Freedland, Stephen J.] Vet Affairs Med Ctr, Dept Surg, Durham, VA USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu FU Prostate Cancer Foundation FX Prostate Cancer Foundation. NR 36 TC 212 Z9 215 U1 2 U2 10 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 JAN 6 PY 2010 VL 102 IS 1 BP 39 EP 46 DI 10.1093/jnci/djp404 PG 8 WC Oncology SC Oncology GA 542NH UT WOS:000273500400008 PM 19996060 ER PT J AU Bangsberg, DR Deeks, SG AF Bangsberg, David R. Deeks, Steven G. TI Spending More to Save More: Interventions to Promote Adherence SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID ADMINISTERED ANTIRETROVIRAL THERAPY; RESOURCE-POOR SETTINGS; RANDOMIZED-TRIAL; HIV-1-INFECTED PATIENTS; HIV; HAART; RESISTANCE; MORTALITY; BARRIERS; MOMBASA C1 [Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94110 USA. RP Bangsberg, DR (reprint author), Harvard Initiat Global Hlth, 104 Mt Auburn St, Cambridge, MA 02138 USA. EM david_bangsberg@harvard.edu FU NIAID NIH HHS [K24AI069994, K24 AI069994]; NIMH NIH HHS [R01 MH054907]; PHS HHS [K-24 87227, R01 54907] NR 23 TC 11 Z9 11 U1 1 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 5 PY 2010 VL 152 IS 1 BP 54 EP W13 DI 10.7326/0003-4819-152-1-201001050-00012 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 543FJ UT WOS:000273556600009 PM 20048272 ER PT J AU Mahoney, EM Wang, KJ Arnold, SV Proskorovsky, I Wiviott, S Antman, E Braunwald, E Cohen, DJ AF Mahoney, Elizabeth M. Wang, Kaijun Arnold, Suzanne V. Proskorovsky, Irina Wiviott, Stephen Antman, Elliott Braunwald, Eugene Cohen, David J. TI Cost-Effectiveness of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndromes and Planned Percutaneous Coronary Intervention Results From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38 SO CIRCULATION LA English DT Article DE coronary disease; cost-benefit analysis; infarction; revascularization; thrombus ID ST-SEGMENT ELEVATION; CARDIOVASCULAR EVENTS; CONFIDENCE-INTERVALS; CLINICAL-OUTCOMES; IMPACT AB Background-In patients with acute coronary syndromes and planned percutaneous coronary intervention, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) demonstrated that treatment with prasugrel versus clopidogrel was associated with reduced rates of cardiovascular death, MI, or stroke and an increased risk of major bleeding. We evaluated the cost-effectiveness of prasugrel versus clopidogrel from the perspective of the US healthcare system by using data from TRITON-TIMI 38. Methods and Results-Detailed resource use data were prospectively collected for all patients recruited from 8 countries (United States, Australia, Canada, Germany, Italy, Spain, United Kingdom, and France; n=3373 prasugrel, n=3332 clopidogrel). Hospitalization costs were estimated on the basis of diagnosis-related group and in-hospital complications. Cardiovascular medication costs were estimated by using net wholesale prices (clopidogrel =$4.62/d; prasugrel =$5.45/d). Life expectancy was estimated from in-trial cardiovascular and bleeding events with the use of statistical models of long-term survival from a similar population from the Saskatchewan Health Database. Over a median follow-up of 14.7 months, average total costs (including study drug) were $221 per patient lower with prasugrel (95% confidence interval, -759 to 299), largely because of a lower rate of rehospitalization involving percutaneous coronary intervention. Prasugrel was associated with life expectancy gains of 0.102 years (95% confidence interval, 0.030 to 0.180), primarily because of the decreased rate of nonfatal MI. Thus, compared with clopidogrel, prasugrel was an economically dominant treatment strategy. If a hypothetical generic cost for clopidogrel of $1/d is used, the incremental net cost with prasugrel was $996 per patient, yielding an incremental cost-effectiveness ratio of $9727 per life-year gained. Conclusion-Among acute coronary syndrome patients with planned percutaneous coronary intervention, treatment with prasugrel versus clopidogrel for up to 15 months is an economically attractive treatment strategy. C1 [Mahoney, Elizabeth M.; Wang, Kaijun; Arnold, Suzanne V.; Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Proskorovsky, Irina] United BioSource Corp, Dorval, PQ, Canada. [Wiviott, Stephen; Antman, Elliott; Braunwald, Eugene] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Mahoney, Elizabeth M.; Cohen, David J.] Univ Missoun Kansas City, Sch Med, Kansas City, MO USA. RP Mahoney, EM (reprint author), St Lukes Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA. EM emahoney1@saint-lukes.org FU Eli Lilly Co, Inc.; Daiichi Sankyo; Sanofi-Aventis; Bristol-Myers Squibb; Schering-Plough; The Medicines Co; Accumetrics; Cordis; Boston Scientific FX This health economic study was funded by a research grant to Drs Mahoney and Cohen from Eli Lilly & Co, Inc.; Dr Mahoney has received grant support from Eli Lilly, Daiichi Sankyo, Sanofi-Aventis, and Bristol-Myers Squibb and has received lecture fees from Sanofi-Aventis and Bristol-Myers Squibb. Dr Cohen has received grant support from Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, Schering-Plough, The Medicines Co, Accumetrics, Cordis, and Boston Scientific. Drs Wiviott, Antman, and Braunwald have received research grants from Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis. In addition, Dr Braunwald has received consulting or paid advisory board fees from Daiichi Sankyo and Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Wiviott has received consulting or advisory board fees from Daiichi Sankyo and Sanofi-Aventis and lecture fees from Eli Lilly and Daiichi Sankyo. Dr Antman has received consulting or advisory board fees from Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. The other authors report no conflicts. NR 23 TC 75 Z9 83 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 5 PY 2010 VL 121 IS 1 BP 71 EP U99 DI 10.1161/CIRCULATIONAHA.109.900704 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 539PH UT WOS:000273267700011 PM 20026770 ER PT J AU Zuckerbraun, BS Shiva, S Ifedigbo, E Mathier, MA Mollen, KP Rao, J Bauer, PM Choi, JJW Curtis, E Choi, AMK Gladwin, MT AF Zuckerbraun, Brian S. Shiva, Sruti Ifedigbo, Emeka Mathier, Michael A. Mollen, Kevin P. Rao, Jayashree Bauer, Philip M. Choi, Justin J. W. Curtis, Erin Choi, Augustine M. K. Gladwin, Mark T. TI Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase-Dependent Nitric Oxide Generation SO CIRCULATION LA English DT Article DE hypoxia; nitric oxide; monocrotaline sodium; pulmonary artery smooth muscle cells; xanthine oxidoreductase ID ACTIVATED-PROTEIN-KINASE; L-ARGININE; CELL-PROLIFERATION; ISCHEMIA/REPERFUSION INJURY; ISCHEMIA-REPERFUSION; EXERCISE CAPACITY; ORGANIC NITRATES; IN-VIVO; EXPRESSION; SYNTHASE AB Background-Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension. Methods and Results-We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide-dependent induction of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well. Conclusion-These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension. (Circulation. 2010; 121: 98-109.) C1 [Ifedigbo, Emeka; Choi, Augustine M. K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Zuckerbraun, Brian S.; Mollen, Kevin P.; Rao, Jayashree; Bauer, Philip M.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Shiva, Sruti] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Ifedigbo, Emeka; Choi, Justin J. W.; Choi, Augustine M. K.; Gladwin, Mark T.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Mathier, Michael A.] Univ Pittsburgh, Sch Med, Div Cardiol, Pittsburgh, PA USA. [Zuckerbraun, Brian S.] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Shiva, Sruti; Choi, Justin J. W.; Curtis, Erin; Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Choi, AMK (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM amchoi@rics.bwh.harvard.edu; gladwinmt@upmc.edu FU American Heart Association [0535203N] FX This work was supported by the American Heart Association, Scientist Development Grant 0535203N (B.S.Z.). NR 49 TC 99 Z9 104 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 5 PY 2010 VL 121 IS 1 BP 98 EP 109 DI 10.1161/CIRCULATIONAHA.109.891077 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 539PH UT WOS:000273267700014 PM 20026772 ER PT J AU Goetti, R Candinas, R Leschka, S Hoffmann, U Alkadhi, H AF Goetti, Robert Candinas, Reto Leschka, Sebastian Hoffmann, Udo Alkadhi, Hatem TI Bronchocoronary Collateral Circulation Clinical Utility of Cardiac Computed Tomography SO CIRCULATION LA English DT Editorial Material ID BRONCHIAL ARTERY FISTULA C1 [Alkadhi, Hatem] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Goetti, Robert; Leschka, Sebastian; Alkadhi, Hatem] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Candinas, Reto] Pk Clin, Zurich, Switzerland. RP Alkadhi, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM halkadhi@partners.org RI Goetti, Robert/I-8961-2012 NR 4 TC 2 Z9 2 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 JAN 5 PY 2010 VL 121 IS 1 BP 180 EP 181 DI 10.1161/CIRCULATIONAHA.109.906842 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 539PH UT WOS:000273267700022 PM 20048235 ER PT J AU Mendez, MF AF Mendez, Mario F. TI What progressive aphasia says about its neuropathology SO NEUROLOGY LA English DT Editorial Material ID FRONTOTEMPORAL LOBAR DEGENERATION; PATHOLOGY; ALZHEIMER; VARIANTS; PATTERNS; DISEASE C1 [Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Neurobehav Unit, VA Greater Los Angeles Healthcare Syst & Neurol &, Los Angeles, CA 90095 USA. RP Mendez, MF (reprint author), VA Greater Los Angeles Healthcare, Neurobehav Unit, 116AF,Bldg 500,3S,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM mmendez@ucla.edu FU NIA NIH HHS [R01 AG034499] NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 5 PY 2010 VL 74 IS 1 BP 16 EP 17 DI 10.1212/WNL.0b013e3181c719b3 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 537GE UT WOS:000273100400003 PM 19940268 ER PT J AU Ellenbogen, JM AF Ellenbogen, Jeffrey M. TI Sleep-specific atrioventricular block SO NEUROLOGY LA English DT Editorial Material C1 Mass Gen Hosp, Div Sleep Med, Dept Neurol, Boston, MA 02114 USA. RP Ellenbogen, JM (reprint author), Mass Gen Hosp, Div Sleep Med, Dept Neurol, 55 Fruit St,Wang ACC 720, Boston, MA 02114 USA. EM jeffrey_ellenbogen@hms.harvard.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 5 PY 2010 VL 74 IS 1 BP 90 EP 90 DI 10.1212/WNL.0b013e3181c7daba PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 537GE UT WOS:000273100400015 PM 20038779 ER PT J AU Rovira, M Scott, SG Liss, AS Jensen, J Thayer, SP Leach, SD AF Rovira, Meritxell Scott, Sherri-Gae Liss, Andrew S. Jensen, Jan Thayer, Sarah P. Leach, Steven D. TI Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ALDH1; CD133; pancreatic; pancreatosphere; stem cell ID ALDEHYDE DEHYDROGENASE-ACTIVITY; BETA-CELLS; STEM-CELLS; EXOCRINE PANCREAS; ENDOCRINE-CELLS; RAT PANCREAS; IN-VIVO; DIFFERENTIATION; REGENERATION; POPULATION AB The question of whether dedicated progenitor cells exist in adult vertebrate pancreas remains controversial. Centroacinar cells and terminal duct (CA/TD) cells lie at the junction between peripheral acinar cells and the adjacent ductal epithelium, and are frequently included among cell types proposed as candidate pancreatic progenitors. However these cells have not previously been isolated in a manner that allows formal assessment of their progenitor capacities. We have found that a subset of adult CA/TD cells are characterized by high levels of ALDH1 enzymatic activity, related to high-level expression of both Aldh1a1 and Aldh1a7. This allows their isolation by FACS using a fluorogenic ALDH1 substrate. FACS-isolated CA/TD cells are relatively depleted of transcripts associated with differentiated pancreatic cell types. In contrast, they are markedly enriched for transcripts encoding Sca1, Sdf1, c-Met, Nestin, and Sox9, markers previously associated with progenitor populations in embryonic pancreas and other tissues. FACS-sorted CA/TD cells are uniquely able to form self-renewing "pancreatospheres" in suspension culture, even when plated at clonal density. These spheres display a capacity for spontaneous endocrine and exocrine differentiation, as well as glucose-responsive insulin secretion. In addition, when injected into cultured embryonic dorsal pancreatic buds, these adult cells display a unique capacity to contribute to both the embryonic endocrine and exocrine lineages. Finally, these cells demonstrate dramatic expansion in the setting of chronic epithelial injury. These findings suggest that CA/TD cells are indeed capable of progenitor function and may contribute to the maintenance of tissue homeostasis in adult mouse pancreas. C1 [Rovira, Meritxell; Scott, Sherri-Gae; Leach, Steven D.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Rovira, Meritxell; Scott, Sherri-Gae; Leach, Steven D.] Johns Hopkins Univ, Dept Surg, Baltimore, MD 21205 USA. [Liss, Andrew S.; Thayer, Sarah P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Liss, Andrew S.; Thayer, Sarah P.] Harvard Univ, Boston, MA 02114 USA. [Jensen, Jan] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44195 USA. RP Leach, SD (reprint author), Johns Hopkins Univ, McKusick Nathans Inst Genet Med, 733 N Wolfe St,BRB 471, Baltimore, MD 21205 USA. EM sleach1@jhmi.edu OI Jensen, Jan/0000-0003-0657-4032 FU Chicago Diabetes Project; Juvenile Diabetes Research Foundation; American College of Surgeons Clowes Award; National Institutes of Health [DK61215, DK070636, DK071329] FX We thank Dr. Michael Wolfgang for generously providing pCAG:mCherry mice; Drs. Michael Shamblott, Mehboob Hussain, Michael Parsons, and members of the Leach Lab for many helpful discussions; Danielle Blake for outstanding technical and administrative support; and Dr. Mark Soloski, Lee Blosser, and Ada Tam of the Johns Hopkins Flow Cytometry Core for expert FACS analysis. This work was supported by the Chicago Diabetes Project (M. R., J.J., and S. D. L.), the Juvenile Diabetes Research Foundation (J.J.), an American College of Surgeons Clowes Award (to S. P. T.), and National Institutes of Health Grants DK61215 (to S. D. L.), DK070636 (to J.J.), and DK071329 (to S. P. T.). NR 35 TC 133 Z9 136 U1 2 U2 13 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 JAN 5 PY 2010 VL 107 IS 1 BP 75 EP 80 DI 10.1073/pnas.0912589107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FX UT WOS:000273559200014 PM 20018761 ER PT J AU Herrero, L Shapiro, H Nayer, A Lee, J Shoelson, SE AF Herrero, Laura Shapiro, Hagit Nayer, Ali Lee, Jongsoon Shoelson, Steven E. TI Inflammation and adipose tissue macrophages in lipodystrophic mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diabetes; insulin resistance; obesity ID INDUCED INSULIN-RESISTANCE; NF-KAPPA-B; DIABETES-MELLITUS; IKK-BETA; OXIDATIVE STRESS; INNATE IMMUNITY; OBESITY; FAT; METABOLISM; CELLS AB Lipodystrophy and obesity are opposites in terms of a deficiency versus excess of adipose tissue mass, yet these conditions are accompanied by similar metabolic consequences, including insulin resistance, dyslipidemia, hepatic steatosis, and increased risk for diabetes and atherosclerosis. Hepatic and myocellular steatosis likely contribute to metabolic dysregulation in both states. Inflammation and macrophage infiltration into adipose tissue also appear to participate in the pathogenesis of obesity-induced insulin resistance, but their contributions to lipodystrophy-induced insulin resistance have not been evaluated. We used aP2-nSREBP-1c transgenic (Tg) mice, an established model of lipodystrophy, to ask this question. Circulating cytokine elevations suggested systemic inflammation but even more dramatic was the number of infiltrating macrophages in all white and brown adipose tissue depots of the Tg mice; in contrast, there was no evidence of inflammatory infiltrates or responses in any other tissue including liver. Despite there being overt evidence of adipose tissue inflammation, antiinflammatory strategies including salicylate treatment and genetic suppression of myeloid NF-kappa B signaling that correct insulin resistance in obesity were ineffective in the lipodystrophic mice. We further showed that adipose tissue macrophages (ATMs) in lipodystrophy and obesity are very different in terms of activation state, gene expression patterns, and response to lipopolysaccharide. Although ATMs are even more abundant in lipodystrophy than in obesity, they have distinct phenotypes and likely roles in tissue remodeling, but do not appear to be involved in the pathogenesis of insulin resistance. C1 [Shoelson, Steven E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Shoelson, SE (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02115 USA. EM Steven.Shoelson@Joslin.Harvard.edu RI Herrero, Laura/D-4011-2014 OI Herrero, Laura/0000-0003-4244-4673 FU National Institutes of Health [R01 DK45943, R37 DK51729, R01 DK73547, P30 DK36836]; Ministry of Education and Science of Spain; American Diabetes Association [7-04-MN-47]; Helen and Morton Adler Chair FX We thank O. Gavrilova for helpful discussions, M. Karin for providing the Ikk betaDelta mye mice, C. Bertochi and D. Jamieson for expert research assistance, and J. LaVecchio and G. Buruzula at Joslin Diabetes Endocrinology Research Center/Harvard Stem Cell Institute Flow Cytometry Core. These studies were supported by National Institutes of Health Grants R01 DK45943, R37 DK51729, and R01 DK73547 to S. E.S.; P30 DK36836 (Joslin Diabetes Endocrinology Research Center); postdoctoral fellowships from the Ministry of Education and Science of Spain (L. H.) and American Diabetes Association (7-04-MN-47), and the Helen and Morton Adler Chair (S. E. S.). NR 34 TC 68 Z9 70 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 5 PY 2010 VL 107 IS 1 BP 240 EP 245 DI 10.1073/pnas.0905310107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FX UT WOS:000273559200042 PM 20007767 ER PT J AU Yoda, A Yoda, Y Chiaretti, S Bar-Natan, M Mani, K Rodig, SJ West, N Xiao, Y Brown, JR Mitsiades, C Sattler, M Kutok, JL DeAngelo, DJ Wadleigh, M Piciocchi, A Dal Cin, P Bradner, JE Griffin, JD Anderson, KC Stone, RM Ritz, J Foa, R Aster, JC Frank, DA Weinstock, DM AF Yoda, Akinori Yoda, Yuka Chiaretti, Sabina Bar-Natan, Michal Mani, Kartik Rodig, Scott J. West, Nathan Xiao, Yun Brown, Jennifer R. Mitsiades, Constantine Sattler, Martin Kutok, Jeffrey L. DeAngelo, Daniel J. Wadleigh, Martha Piciocchi, Alfonso Dal Cin, Paola Bradner, James E. Griffin, James D. Anderson, Kenneth C. Stone, Richard M. Ritz, Jerome Foa, Robin Aster, Jon C. Frank, David A. Weinstock, David M. TI Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE JAK2; TSLPR; TSLP ID THYMIC STROMAL LYMPHOPOIETIN; GENE-EXPRESSION PATTERNS; GROWTH-FACTOR RECEPTOR; DOWN-SYNDROME; CHROMOSOMAL TRANSLOCATIONS; ACTIVATING MUTATIONS; CYTOKINE RECEPTOR; JAK2 MUTATION; BCP-ALL; TRANSFORMATION AB The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL-derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is over-expressed in approximately 15% of adult and high-risk pediatric BALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with the IGH locus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-of-function mutation that promotes constitutive dimerization and cytokine independent growth. A mutually exclusive subset harbors activating mutations in JAK2. In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL. Expression of WT CRLF2 with mutant JAK2 also promotes cytokine independent growth that, unlike CRLF2 Phe232Cys or ligand-induced signaling by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, cells dependent on CRLF2 signaling are sensitive to small molecule inhibitors of either JAKs or protein kinase C family kinases. Together, these findings implicate CRLF2 as an important factor in B-ALL with diagnostic, prognostic, and therapeutic implications. C1 [Yoda, Akinori; Yoda, Yuka; Bar-Natan, Michal; Mani, Kartik; West, Nathan; Brown, Jennifer R.; Mitsiades, Constantine; Sattler, Martin; DeAngelo, Daniel J.; Wadleigh, Martha; Bradner, James E.; Griffin, James D.; Anderson, Kenneth C.; Stone, Richard M.; Ritz, Jerome; Frank, David A.; Weinstock, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chiaretti, Sabina; Foa, Robin] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, Div Hematol, I-00185 Rome, Italy. [Rodig, Scott J.; Xiao, Yun; Kutok, Jeffrey L.; Dal Cin, Paola; Aster, Jon C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Piciocchi, Alfonso] Grp Malattie Ematol Adulto Data Ctr, I-00161 Rome, Italy. RP Weinstock, DM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM dweinstock@partners.org OI Ritz, Jerome/0000-0001-5526-4669 FU Burroughs Wellcome Fund Career Award in the Biomedical Sciences; Compagnia di San Paolo, Turin; Dunkin Donuts Rising Star Program; Kristen Amico Fund; Claudia Adams Barr Program in Cancer Research FX The authors thank Dr. Bob Distel and Yanan Kuang from the Dana-Farber Cancer Institute Translational Research Laboratory for assistance with HPLC; Marc Dibona for assistancewith FISH; Drs. Shai Izraeli and A. Thomas Look for helpful discussion; and Dr. Roberto Bellucci, Gorka Murga, IleneGalinsky, RNP, Dr. AnnMullally, and Dr. Takaomi Sanda for assistance with obtaining primary samples and cell lines. This work was supported by a Burroughs Wellcome Fund Career Award in the Biomedical Sciences (D. M. W.), the Compagnia di San Paolo, Turin, the Dunkin Donuts Rising Star Program, the Kristen Amico Fund, and the Claudia Adams Barr Program in Cancer Research. NR 42 TC 140 Z9 143 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 5 PY 2010 VL 107 IS 1 BP 252 EP 257 DI 10.1073/pnas.0911726107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FX UT WOS:000273559200044 PM 20018760 ER PT J AU O'Donoghue, ML Braunwald, E Antman, EM Murphy, SA Wiviott, SD AF O'Donoghue, Michelle L. Braunwald, Eugene Antman, Elliott M. Murphy, Sabina A. Wiviott, Stephen D. TI Combination therapy with clopidogrel and proton-pump inhibitors reply SO LANCET LA English DT Letter C1 [O'Donoghue, Michelle L.; Braunwald, Eugene; Antman, Elliott M.; Murphy, Sabina A.; Wiviott, Stephen D.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM modonoghue@partners.org NR 4 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 0140-6736 J9 LANCET JI Lancet PD JAN 2 PY 2010 VL 375 IS 9708 BP 28 EP 29 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 539BZ UT WOS:000273229700023 ER PT J AU Stienen, BMC de Gelder, B AF Stienen, B. M. C. de Gelder, B. TI Watch your body language! Relative affective blindsight for fearful bodily expressions SO PERCEPTION LA English DT Meeting Abstract C1 [Stienen, B. M. C.; de Gelder, B.] Tilburg Univ, Cognit & Affect Neurosci Lab, Tilburg, Netherlands. [de Gelder, B.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [de Gelder, B.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. EM bstienen@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 4 PU PION LTD PI LONDON PA 207 BRONDESBURY PARK, LONDON NW2 5JN, ENGLAND SN 0301-0066 J9 PERCEPTION JI Perception PY 2010 VL 39 SU S BP 31 EP 31 PG 1 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA 753BV UT WOS:000289740100093 ER PT J AU de Gelder, B AF de Gelder, B. TI Nonconscious vision and new explorations of residual visual abilities for face and body perception following V1 lesions SO PERCEPTION LA English DT Meeting Abstract C1 [de Gelder, B.] Tilburg Univ, Cognit & Affect Neurosci Lab, Tilburg, Netherlands. [de Gelder, B.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM B.deGelder@uvt.nl NR 0 TC 0 Z9 0 U1 0 U2 1 PU PION LTD PI LONDON PA 207 BRONDESBURY PARK, LONDON NW2 5JN, ENGLAND SN 0301-0066 J9 PERCEPTION JI Perception PY 2010 VL 39 SU S BP 65 EP 65 PG 1 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA 753BV UT WOS:000289740100196 ER PT S AU Baillet, S Tadel, F Leahy, RM Mosher, JC Delorme, A Makeig, S Oostenveld, R Hamalainen, M Dalal, SS Zumer, J Clerc, M Wolters, CH Kiebel, S Jensen, O AF Baillet, S. Tadel, F. Leahy, R. M. Mosher, J. C. Delorme, A. Makeig, S. Oostenveld, R. Haemalainen, M. Dalal, S. S. Zumer, J. Clerc, M. Wolters, C. H. Kiebel, S. Jensen, O. BE Supek, S Susac, A TI Academic Software Toolboxes for the Analysis of MEG Data SO 17TH INTERNATIONAL CONFERENCE ON BIOMAGNETISM ADVANCES IN BIOMAGNETISM - BIOMAG2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 39th Annual Clinical Aphasiology Conference CT 17th International Conference on Biomagnetism (Biomag 2010) CY MAY 26-30, 2009 CY MAR 28-APR 01, 2010 CL Keystone, CO CL Dubrovnik, CROATIA SP Univ Zagreb, Fac Sci, Dept Phys, Croatian Biophys Soc, Croatian Cardiac Soc, Int Federat Med & Biol Engn, Croatian Inst Brain Res, Croatian Neurol Soc, Croatian Phys Soc, Croatian Soc Med & Biol Engn, Croatian Soc Neurosci, Zagreb Epilepsy Ctr DE MEG; source analysis; data analysis; imaging; mapping; connectivity; forward modeling AB Free MEG and EEG data analysis software packages springing from academic research are now widely used in published work. These toolboxes and applications are typically developed by or in close contact with researchers addressing cognitive or clinical neuroscience questions. Thus they often contain the latest methodological developments from the research community. It is therefore vital to educate MEG researchers and make them aware of the new possibilities offered by these toolboxes. The aim of this paper is to illustrate the characteristics and advantages of the various toolboxes to users and developers alike. We present each toolbox with their key features and target audience. C1 [Oostenveld, R.; Jensen, O.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6500 HB Nijmegen, Netherlands. [Baillet, S.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Tadel, F.; Leahy, R. M.] Univ So Calif, Neuroimaing Grp, Los Angeles, CA USA. [Mosher, J. C.] Cleveland Clin, Cleveland, OH USA. [Delorme, A.] Univ Paul Sabatier, CNRS, CERCO, Toulouse, France. [Delorme, A.; Makeig, S.] Univ Calif San Diego, Swartz Ctr Computat Neurosci, Inst Neural Computat, La Jolla, CA 92093 USA. [Haemalainen, M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Dalal, S. S.] INSERM, Dynam Cerebrale Cognit, Lyon, France. [Zumer, J.] Univ Nottingham, Sir Peter Mansfield Magnet Resonance Ctr, Sch Phys & Astron, Nottingham NG7 2RD, England. [Clerc, M.] Sophia Antipolis Mediterranee, INRIA, F-06902 Sophia Antipolis, France. [Wolters, C. H.] Univ Munster, Inst Biomagnetism & Biosignalanal, D-48149 Munster, Germany. [Kiebel, S.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. RP Jensen, O (reprint author), Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6500 HB Nijmegen, Netherlands. RI Jensen, Ole/D-2120-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-12196-8 J9 IFMBE PROC PY 2010 VL 28 BP 101 EP + PG 2 WC Engineering, Biomedical; Materials Science, Biomaterials; Physics, Applied SC Engineering; Materials Science; Physics GA BRE15 UT WOS:000282468700019 ER PT S AU Iwaki, S Belliveau, JW AF Iwaki, Sunao Belliveau, John W. BE Supek, S Susac, A TI Neural Interactions between Dorsal and Ventral Visual Subsystems While Perceiving 3-D Structure from 2-D Motion SO 17TH INTERNATIONAL CONFERENCE ON BIOMAGNETISM ADVANCES IN BIOMAGNETISM - BIOMAG2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 39th Annual Clinical Aphasiology Conference CT 17th International Conference on Biomagnetism (Biomag 2010) CY MAY 26-30, 2009 CY MAR 28-APR 01, 2010 CL Keystone, CO CL Dubrovnik, CROATIA SP Univ Zagreb, Fac Sci, Dept Phys, Croatian Biophys Soc, Croatian Cardiac Soc, Int Federat Med & Biol Engn, Croatian Inst Brain Res, Croatian Neurol Soc, Croatian Phys Soc, Croatian Soc Med & Biol Engn, Croatian Soc Neurosci, Zagreb Epilepsy Ctr DE 3D structure perception from motion; MEG; fMRI; combined analysis; event-related desynchronization ID SURFACE-BASED ANALYSIS; STRUCTURE-FROM-MOTION; NEURONS; CORTEX; FMRI AB Two-dimensional optic flow is an important cue to perceive 3D structure of objects. Recent neuroimaging studies suggest the involvement of both the ventral and the dorsal visual pathways in the perception of 3D structure from motion (3D-SFM), though the neural dynamics underlying the 3D-SEM is not fully understood. Here, we combine magnetoencephalography (MEG) and fMRI to detect the dynamic brain responses to 3D-SFM. We manipulated the coherence of randomly moving dots to create different levels of 3D perception and investigated the associated changes in brain activity. Results of the fMRI analysis were used to impose plausible constraints on the MEG inverse calculation to improve spatial resolution of the spatiotemporal activity estimates. Time-frequency analysis was also employed to elucidate spatiotemporal dynamic changes in the spontaneous brain activities. MEG-fMRI combined analysis showed that the activities the posterior infero-temporal (pIT), parieto-occipital (PO), and intra-parietal (IP) regions were increased at different latencies during highly coherent motion conditions in which subjects perceived a robust 3D object. Results of the time-frequency analysis indicated the suppression of alpha- and beta-band activities in these regions which reflect the commitment of these areas in the perception of 3D-SFM. Current results suggest that the interactions between the dorsal and ventral visual subsystems are crucial for the perception of 3D object from 2D optic flow. C1 [Iwaki, Sunao] Natl Inst Adv Ind Sci & Technol, Inst Human Sci & Biomed Engn, 1-8-31 Midorigaoka, Ikeda, Osaka, Japan. [Iwaki, Sunao; Belliveau, John W.] Massachusetts Gen Hosp, Ctr BioMed Engn, Boston, MA USA. RP Iwaki, S (reprint author), Natl Inst Adv Ind Sci & Technol, Inst Human Sci & Biomed Engn, 1-8-31 Midorigaoka, Ikeda, Osaka, Japan. RI Iwaki, Sunao/B-1079-2011 OI Iwaki, Sunao/0000-0002-7123-7203 NR 16 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-12196-8 J9 IFMBE PROC PY 2010 VL 28 BP 286 EP + PG 2 WC Engineering, Biomedical; Materials Science, Biomaterials; Physics, Applied SC Engineering; Materials Science; Physics GA BRE15 UT WOS:000282468700066 ER PT S AU Vaina, LM Calabro, F Lin, FH Hamalainen, MS AF Vaina, Lucia Maria Calabro, Finnegan Lin, Fa-Hsuan Haemaelaeinen, Matti S. BE Supek, S Susac, A TI Long-Range Coupling of Prefrontal Cortex and Visual (MT) or Polysensory (STP) Cortical Areas in Motion Perception SO 17TH INTERNATIONAL CONFERENCE ON BIOMAGNETISM ADVANCES IN BIOMAGNETISM - BIOMAG2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 39th Annual Clinical Aphasiology Conference CT 17th International Conference on Biomagnetism (Biomag 2010) CY MAY 26-30, 2009 CY MAR 28-APR 01, 2010 CL Keystone, CO CL Dubrovnik, CROATIA SP Univ Zagreb, Fac Sci, Dept Phys, Croatian Biophys Soc, Croatian Cardiac Soc, Int Federat Med & Biol Engn, Croatian Inst Brain Res, Croatian Neurol Soc, Croatian Phys Soc, Croatian Soc Med & Biol Engn, Croatian Soc Neurosci, Zagreb Epilepsy Ctr DE visual search; auditory facilitation; MEG; dynamic Granger causality ID MULTIVARIATE AUTOREGRESSIVE MODELS/; EIGENMODES; PARAMETERS; CAUSALITY AB To investigate how, where and when moving auditory cues interact with the perception of object-motion during self-motion, we conducted psychophysical, MEG, and fMRI experiments in which the subjects viewed nine textured objects during simulated forward self-motion. On each trial, one object was randomly assigned its own looming motion within the scene. Subjects reported which of four labeled objects had independent motion within the scene in two conditions: (1) visual information only and (2) with additional moving-auditory cue. In MEG, comparison of the two conditions showed: (i) MT activity is similar across conditions, (ii) late after the stimulus presentation there is additional activity in the auditory cue condition ventral to MT, (iii) with the auditory cue, the right auditory cortex (AC) shows early activity together with STS, (iv) these two activities have different time courses and the STS signals occur later in the epoch together with frontal activity in the right hemisphere, (v) for the visual-only condition activity in PPC (posterior parietal cortex) is stronger than in the auditory-cue condition. fMRI conducted for visual-only condition reveals activations in a network of parietal and frontal areas and in MT. In addition, Dynamic Granger Causality analysis showed for auditory cues a strong connection of the AC with STP but not with MT suggesting binding of visual and auditory information at STP. Also, while in the visual-only condition PFC is connected with MT, in the auditory-cue condition PFC is con-nected to STP (superior temporal polysensory) area. These results indicate that PFC allocates attention to the "object" as a whole, in STP to a moving visual-auditory object, and in MT to a moving visual object. C1 [Vaina, Lucia Maria; Lin, Fa-Hsuan; Haemaelaeinen, Matti S.] Massachusetts Gen Hosp, Athinoula A Martinos Cntr Biomed Imaging, Charlestown, MA USA. [Vaina, Lucia Maria; Calabro, Finnegan] Boston Univ, Brain & Vis Res lab Biomed Engn, Boston, MA USA. RP Vaina, LM (reprint author), Boston Univ Biomed Engn, 44 Cummington St, Boston, MA 02215 USA. RI Lin, Fa-Hsuan/G-6988-2012; OI Lin, Fa-Hsuan/0000-0002-9539-1731; Calabro, Finnegan/0000-0002-8092-3942 FU NIH [R01NS064100]; Center for Functional Neuroimaging Technologies [P41 RR14075] FX This work was supported by NIH grant R01NS064100 to LMV, and the NCRR supported Center for Functional Neuroimaging Technologies P41 RR14075 (MSH, FHL). NR 8 TC 1 Z9 1 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-12196-8 J9 IFMBE PROC PY 2010 VL 28 BP 298 EP + PG 2 WC Engineering, Biomedical; Materials Science, Biomaterials; Physics, Applied SC Engineering; Materials Science; Physics GA BRE15 UT WOS:000282468700069 ER PT S AU Kurugol, S Dy, JG Sharp, GC Brooks, DH AF Kurugol, Sila Dy, Jennifer G. Sharp, Gregory C. Brooks, Dana H. GP IEEE TI 3D LEVEL SET ESOPHAGUS SEGMENTATION IN THORACIC CT IMAGES USING SPATIAL, APPEARANCE AND SHAPE MODELS SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE CT; 3D Image Segmentation; Spatial; Appearance; Shape Model; Radiation Oncology AB We propose a 3D segmentation algorithm to locate the esophagus in thoracic CT scans using a learning based approach. To ease the training data requirement and allow maximum inter-subject flexibility, we built a simple algorithm based on normalization to anatomical reference points to match a training set of thoracic CTs instead of a full statistical registration based on neighboring structures. We use spatial and appearance models to locate the centerline. We build a shape model by subtracting the centerline and applying PCA to the training data sets. The shape model includes a mean shape plus the weighted combination of modes. To locate the esophageal wall, we optimize a cost function including terms for appearance, shape model, smoothness constraints and air/contrast model using a 3D level set framework. C1 [Kurugol, Sila; Dy, Jennifer G.; Brooks, Dana H.] Northeastern Univ, ECE Dept, 360 Huntington Ave, Boston, MA 02115 USA. [Sharp, Gregory C.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02114 USA. RP Kurugol, S (reprint author), Northeastern Univ, ECE Dept, 360 Huntington Ave, Boston, MA 02115 USA. FU NIH/NCRR Center for Integrative Biomedical Computing (CIBC) [P41-RR12553-09]; NSF [IIS-0347532] FX Support for the work of SK and DHB provided in part by the NIH/NCRR Center for Integrative Biomedical Computing (CIBC), P41-RR12553-09, JD was also partly supported by NSF IIS-0347532 NR 6 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 444 EP 447 DI 10.1109/ISBI.2010.5490315 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400114 ER PT S AU Wahlby, C Riklin-Raviv, T Ljosa, V Conery, AL Golland, P Ausubel, FM Carpenter, AE AF Waehlby, Carolina Riklin-Raviv, Tammy Ljosa, Vebjorn Conery, Annie L. Golland, Polina Ausubel, Frederick M. Carpenter, Anne E. GP IEEE TI RESOLVING CLUSTERED WORMS VIA PROBABILISTIC SHAPE MODELS SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE Caenorhabditis elegans; image segmentation; active shape model; high-throughput screening ID CAENORHABDITIS-ELEGANS AB The roundworm Caenorhabditis elegans is an effective model system for biological processes such as immunity, behavior, and metabolism. Robotic sample preparation together with automated microscopy and image analysis has recently enabled high-throughput screening experiments using C. elegans. So far, such experiments have been limited to per-image measurements due to the tendency of the worms to cluster, which prevents extracting features from individual animals. We present a novel approach for the extraction of individual C. elegans from clusters of worms in high-throughput microscopy images. The key ideas are the construction of a low-dimensional shape-descriptor space and the definition of a probability measure on it. Promising segmentation results are shown. C1 [Waehlby, Carolina; Ljosa, Vebjorn; Carpenter, Anne E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Riklin-Raviv, Tammy; Golland, Polina] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Conery, Annie L.; Ausubel, Frederick M.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Dept Biol Mol, Boston, MA 02114 USA. RP Wahlby, C (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RI Riklin Raviv, Tammy/A-3462-2013 FU NIH [R01 AI072508, P01 AI083214, R01 AI085581, U54 EB005149] FX This work was supported in part by grant numbers R01 AI072508, P01 AI083214, R01 AI085581 and U54 EB005149 from NIH NR 17 TC 9 Z9 9 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 552 EP 555 DI 10.1109/ISBI.2010.5490286 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400141 ER PT S AU Do, S Karl, WC Kalra, MK Brady, TJ Pien, H AF Do, Synho Karl, W. Clem Kalra, Mannudeep K. Brady, Thomas J. Pien, Homer GP IEEE TI A VARIATIONAL APPROACH FOR RECONSTRUCTING LOW DOSE IMAGES IN CLINICAL HELICAL CT SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE variational approach; iterative reconstruction technique; low dose imaging; cone-beam spiral; MDCT ID TOTAL-VARIATION MINIMIZATION; RESTORATION; TOMOGRAPHY; REDUCTION AB Exposure to medical radiation is an important healthcare concern. In this paper we present a variational formulation for image reconstruction from low-dose transmission X-ray CT as well as its application to real clinical data. Our projection domain reconstruction method is based on high-order total variation penalties. We apply the method to clinical neck data obtained from a current 64-channel MDCT helical scanner, where small features and large dynamic range variation are pervasive. The ability to generate high-quality images even at 75% dose reduction is demonstrated. In particular, our approach exhibits image SNR comparable to full-dose filtered backprojection images while avoiding the obvious stair case and blockiness artifacts typically encountered in such methods. C1 [Do, Synho; Kalra, Mannudeep K.; Brady, Thomas J.; Pien, Homer] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Do, Synho; Kalra, Mannudeep K.; Brady, Thomas J.; Pien, Homer] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. [Karl, W. Clem] Boston Univ, Dept Elect & Comp Engn, Boston, MA 02215 USA. RP Do, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 11 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 784 EP 787 DI 10.1109/ISBI.2010.5490057 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400201 ER PT S AU Chun, SY Schretter, C Fessler, JA AF Chun, Se Young Schretter, Colas Fessler, Jeffrey A. GP IEEE TI SUFFICIENT CONDITION FOR LOCAL INVERTIBILITY OF SPATIO-TEMPORAL 4D B-SPLINE DEFORMATIONS SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE 4D deformation; local invertibility; diffeomorphism; sufficient condition; image registration ID NONRIGID IMAGE REGISTRATION; OPTIMIZATION; MOTION AB Recent advances in medical imaging technologies have made 4D image sequences available in clinical routine. As a consequence, image registration techniques are evolving from alignment of pairs of static volumetric images to spatiotemporal registration of dynamic (4D) images. Since the elastic image registration problem is ill-posed, additional prior information or constraints are usually required to regularize the problem. This work proposes to enforce local invertibility (diffeomorphism) of 4D deformations. A novel sufficient condition for local invertibility over continuous space and time is proposed and a practical regularization prior is designed from the theory. The method has been applied to an image registration (motion tracking) of a dynamic 4D CT image sequence. Results show that using proposed regularizer leads to deformations that are more plausible for respiratory motion than the standard approach without additional temporal regularization. C1 [Chun, Se Young] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chun, Se Young] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Schretter, Colas] Univ Aachen, Rhein Westfal TH Aachen, Aachen, Germany. [Fessler, Jeffrey A.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Chun, SY (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Chun, Se Young/B-6653-2013; OI Chun, Se Young/0000-0001-8739-8960 FU [1P01 CA87634] FX This work is supported in part by 1P01 CA87634. NR 15 TC 2 Z9 2 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 1221 EP 1224 DI 10.1109/ISBI.2010.5490215 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400312 ER PT S AU Olson, KR Caldwell, AC AF Olson, Kristian R. Caldwell, Aya C. GP IEEE TI Designing an early stage prototype using readily available material for a neonatal incubator for poor settings SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID KANGAROO MOTHER CARE; THERMAL ENVIRONMENT; NEWBORN-INFANTS; TEMPERATURE; SURVIVAL; DEATHS; HEALTH; ZAMBIA C1 [Olson, Kristian R.] Massachusetts Gen Hosp, Clinician Eductor Serv, CIMIT Global Hlth Initiat, 50 Staniford,Suite 503B, Boston, MA 02114 USA. [Olson, Kristian R.] Massachusetts Gen Hosp, HMS, Boston, MA 02114 USA. [Caldwell, Aya C.] Massachusetts Gen Hosp, CIMIT, Boston, MA 02114 USA. RP Olson, KR (reprint author), Massachusetts Gen Hosp, Clinician Eductor Serv, CIMIT Global Hlth Initiat, 50 Staniford,Suite 503B, Boston, MA 02114 USA. EM krolson@partners.org; acaldwell1@partners.org FU Center for Integration of Medicine and Innovative Technology (CIMIT) FX This work was supported in part by the Center for Integration of Medicine and Innovative Technology (CIMIT). NR 24 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 1100 EP 1103 DI 10.1109/IEMBS.2010.5627347 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964001125 ER PT S AU Kodituwakku, S Lazar, SW Indic, P Brown, EN Barbieri, R AF Kodituwakku, Sandun Lazar, Sara W. Indic, Premananda Brown, Emery N. Barbieri, Riccardo GP IEEE TI Point Process Time-Frequency Analysis of Respiratory Sinus Arrhythmia under Altered Respiration Dynamics SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID HEART-RATE-VARIABILITY; MEDITATION; MODEL AB Respiratory sinus arrhythmia (RSA) is largely mediated by the autonomic nervous system through its modulating influence on the heartbeat. We propose an algorithm for quantifying instantaneous RSA as applied to heart beat interval and respiratory recordings under dynamic respiration conditions. The blood volume pressure derived heart beat series (pulse intervals, PI) are modeled as an inverse gaussian point process, with the instantaneous mean PI modeled as a bivariate regression incorporating both past PI and respiration values observed at the beats. A point process maximum likelihood algorithm is used to estimate the model parameters, and instantaneous RSA is estimated by a frequency domain transfer function approach. The model is statistically validated using Kolmogorov-Smirnov (KS) goodness-of-fit analysis, as well as independence tests. The algorithm is applied to subjects engaged in meditative practice, with distinctive dynamics in the respiration patterns elicited as a result. Experimental results confirm the ability of the algorithm to track important changes in cardiorespiratory interactions elicited during meditation, otherwise not evidenced in control resting states. C1 [Kodituwakku, Sandun] Australian Natl Univ, Sch Engn, Appl Signal Proc Grp, Canberra, ACT, Australia. [Brown, Emery N.] Massachusetts Gen Hosp, Harvard Med Sch, Neurosci Stat Res Lab, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Hlth Sci & Technol, Harvard MIT Div, Cambridge, MA 02139 USA. [Lazar, Sara W.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiatry, Boston, MA 02114 USA. [Indic, Premananda] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. RP Kodituwakku, S (reprint author), Australian Natl Univ, Sch Engn, Appl Signal Proc Grp, Canberra, ACT, Australia. EM sandun.kodituwakku@anu.edu.au; lazar@nmr.mgh.harvard.edu; premananda.indic@umassmed.edu; brown@neurostat.mgh.harvard.edu; barbieri@neurostat.mit.edu RI Lazar, Sara/G-3809-2012; OI Lazar, Sara/0000-0003-1126-8363; Barbieri, Riccardo/0000-0001-9381-3833 FU National Institutes of Health (NIH) [R01-HL084502, DP1-OD003646, R01-DA015644] FX This work was supported by the National Institutes of Health (NIH) under Grant R01-HL084502, Grant R01-DA015644, Grant DP1-OD003646. NR 19 TC 2 Z9 2 U1 0 U2 5 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 1622 EP 1625 DI 10.1109/IEMBS.2010.5626648 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964002007 ER PT S AU Hayes, TL Riley, T Pavel, M Kaye, JA AF Hayes, Tamara L. Riley, Thomas Pavel, Misha Kaye, Jeffrey A. GP IEEE TI Estimation of Rest-Activity Patterns using Motion Sensors SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID SLEEP; ACTIGRAPHY; BED AB Disrupted sleep patterns are a significant problem in the elderly, leading to increased cognitive dysfunction and risk of nursing home placement. A cost-effective and unobtrusive way to remotely monitor changing sleep patterns over time would enable improved management of this important health problem. We have developed an algorithm to derive sleep parameters such as bed time, rise time, sleep latency, and nap time from passive infrared sensors distributed around the home. We evaluated this algorithm using 404 days of data collected in the homes of 8 elderly community-dwelling elders. Data from this algorithm were highly correlated to ground truth measures (bed mats) and were surprisingly robust to variability in sensor layout and sleep habits. C1 [Hayes, Tamara L.; Riley, Thomas] Oregon Hlth & Sci Univ OHSU, Biomed Engn Dept BME, 3303 SW Bond Ave, Portland, OR 97239 USA. [Kaye, Jeffrey A.] ORCATECH, OHSU, Dept Neurol, Portland, OR 97239 USA. [Kaye, Jeffrey A.] Portland VA Med Ctr, Portland, OR 97239 USA. [Pavel, Misha] ORCATECH OHSU, BME Dept, Portland, OR 97239 USA. RP Hayes, TL (reprint author), Oregon Hlth & Sci Univ OHSU, Biomed Engn Dept BME, 3303 SW Bond Ave, Portland, OR 97239 USA. EM hayest@bme.ogi.edu; rileyt@bme.ogi.edu; pavel@bme.ogi.edu; kaye@ohsu.edu OI Kaye, Jeffrey/0000-0002-9971-3478 FU Intel Corporation; NIH [P30 AG024978] FX This study was funded by Intel Corporation and by NIH grant P30 AG024978. Dr. Hayes has a significant financial interest in Intel Corporation, a company that may have a commercial interest in the results of this research and technology. This potential conflict has been reviewed and managed by OHSU. NR 9 TC 7 Z9 7 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 2147 EP 2150 DI 10.1109/IEMBS.2010.5628022 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964002136 ER PT S AU Mauri, M Magagnin, V Cipresso, P Mainardi, L Brown, EN Cerutti, S Villamira, M Barbieri, R AF Mauri, Maurizio Magagnin, Valentina Cipresso, Pietro Mainardi, Luca Brown, Emery N. Cerutti, Sergio Villamira, Marco Barbieri, Riccardo GP IEEE TI Psychophysiological signals associated with affective states SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID COMPUTER AB We present a preliminary quantitative study aimed at developing an optimal standard protocol for automatic classification of specific affective states as related to human-computer interactions. This goal is mainly achieved by comparing standard psychological test-reports to quantitative measures derived from simultaneous non-invasive acquisition of psychophysiological signals of interest, namely respiration, galvanic skin response, blood volume pulse, electrocardiogram and electroencephalogram. Forty-three healthy students were exposed to computer-mediated stimuli, while wearable non-invasive sensors were applied in order to collect the physiological data. The stimuli were designed to elicit three distinct affective states: relaxation, engagement and stress. In this work we report how our quantitative analysis has helped in redefining important aspects of the protocol, and we show preliminary findings related to the specific psychophysiological patterns correlating with the three target affective states. Results further suggest that some of the quantitative measures might be useful in characterizing specific affective states. C1 [Mauri, Maurizio; Cipresso, Pietro; Villamira, Marco] Univ Milan, IULM, Via Carlo Bo 2, I-20143 Milan, Italy. [Brown, Emery N.; Barbieri, Riccardo] Massachusetts Gen Hosp, Harvard Med Sch, Neurosci Stat Res Lab, Boston, MA 02114 USA. [Brown, Emery N.; Barbieri, Riccardo] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Mainardi, Luca; Cerutti, Sergio] Univ Milan, Dept Bioingn, Milan, Italy. [Magagnin, Valentina] IRCCS Galeazzi, Ist Ortoped, Milan, Italy. RP Mauri, M (reprint author), Univ Milan, IULM, Via Carlo Bo 2, I-20143 Milan, Italy. EM maurizio.mauri@iulm.it; valentina.magagnin@tin.it; pietro.cipresso@iulm.it; luca.mainardi@biomed.polimi.it; enb@neurostat.mit.edu; Sergio.cerutti@biomed.polimi.it; Barbieri@neurostat.mit.edu RI Cipresso, Pietro/G-4676-2011; OI Cipresso, Pietro/0000-0002-0662-7678; Barbieri, Riccardo/0000-0001-9381-3833 FU NIH [R01-HL084502, DP1-OD003646] FX This work was supported by NIH Grants R01-HL084502, and DP1-OD003646. NR 14 TC 14 Z9 14 U1 0 U2 6 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 3563 EP 3566 DI 10.1109/IEMBS.2010.5627465 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964003242 ER PT S AU Chen, Z Purdon, PL Brown, EN Barbieri, R AF Chen, Zhe Purdon, Patrick L. Brown, Emery N. Barbieri, Riccardo GP IEEE TI A Differential Autoregressive Modeling Approach within a Point Process Framework for Non-stationary Heartbeat Intervals Analysis SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID BAROREFLEX SENSITIVITY; GENERAL-ANESTHESIA; RATE-VARIABILITY; SEQUENCE AB Modeling heartbeat variability remains a challenging signal-processing goal in the presence of highly non-stationary cardiovascular control dynamics. We propose a novel differential autoregressive modeling approach within a point process probability framework for analyzing R-R interval and blood pressure variations. We apply the proposed model to both synthetic and experimental heartbeat intervals observed in time-varying conditions. The model is found to be extremely effective in tracking non-stationary heartbeat dynamics, as evidenced by the excellent goodness-of-fit performance. Results further demonstrate the ability of the method to appropriately quantify the non-stationary evolution of baroreflex sensitivity in changing physiological and pharmacological conditions. C1 [Chen, Zhe; Purdon, Patrick L.; Brown, Emery N.; Barbieri, Riccardo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab, Boston, MA 02114 USA. RP Chen, Z (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab, Boston, MA 02114 USA. EM zhechen@mit.edu OI Barbieri, Riccardo/0000-0001-9381-3833; Chen, Zhe/0000-0002-6483-6056 NR 12 TC 4 Z9 4 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 3567 EP 3570 DI 10.1109/IEMBS.2010.5627462 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964003243 ER PT S AU Balakrishnan, G Shoeb, A Syed, Z AF Balakrishnan, Guha Shoeb, Ali Syed, Zeeshan GP IEEE TI Creating Symbolic Representations of Electroencephalographic Signals: An Investigation of Alternate Methodologies on Intracranial Data SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID EEG AB The electroencephalogram (EEG) is widely used in the investigation of neurological disorders. Continuous long-term EEG data offers the opportunity to assess patient health over long periods of time, and to discover previously unknown physiological phenomena. However, the sheer volume of information generated by long-term EEG monitoring also poses a serious challenge for both analysis and visualization. Symbolization has been successful in addressing information overload in many disciplines. In this paper, we present different approaches to transform EEG signals into symbolic sequences. This discrete symbolic representation reduces the amount of EEG data by several orders of magnitude and makes the task of discovering and visualizing interesting activity more manageable. We describe alternate methodologies to symbolize EEG data from patients with epilepsy. When evaluated on long-term intracranial data from 10 patients, our symbolization produced results that were consistent with clinical labels of seizures (for 97% of the seizures and 68% of the seizure segments), and often produced finer-grained distinctions. C1 [Balakrishnan, Guha; Syed, Zeeshan] Univ Michigan, Dept Elect Engn & Comp Sci, Ann Arbor, MI 48109 USA. [Shoeb, Ali] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Balakrishnan, G (reprint author), Univ Michigan, Dept Elect Engn & Comp Sci, Ann Arbor, MI 48109 USA. EM ashoeb@partners.org NR 4 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 4683 EP 4686 DI 10.1109/IEMBS.2010.5626414 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964005019 ER PT J AU Alonzo, CA Yun, SH AF Alonzo, Carlo Amadeo Yun, Seok Hyun GP IEEE TI Picosecond Sliding Frequency Mode-locked Fiber Laser SO 2010 CONFERENCE ON LASERS AND ELECTRO-OPTICS (CLEO) AND QUANTUM ELECTRONICS AND LASER SCIENCE CONFERENCE (QELS) LA English DT Proceedings Paper CT Conference on Lasers and Electro-Optics (CLEO)/Quantum Electronics and Laser Science Conference (QELS) CY MAY 16-21, 2010 CL San Jose, CA AB We demonstrate an Er3+-doped fiber laser with a broad bandwidth (2.6 nm) intracavity filter that produces 10-ps pulses at 38-MHz repetition. Pulse center-wavelengths shift at 1.6-pm intervals over a 60-nm range about 1542 nm. (C) 2010 Optical Society of America C1 [Alonzo, Carlo Amadeo; Yun, Seok Hyun] Massachusetts Gen Hosp, Harvard Sch Med, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. RP Alonzo, CA (reprint author), Massachusetts Gen Hosp, Harvard Sch Med, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM syun@hms.harvard.edu NR 4 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-55752-890-2 PY 2010 PG 2 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA BUW45 UT WOS:000290513600156 ER PT J AU Scarcelli, G Yun, SH AF Scarcelli, Giuliano Yun, Seok H. GP IEEE TI Brillouin microscopy for ocular biomechanics SO 2010 CONFERENCE ON LASERS AND ELECTRO-OPTICS (CLEO) AND QUANTUM ELECTRONICS AND LASER SCIENCE CONFERENCE (QELS) LA English DT Proceedings Paper CT Conference on Lasers and Electro-Optics (CLEO)/Quantum Electronics and Laser Science Conference (QELS) CY MAY 16-21, 2010 CL San Jose, CA ID SCATTERING; PRESBYOPIA AB We present Brillouin confocal microscopy with high throughput and high extinction for non-invasive mechanical measurements of tissue and biomaterials. In particular, we demonstrate biomechanical characterization of crystalline lens and cornea. (C) 2009 Optical Society of America C1 [Scarcelli, Giuliano; Yun, Seok H.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Harvard Med Sch, 50 Blossom St, Boston, MA 02114 USA. RP Scarcelli, G (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Harvard Med Sch, 50 Blossom St, Boston, MA 02114 USA. EM gscarcelli@partners.org NR 7 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-55752-890-2 PY 2010 PG 2 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA BUW45 UT WOS:000290513602066 ER PT S AU Wu, W Chen, Z Gao, SK Brown, EN AF Wu, Wei Chen, Zhe Gao, Shangkai Brown, Emery N. GP IEEE TI Hierarchical Bayesian Modeling of Inter-Trial Variability and Variational Bayesian Learning of Common Spatial Patterns from Multichannel EEG SO 2010 IEEE INTERNATIONAL CONFERENCE ON ACOUSTICS, SPEECH, AND SIGNAL PROCESSING SE International Conference on Acoustics Speech and Signal Processing ICASSP LA English DT Proceedings Paper CT 2010 IEEE International Conference on Acoustics, Speech, and Signal Processing CY MAR 10-19, 2010 CL Dallas, TX SP IEEE Signal Proc Soc AB In numerous neuroscience studies, multichannel EEG data are often recorded over multiple trial periods under the same experimental condition. To date, little effort is aimed to learn spatial patterns from EEG data to account for trial-to-trial variability. In this paper, a hierarchical Bayesian framework is introduced to model inter-trial source variability while extracting common spatial patterns under multiple experimental conditions in a supervised manner. We also present a variational Bayesian algorithm for model inference, by which the number of sources can be determined effectively via automatic relevance determination (ARD). The efficacy of the proposed learning algorithm is validated with both synthetic and real EEG data. Using two brain-computer interface (BCI) motor imagery data sets we show the proposed algorithm consistently outperforms the common spatial patterns (CSP) algorithm while attaining comparable performance with a recently proposed discriminative approach. C1 [Wu, Wei; Chen, Zhe; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Wu, Wei; Gao, Shangkai] Tsinghua Univ, Dept Biomed Engn, Beijing 100084, Peoples R China. [Wu, Wei; Chen, Zhe; Brown, Emery N.] Harvard Med Sch, Massachusetts Gen Hosp, Neurosci Stat Res Lab, Boston, MA 02114 USA. RP Wu, W (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM weiwu@neurostat.mit.edu OI Chen, Zhe/0000-0002-6483-6056 FU NIH [DP1-OD003646]; National Natural Science Foundation of China [30630022] FX This work was supported by NIH Grant DP1-OD003646 and the National Natural Science Foundation of China under Grant 30630022. NR 14 TC 0 Z9 0 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1520-6149 BN 978-1-4244-4296-6 J9 INT CONF ACOUST SPEE PY 2010 BP 501 EP 504 DI 10.1109/ICASSP.2010.5495663 PG 4 WC Acoustics; Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Acoustics; Computer Science; Engineering GA BTJ55 UT WOS:000287096000123 ER PT S AU Shanechi, MM Wornell, GW Williams, Z Brown, EN AF Shanechi, Maryam Modir Wornell, Gregory W. Williams, Ziv Brown, Emery N. GP IEEE TI A PARALLEL POINT-PROCESS FILTER FOR ESTIMATION OF GOAL-DIRECTED MOVEMENTS FROM NEURAL SIGNALS SO 2010 IEEE INTERNATIONAL CONFERENCE ON ACOUSTICS, SPEECH, AND SIGNAL PROCESSING SE International Conference on Acoustics Speech and Signal Processing ICASSP LA English DT Proceedings Paper CT 2010 IEEE International Conference on Acoustics, Speech, and Signal Processing CY MAR 10-19, 2010 CL Dallas, TX SP IEEE Signal Proc Soc DE Brain machine interfaces; recursive Bayesian filters; neural signal processing; optimal control AB Brain machine interfaces work by mapping the relevant neural activity to the intended movement known as 'decoding'. Here, we develop a recursive Bayesian decoder for goal-directed movements from neural observations, which exploits the optimal feedback control model of the sensorimotor system to build better prior state-space models. These controlled state models depend on the movement duration that is not known a priori. We thus consider a discretization of the task duration and develop a decoder consisting of a bank of parallel point-process filters, each combining the neural observation with the controlled state model of a discretization point. The final reconstruction is made by optimally combining these filter estimates. Using very coarse discretization and hence only a few parallel branches, our decoder reduces the root mean square (RMS) error in trajectory reconstruction in reaches made by a rhesus monkey by approximately 40%. C1 [Shanechi, Maryam Modir; Wornell, Gregory W.] EECS MIT, Cambridge, MA 02139 USA. [Williams, Ziv; Brown, Emery N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brown, Emery N.] HST MIT, Cambridge, MA USA. RP Shanechi, MM (reprint author), EECS MIT, Cambridge, MA 02139 USA. FU NIH [DP1-0D003646-01, R01-EB006385]; Microsoft Research FX This work was supported in part by NIH under Grant Nos. DP1-0D003646-01 and R01-EB006385 and by a grant from Microsoft Research. NR 9 TC 5 Z9 5 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1520-6149 BN 978-1-4244-4296-6 J9 INT CONF ACOUST SPEE PY 2010 BP 521 EP 524 DI 10.1109/ICASSP.2010.5495644 PG 4 WC Acoustics; Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Acoustics; Computer Science; Engineering GA BTJ55 UT WOS:000287096000128 ER PT S AU Purdon, PL Lamus, C Hamalainen, MS Brown, EN AF Purdon, P. L. Lamus, C. Haemaelaeinen, M. S. Brown, E. N. GP IEEE TI A STATE SPACE APPROACH TO MULTIMODAL INTEGRATION OF SIMULTANEOUSLY RECORDED EEG AND FMRI SO 2010 IEEE INTERNATIONAL CONFERENCE ON ACOUSTICS, SPEECH, AND SIGNAL PROCESSING SE International Conference on Acoustics Speech and Signal Processing ICASSP LA English DT Proceedings Paper CT 2010 IEEE International Conference on Acoustics, Speech, and Signal Processing CY MAR 10-19, 2010 CL Dallas, TX SP IEEE Signal Proc Soc DE EEG; fMRI; Multimodal Imaging ID HUMAN BRAIN; MAGNETOENCEPHALOGRAPHY AB We develop a state space approach to multimodal integration of simultaneously recorded EEG and fMRI. The EEG is represented with a distributed current source model using realistic MRI-based forward models, whose temporal evolution is governed by a linear state space model. The fMRI signal is similarly modeled by a linear state space model describing the hemodynamic response to underlying EEG current activity. We explore the feasibility of high dimensional dynamic estimation of simultaneous EEG/fMRI using simulation studies of the alpha wave. C1 [Purdon, P. L.; Brown, E. N.] Massachusetts Gen Hosp, Dept Anaethesia & Crit Care, Boston, MA 02114 USA. [Purdon, P. L.; Lamus, C.; Brown, E. N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA USA. [Haemaelaeinen, M. S.] MIT, MGH, HMS, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Haemaelaeinen, M. S.; Brown, E. N.] Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA USA. RP Purdon, PL (reprint author), Massachusetts Gen Hosp, Dept Anaethesia & Crit Care, Boston, MA 02114 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1520-6149 BN 978-1-4244-4296-6 J9 INT CONF ACOUST SPEE PY 2010 BP 5454 EP 5457 DI 10.1109/ICASSP.2010.5494906 PG 4 WC Acoustics; Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Acoustics; Computer Science; Engineering GA BTJ55 UT WOS:000287096005092 ER PT S AU Chen, Y Chang, JH Greenlee, AS Cheung, KC Slocum, AH Gupta, R AF Chen, Yi Chang, Jean H. Greenlee, Alison S. Cheung, Kenneth C. Slocum, Alex H. Gupta, Rajiv GP IEEE TI Multi-turn, Tension-stiffening Catheter Navigation System SO 2010 IEEE INTERNATIONAL CONFERENCE ON ROBOTICS AND AUTOMATION (ICRA) SE IEEE International Conference on Robotics and Automation ICRA LA English DT Proceedings Paper CT IEEE International Conference on Robotics and Automation (ICRA) CY MAY 03-08, 2010 CL Anchorage, AK SP IEEE ID ABLATION; DRAINAGE AB In poorly constrained extra-vascular environments such as hollow viscera, current catheter navigation techniques are restricted to simple paths and therefore limit a doctor's ability to position the catheter. This paper presents a new catheter positioning system that enables faster and more accurate catheter placement, with fewer scans. The proposed robotic catheter navigation system can execute curved paths and maintain any number of three-dimensional turns using tension stiffening guide-wires composed of a set of disposable friction-locking beads. An external, reusable control system is used to automate the movement of the catheter. This control system uses a custom-designed graphical kinematic analysis program that predicts contact forces, changes in conformation due to external forces, tip deflection and failure modes of the catheter as it advances. C1 [Chen, Yi; Chang, Jean H.; Greenlee, Alison S.; Slocum, Alex H.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Cheung, Kenneth C.] MIT, Ctr Bits & Atoms, Cambridge, MA 02139 USA. [Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Chen, Y (reprint author), MIT, Dept Mech Engn, Cambridge, MA 02139 USA. EM yichen@mit.edu NR 16 TC 6 Z9 6 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1050-4729 BN 978-1-4244-5040-4 J9 IEEE INT CONF ROBOT PY 2010 BP 5570 EP 5575 DI 10.1109/ROBOT.2010.5509786 PG 6 WC Automation & Control Systems; Engineering, Electrical & Electronic; Robotics SC Automation & Control Systems; Engineering; Robotics GA BSD39 UT WOS:000284150004060 ER PT S AU Cal-Gonzalez, J Herraiz, JL Espana, S Desco, M Vaquero, JJ Udias, JM AF Cal-Gonzalez, J. Herraiz, J. L. Espana, S. Desco, M. Vaquero, J. J. Udias, J. M. GP IEEE TI Validation of PeneloPET Positron Range Estimations SO 2010 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD (NSS/MIC) SE IEEE Nuclear Science Symposium Conference Record LA English DT Proceedings Paper CT IEEE Nuclear Science Symposium (NSS)/Medical Imaging Conference (MIC)/17th International Workshop on Room-Temperature Semiconductor X-ray and Gamma-ray Detectors CY OCT 30-NOV 06, 2010 CL Knoxville, TN SP Inst Elect & Elect Engineers, Nucl & Plasma Sci Soc, IEEE ID SPATIAL-RESOLUTION; PET; SIMULATION AB Positron range depends on the materials in which positron propagates and on positron emitter isotope. As positron range limits the spatial resolution of PET images, good quantitative estimates of it should be included in any realistic simulation of PET acquisitions. In this work we compare positron range estimates obtained with PeneloPET to previous available simulations and experimental data. PeneloPET was used to simulate the positron range of F-18, C-11, N-13, O-15, Ga-68 and Rb-82 in the following tissues: cortical bone, soft bone, skin, muscle, brain, water, adipose tissue and lung. The 3D and 1D annihilation Point Spread Functions (aPSF) were calculated for each isotope-material combination. We have studied with more detail the 3D aPSF (radial distributions) and the cumulative fraction of annihilation events. These aPSF distributions were also studied for non-uniform media. Results obtained were consistent with other results previously reported in the literature as well as with experimentally measured data. C1 [Cal-Gonzalez, J.; Herraiz, J. L.; Udias, J. M.] UCM, Grp Fis Nucl, Dpto Fis Atom Mol & Nucl, Madrid, Spain. [Espana, S.] Univ Complutense Madrid, Grp Fis Nucl, Madrid, Spain. [Espana, S.] Harvard Univ, Sch Med, Boston, MA USA. [Espana, S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Desco, M.] Univ Gregorio Marano, Gen Hosp, Unidad Med & Cirugia Expt, Madrid, Spain. [Vaquero, J. J.] Univ Carlos III Madrid, Dept Bioingn & Ingn Aeroesp, Madrid, Spain. RP Cal-Gonzalez, J (reprint author), UCM, Grp Fis Nucl, Dpto Fis Atom Mol & Nucl, Madrid, Spain. EM jacobo@nuclear.fis.ucm.es; sespana-palomares@partners.org; desco@mce.hggm.es; juanjose.vaquero@uc3m.es RI Udias, Jose/A-7523-2010; Vaquero, Juan Jose/D-3033-2009; Espana, Samuel/E-9240-2010; LOPEZ HERRAIZ, JOAQUIN/E-9234-2010; Desco, Manuel/D-2822-2009 OI Udias, Jose/0000-0003-3714-764X; Vaquero, Juan Jose/0000-0001-9200-361X; Espana, Samuel/0000-0001-9092-4597; LOPEZ HERRAIZ, JOAQUIN/0000-0001-7208-8863; Desco, Manuel/0000-0003-0989-3231 FU MEC [FPA2007-62216]; UCM [910059]; CPAN [CSPD-2007-00042]; European Regional Development and ENTEPRASE [PSE-300000-2009-5]; CENIT; Ministerio de Ciencia e Innovacion, Spanish Government; UCM; UE FX Manuscript received November 12, 2010. This work has been supported by MEC (FPA2007-62216), UCM (Grupos UCM, 910059), CPAN (Consolider-Ingenio 2010) CSPD-2007-00042, European Regional Development and ENTEPRASE grant, PSE-300000-2009-5, and the CENIT program project AMIT, Ministerio de Ciencia e Innovacion, Spanish Government. Part of the calculations of this work were performed in the Cluster de Calculo de Alta Capacidad para Tecnicas Fisicas funded in part by UCM and in part by UE under FEDER programme. NR 10 TC 3 Z9 3 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3654 BN 978-1-4244-9106-3 J9 IEEE NUCL SCI CONF R PY 2010 BP 2396 EP 2399 PG 4 WC Engineering, Electrical & Electronic; Nuclear Science & Technology; Physics, Applied SC Engineering; Nuclear Science & Technology; Physics GA BBB94 UT WOS:000306402902122 ER PT S AU Vicente, E Herraiz, JL Canadas, M Cal-Gonzalez, J Espana, S Desco, M Vaquero, JJ Udias, JM AF Vicente, E. Herraiz, J. L. Canadas, M. Cal-Gonzalez, J. Espana, S. Desco, M. Vaquero, J. J. Udias, J. M. GP IEEE TI Validation of NEMA NU4-2008 Scatter Fraction estimation with F-18 and Ga-68 for the ARGUS small-animal PET scanner SO 2010 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD (NSS/MIC) SE IEEE Nuclear Science Symposium Conference Record LA English DT Proceedings Paper CT IEEE Nuclear Science Symposium (NSS)/Medical Imaging Conference (MIC)/17th International Workshop on Room-Temperature Semiconductor X-ray and Gamma-ray Detectors CY OCT 30-NOV 06, 2010 CL Knoxville, TN SP Inst Elect & Elect Engineers, Nucl & Plasma Sci Soc, IEEE AB The scatter fraction (SF) in PET data represents the fraction of coincidence events in which at least one of the two emitted photons have been scattered before being detected. It is usually estimated as the ratio of scattered events to total number of coincidences, when the number of random counts is negligible (less than 1% of true rates). SF provides a measurement of the relative sensitivity of the scanner to scattered radiation. It depends on object size, density and location inside the field of view, as well as on detector size, type of detector crystal and energy window. The performance evaluation guideline for small-animal PET NEMA (National Electrical Manufacturers Association) NU4-2008 proposes the estimation of the SF for three test phantoms made in proportion to the most widely used small animals in the laboratory: mouse, rat and monkey. The method estimates the different coincidence types in sinogram profiles from an off-centered line source inserted in these phantoms. We benchmark the procedure proposed by NEMA to estimate SF with F-18 and also with Ga-68, a radionuclide with lager positron range. Real data acquired with the ARGUS small-animal PET scanner (SEDECAL, Madrid, Spain) as well as simulations of the same scanner with peneloPET are used. The results show that, though SF should be practically the same with both F-18 and Ga-68 isotopes (and indeed our simulations indicate this) NEMA SF estimations with Ga-68 acquisitions are higher. This is due to the fact that Ga-68 positron range affects on the width of the line source profiles. Suggestions to modify the protocol to obtain similar SF estimations when using isotopes with larger positron range than F-18 are made. C1 [Vicente, E.; Herraiz, J. L.; Cal-Gonzalez, J.; Udias, J. M.] Univ Complutense Madrid, Dpto Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. [Vicente, E.] CSIC, Inst Estruct Mat, Madrid, Spain. [Canadas, M.] CIEMAT Ctr Invest Energeticas Medioambientales &, Madrid, Spain. [Espana, S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Espana, S.] Harvard Med Sch, Boston, MA USA. [Desco, M.; Vaquero, J. J.] Univ Carlos III Madrid, Dept Bioingn & Ingn Aeroesp, Madrid, Spain. [Desco, M.] Univ Gregorio Maranon, Gen Hosp, Unidad Med & Cirugia Expt, Madrid, Spain. [Desco, M.] Inst Salud Carlos III, CIBERSAM, Madrid, Spain. RP Vicente, E (reprint author), Univ Complutense Madrid, Dpto Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. EM esther@nuclear.fis.ucm.es RI Espana, Samuel/E-9240-2010; Udias, Jose/A-7523-2010; Vaquero, Juan Jose/D-3033-2009; LOPEZ HERRAIZ, JOAQUIN/E-9234-2010; Desco, Manuel/D-2822-2009 OI Espana, Samuel/0000-0001-9092-4597; Udias, Jose/0000-0003-3714-764X; Vaquero, Juan Jose/0000-0001-9200-361X; LOPEZ HERRAIZ, JOAQUIN/0000-0001-7208-8863; Desco, Manuel/0000-0003-0989-3231 FU MEC [FPA2007-62216]; UCM [910059]; CPAN [CSPD-2007-00042]; European Regional Funds; CDTI; ARTEMIS [S2009/DPI-1802]; European Regional Development; ENTEPRASE,Ministerio de Ciencia e Innovacion [PSE-300000-2009-5]; UCM; UE FX This work has been supported by MEC (FPA2007-62216), UCM (Grupos UCM, 910059), CPAN (Consolider-Ingenio2010) CSPD-2007-00042, European Regional Funds. AMIT Project funded by CDTI (CENIT Programme), ARTEMIS S2009/DPI-1802, European Regional Development and ENTEPRASE grant, PSE-300000-2009-5, Ministerio de Ciencia e Innovacion. Spanish Government. Part of the calculations of this work were performed in the Cluster de Calculo de Alta Capacidad para Tecnicas Flsicas funded in part by UCM and in part by UE under FEDER programme. NR 4 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3654 BN 978-1-4244-9106-3 J9 IEEE NUCL SCI CONF R PY 2010 BP 3553 EP 3557 PG 5 WC Engineering, Electrical & Electronic; Nuclear Science & Technology; Physics, Applied SC Engineering; Nuclear Science & Technology; Physics GA BBB94 UT WOS:000306402903158 ER PT S AU Fachin, F Wardle, BL Chen, GD Toner, M AF Fachin, F. Wardle, B. L. Chen, G. D. Toner, M. GP IEEE TI Integration of Vertically-Aligned Carbon Nanotube Forests in Microfluidic Devices for Multiscale Isolation of Bioparticles SO 2010 IEEE SENSORS SE IEEE Sensors LA English DT Proceedings Paper CT 2010 IEEE Sensors Conference CY NOV 01-04, 2010 CL Kona, HI SP IEEE ID DRUG-DELIVERY; TRANSPORTERS AB Presently, an estimated 35 million people are living with HIV, 300 million with Hepatitis C (HCV), with thousands of human fatalities registered ever day due to these and similar infectious diseases. Efficient, reliable, inexpensive medical solutions are therefore needed to tackle these issues. Identification of HIV and HCV is however not easy. Being significantly smaller than cells and bacteria, these viruses escape the isolation capabilities of both macroscopic and microscopic (MEMS) medical instrumentation. Allowing access to sub-micron species such as viruses and cancer cells, integration of nanotechnologies in medical devices has the potential to revolutionize the field of biomedicine. In this work, we explore the potential of nanoporous, patterned forests of vertically-aligned carbon nanotubes (VACNTs) for bioparticle isolation, demonstrating their ability to access particles over several orders of magnitude in size, from viruses (similar to 40nm) to cells (similar to 10 mu m). Modifying the flow field inside microfluidic channels, CNT-enhanced biodevices result in a seven-fold increase in capture efficiency compared to a nonporous design, as well as the ability to simultaneously isolate multiple distinct biospecies both inside and on the outer surface of the VACNT features. Our technology represents a versatile, highly efficient approach to biological isolation, with applications ranging from point-of-care diagnostics to subsequent therapeutic modalities in both infectious diseases as well as cancer applications. C1 [Fachin, F.; Wardle, B. L.] MIT, Dept Aeronaut & Astronaut, Cambridge, MA 02139 USA. [Chen, G. D.; Toner, M.] Massachusetts Gen Hosp, BioMEMS Resource Ctr, Charlestown, MA 02129 USA. RP Fachin, F (reprint author), MIT, Dept Aeronaut & Astronaut, Cambridge, MA 02139 USA. EM ffachin@mit.edu; wardle@mit.edu; gracec@mit.edu; mehmet_toner@hms.harvard.edu NR 8 TC 4 Z9 4 U1 1 U2 12 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1930-0395 BN 978-1-4244-8168-2 J9 IEEE SENSOR PY 2010 BP 47 EP 51 DI 10.1109/ICSENS.2010.5690852 PG 5 WC Engineering, Electrical & Electronic; Instruments & Instrumentation SC Engineering; Instruments & Instrumentation GA BTS59 UT WOS:000287982100010 ER PT S AU Sundara-Rajan, K Bestick, A Rowe, GI Klute, GK Ledoux, WR Mamishev, AV AF Sundara-Rajan, Kishore Bestick, Aaron Rowe, Gabriel I. Klute, Glenn K. Ledoux, William R. Mamishev, Alexander V. GP IEEE TI Capacitive Sensing of Interfacial Stresses SO 2010 IEEE SENSORS SE IEEE Sensors LA English DT Proceedings Paper CT 2010 IEEE Sensors Conference CY NOV 01-04, 2010 CL Kona, HI SP IEEE ID PROSTHETIC SOCKET INTERFACE; TIBIAL AMPUTEE SUBJECTS; SHEAR STRESSES; PRESSURES; SUCTION AB Studying interfacial stresses is an important step towards understanding load distributions in mechanical, biomedical, and industrial systems. This paper presents a capacitive sensor that is capable of simultaneously measuring compressive and shear stresses. The sensor consists of two electrode layers separated by a set of flexible and compressible polymer pillars. The sensor's response to compressive and shear stresses was tested and characterized up to 320 kPa and 70 kPa respectively. An algorithm to estimate the applied stresses based on sensor output was developed and validated. The applied compressive stresses were estimated with an accuracy of 95.04 % and shear stress with an accuracy of 89.45 %. C1 [Sundara-Rajan, Kishore; Bestick, Aaron; Rowe, Gabriel I.; Mamishev, Alexander V.] Univ Washington, Dept Elect Engn, Sensors Energy & Automat Lab, Seattle, WA 98195 USA. [Klute, Glenn K.; Ledoux, William R.] Ctr Excellence Limb Loss Prevent & Prosthet Engn, VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Sundara-Rajan, K (reprint author), Univ Washington, Dept Elect Engn, Sensors Energy & Automat Lab, Seattle, WA 98195 USA. EM kishore@u.washington.edu FU U.S. National Institute of Health [R21HD052109-02]; Department of Veterans Affairs [A4843C]; Washington NASA Space FX This work was supported in part by the U.S. National Institute of Health under Grant R21HD052109-02, the Department of Veterans Affairs Grant A4843C, and the Washington NASA Space Grant scholarships. NR 20 TC 2 Z9 2 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1930-0395 BN 978-1-4244-8168-2 J9 IEEE SENSOR PY 2010 BP 2569 EP 2572 DI 10.1109/ICSENS.2010.5690146 PG 4 WC Engineering, Electrical & Electronic; Instruments & Instrumentation SC Engineering; Instruments & Instrumentation GA BTS59 UT WOS:000287982100569 ER PT S AU Efthimiadis, EN Hammond, KW Laundry, R Thielke, SM AF Efthimiadis, Efthimis N. Hammond, Kenric W. Laundry, Ryan Thielke, Stephen M. GP IEEE TI Developing an EMR Simulator to Assess Users' Perception of Document Quality SO 43RD HAWAII INTERNATIONAL CONFERENCE ON SYSTEMS SCIENCES VOLS 1-5 (HICSS 2010) SE Proceedings of the Annual Hawaii International Conference on System Sciences LA English DT Proceedings Paper CT 43rd Hawaii International Conference on Systems Sciences (HICSS 2010) CY JAN 05-08, 2010 CL Honolulu, HI SP Univ Hawaii, Shidler Coll Business ID PHYSICIAN ORDER ENTRY; ERRORS; SYSTEM; RECORD AB Simulators are used in research and training because they provide a realistic and safe environment for participants In the course of conducting a comprehensive study of patient care documentation in electronic medical record (EMR) systems we found that use of a simulated EMR system could address logistic and conceptual barriers encountered in deploying a research instrument to assess user perceptions of patient care document quality Designed for use by practitioners, nurses, and administrators at four VA hospital sites, the web-based EMR simulator presents clinical documents as they appear in VA's CPRS production EMR, and administers a document quality assessment questionnaire The EMR simulator was developed to overcome the contradiction of studying computerized documents with a paper instrument, to permit self-administration at multiple sites and to manage data collection This paper discusses the motivation to evaluate EMR document quality, development of the quality questionnaire, and how the design of the simulator evolved and was pilot tested C1 [Efthimiadis, Efthimis N.; Laundry, Ryan] Univ Washington, Informat Sch, Seattle, WA 98195 USA. [Hammond, Kenric W.; Thielke, Stephen M.] VA Puget Sound Hlth Care Syst, Tacoma, WA 98498 USA. [Hammond, Kenric W.; Thielke, Stephen M.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Efthimiadis, EN (reprint author), Univ Washington, Informat Sch, Seattle, WA 98195 USA. NR 26 TC 0 Z9 0 U1 2 U2 2 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 1060-3425 BN 978-1-4244-5509-6 J9 P ANN HICSS PY 2010 BP 2491 EP + PG 3 WC Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BRD18 UT WOS:000282391802072 ER PT B AU Boudsocq, M Sheen, J AF Boudsocq, Marie Sheen, Jen BE Pareek, A Sopory, SK Bohnert, HJ Govindjee, X TI Stress Signaling II: Calcium Sensing and Signaling SO ABIOTIC STRESS ADAPTATION IN PLANTS: PHYSIOLOGICAL, MOLECULAR AND GENOMIC FOUNDATION LA English DT Article; Book Chapter DE Calcineurin B-like; calcium; calcium-dependent protein kinase; calcium sensing; calcium signatures; calmodulin; stress signaling ID DEPENDENT PROTEIN-KINASE; BINDING TRANSCRIPTION FACTOR; PLANT CALMODULIN ISOFORMS; DECODING CA2+ SIGNALS; ABSCISIC-ACID; ARABIDOPSIS-THALIANA; GENE-EXPRESSION; SALT STRESS; GUARD-CELLS; IN-VITRO AB Calcium is an essential second messenger in plant signaling networks. Many environmental and developmental stimuli induce an increase in cytosolic calcium to trigger different physiological responses. The specificity of Ca2+ signaling is achieved by a combination of distinct calcium signatures that are generated by specific calcium channels, pumps and transporters, and diverse calcium sensors that differ by their expression pattern, sub-cellular localization, substrate specificities and calcium sensitivities. Calcium binding modifies the structural conformation or enzymatic activity of the calcium sensors, which subsequently regulate downstream targets. Calmodulin is the most important Ca2+ transducer in eukaryotes and regulates numerous proteins with diverse cellular functions, including protein kinases. Plants also possess specific multigene families of protein kinases that play crucial roles in mediating calcium signaling. The multiplicity and diversity of plant calcium sensors, as well as the interconnections between various signal transduction pathways, constitute a tightly regulated signaling network that induces specific stress responses to improve plant survival. C1 [Boudsocq, Marie; Sheen, Jen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Boudsocq, Marie; Sheen, Jen] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Boudsocq, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. EM sheen@molbio.mgh.harvard.edu NR 107 TC 19 Z9 20 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-90-481-3111-2 PY 2010 BP 75 EP 90 DI 10.1007/978-90-481-3112-9_4 D2 10.1007/978-90-481-3112-9 PG 16 WC Biotechnology & Applied Microbiology; Plant Sciences SC Biotechnology & Applied Microbiology; Plant Sciences GA BOP19 UT WOS:000277200100004 ER PT J AU Steinman, MA Boscardin, CK Aguayo, L Baron, RB AF Steinman, Michael A. Boscardin, Christy K. Aguayo, Leslie Baron, Robert B. TI Commercial Influence and Learner-Perceived Bias in Continuing Medical Education SO ACADEMIC MEDICINE LA English DT Article ID INDUSTRY SUPPORT; PHYSICIANS; PROMOTION; DOCTORS; GIFTS; TOOL; CME AB Purpose To directly examine the relationship between commercial support of continuing medical education (CME) and perceived bias in the content of these activities. Method Cross-sectional study of 213 accredited live educational programs organized by a university provider of CME from 2005 to 2007. A standard question from course evaluations was used to determine the degree to which attendees believed commercial bias was present. Binomial regression models were used to determine the association between course features that may introduce commercial bias and the extent of perceived bias at those CME activities. Results Mean response rate for attendee evaluations was 56% (SD 15%). Commercial support covered 20%-49% of costs for 45 (21%) educational activities, and >= 50% of costs for 46 activities (22%). Few course participants perceived commercial bias, with a median of 97% (interquartile range 95%-99%) of respondents stating that the activity they attended was free of commercial bias. There was no association between extent of commercial support and the degree of perceived bias in CME activities. Similarly, perceived bias did not vary for 11 of 12 event characteristics evaluated as potential sources of commercial bias, or by score on a risk index designed to prospectively assess risk of commercial bias. Conclusions Rates of perceived bias were low for the vast majority of CME activities in the sample and did not differ by the degree of industry support or other event characteristics. Further study is needed to determine whether commercial influence persisted in more subtle forms that were difficult for participants to detect. C1 [Steinman, Michael A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Steinman, Michael A.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Boscardin, Christy K.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Boscardin, Christy K.; Aguayo, Leslie] Univ Calif San Francisco, Off Med Educ, San Francisco, CA 94143 USA. RP Steinman, MA (reprint author), San Francisco VA Med Ctr, Box 181-G,4150 Clement St, San Francisco, CA 94121 USA. EM mike.steinman@ucsf.edu OI Boscardin, Christy/0000-0002-9070-8859 FU VA Health Services Research and Development Service [CDTA 01-013]; National Institute on Aging [K23 AG030999] FX Funding for this work was provided by VA Health Services Research and Development Service (CDTA 01-013) and by the National Institute on Aging (K23 AG030999) (both for Dr. Steinman). NR 35 TC 14 Z9 14 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JAN PY 2010 VL 85 IS 1 BP 74 EP 79 DI 10.1097/ACM.0b013e3181c51d3f PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 576GC UT WOS:000276131300020 PM 20042828 ER PT J AU Gibbs-Strauss, SL Samkoe, KS O'Hara, JA Davis, SC Hoopes, PJ Hasan, T Pogue, BW AF Gibbs-Strauss, Summer L. Samkoe, Kimberley S. O'Hara, Julia A. Davis, Scott C. Hoopes, P. Jack Hasan, Tayyaba Pogue, Brian W. TI Detecting Epidermal Growth Factor Receptor Tumor Activity In Vivo During Cetuximab Therapy of Murine Gliomas SO ACADEMIC RADIOLOGY LA English DT Article DE EGFR; glioma; spectroscopy; MRI; cetuximab ID GLIOBLASTOMA-MULTIFORME; MONOCLONAL-ANTIBODY; MALIGNANT GLIOMAS; TARGETED THERAPY; COMBINATION; CANCER; MODEL AB Rationale and Objectives: Noninvasive molecular imaging of glioma tumor receptor activity was assessed with diagnostic in vivo fluorescence monitoring during targeted therapy. The study goals were to assess the range of use for treatment monitoring and stratification of tumor types using epidermal growth factor (EGF) receptor (EGFR) status with administration of fluorescently labeled EGF and determine its utility for tumor detection compared to magnetic resonance imaging (MRI). Materials and Methods: EGFR+ and EGFR- glioma tumor lines (human glioma [U251-GFP] and rat gliosarcoma [9L-GFP], respectively) were used to assess these goals, having a 20-fold difference between their EGF uptakes. Results: Treatment with cetuximab in the EGFR+ tumor-bearing animals led to decreased EGF tumor uptake, whereas for the EGFR-tumors, no change in fluorescence signal followed treatment. This diagnostic difference in EGFR expression could be used to stratify the tumor-bearing animals into groups of potential responders and nonresponders, and receiver-operating characteristic curve analysis revealed an area under the curve (AUC) of 0.92 in separating these tumors. The nonlocalized growth pattern of U251-GFP tumors resulted in detection difficulty on standard MRI, but high EGFR expression made them detectable by fluorescence imaging (AUC = 1.0). The EGFR+ U251-GFP tumor-bearing animals could be noninvasively stratified into treated and untreated groups on the basis of fluorescence intensity difference (P=.035, AUC=0.90). Conclusions: EGFR expression was tracked in vivo with fluorescence and determined to be of use for the stratification of EGFR+ and EGFR- tumors, the detection of EGFR+ tumors, and monitoring of molecular therapy. C1 [Gibbs-Strauss, Summer L.; Samkoe, Kimberley S.; O'Hara, Julia A.; Davis, Scott C.; Hoopes, P. Jack; Pogue, Brian W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Hoopes, P. Jack; Pogue, Brian W.] Dartmouth Coll, Dept Surg, Hanover, NH 03755 USA. [Hasan, Tayyaba; Pogue, Brian W.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hasan, Tayyaba] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gibbs-Strauss, Summer L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Gibbs-Strauss, SL (reprint author), Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. EM sgibbs@bidmc.harvard.edu; pogue@dartmouth.edu FU National Cancer Institute [RO1CA109558, PO1CA84203]; Norris Cotton Cancer Center Shared Resources FX From the Thayer School of Engineering (S.L.G,-S., K.S.S., J.A.O., S.C.D P.J.H., B.W.P.) and the Department of Surgery (P.J.H., B.W.P.), Dartmout College, Hanover NH; the Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA (T.H., B.W.P.), Harvard Medical School, Boston, MA 02115 (T.H.); and Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Room SL-B05, Boston, MA 02215 (S.L.G.-S.). Received April 6, 2009; accepted July 24, 2009. This work was funded by grants RO1CA109558 and PO1CA84203 from the National Cancer Institute (Bethesda, MD) as well as the Norris Cotton Cancer Center Shared Resources (Lebanon, NH). Address correspondence to: S.L.G.-S. e-mail: sgibbs@bidmc.harvard.edu or pogue@dartmouth.edu NR 20 TC 13 Z9 13 U1 0 U2 5 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 JAN PY 2010 VL 17 IS 1 BP 7 EP 17 DI 10.1016/j.acra.2009.07.027 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 540ER UT WOS:000273314500003 PM 19796971 ER PT J AU Atilla-Gokcumen, GE Castoreno, AB Sasse, S Eggert, US AF Atilla-Gokcumen, G. Ekin Castoreno, Adam B. Sasse, Sofia Eggert, Ulrike S. TI Making the Cut: The Chemical Biology of Cytokinesis SO ACS CHEMICAL BIOLOGY LA English DT Review DE Actin; Cleavage furrow/contractile ring; Cytokinesis; Metabolites; Midzone; Myosin; Phosphatidylinositol 4,5-bisphosphate (PIP2); Small molecule probes; Tubulin ID MYOSIN LIGHT-CHAIN; CLEAVAGE FURROW; CELL-DIVISION; FISSION YEAST; ANIMAL CYTOKINESIS; ZEBRAFISH EMBRYOS; AURORA-B; DROSOPHILA SPERMATOCYTES; SIGNALING MOLECULES; MEMBRANE DOMAINS AB Cytokinesis is the last step in the cell cycle, where daughter cells finally separate. It is precisely regulated in both time and space to ensure that each daughter cell receives an equal share of DNA and other cellular materials. Chemical biology approaches have been used very successfully to study the mechanism of cytokinesis. In this review, we discuss the use of small molecule probes to perturb cytokinesis, as well as the role naturally occurring small molecule metabolites such as lipids play during cytokinesis. C1 [Atilla-Gokcumen, G. Ekin; Castoreno, Adam B.; Sasse, Sofia; Eggert, Ulrike S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Atilla-Gokcumen, G. Ekin; Castoreno, Adam B.; Sasse, Sofia; Eggert, Ulrike S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Sasse, Sofia] Univ Munster, D-4400 Munster, Germany. RP Eggert, US (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM ulrike_eggert@dfci.harvard.edu FU National Institutes of Health [R01 GM082834]; Human Frontier Science Program; Claudia Adams Barr Program; Dana-Farber Cancer Institute FX Cytokinesis research in the Eggert lab is supported by National Institutes of Health grant R01 GM082834, a Human Frontier Science Program Young Investigator Grant, the Claudia Adams Barr Program, and the Dana-Farber Cancer Institute. NR 109 TC 20 Z9 20 U1 1 U2 9 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 JAN PY 2010 VL 5 IS 1 BP 79 EP 90 DI 10.1021/cb900256m PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 544JW UT WOS:000273653800006 PM 20014865 ER PT J AU Adami, HO AF Adami, Hans-Olov TI The prostate cancer pseudo-epidemic SO ACTA ONCOLOGICA LA English DT Article ID RADICAL PROSTATECTOMY; RANDOMIZED-TRIAL; SCREENING TRIAL; NATURAL-HISTORY; MORTALITY; ANTIGEN; LIFE AB Screening for prostate cancer with prostate-specific antigen (PSA), a simple blood test, is complex, controversial, intellectually challenging and ethically concerning. Sweden has contributed actively to the knowledge base for PSA screening in the last couple of years and a more informed debate is now possible. I will in this article summarize what we currently know about PSA testing. I discuss the closely related issues of the natural history of early-stage disease and the risks and benefits of radical local treatment. I propose that the mortality reduction following PSA screening is probably modest, whilst substantial harms are well documented. Furthermore, there is growing evidence that the PSA test is profoundly limited for screening purposes. I therefore concur with the growing number of health and professional agencies - notably outside the US that advise against population screening with PSA. Through PSA screening the medical community has generated a pseudo-epidemic of over-diagnosed non-lethal prostate cancer. Molecular tools to distinguish innocent, over-diagnosed prostate cancer from lethal tumors that deserving curative treatment are necessary to improve screening test performance. To date, extensive attempts to identify molecular predictors of outcome have remained unsuccessful, and no ideal screening test is within sight. C1 [Adami, Hans-Olov] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Adami, Hans-Olov] Karolinska Inst, Dept Epidemiol & Biostat, Stockholm, Sweden. RP Adami, HO (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM Adami@hsph.harvard.edu NR 26 TC 13 Z9 13 U1 1 U2 3 PU TAYLOR & FRANCIS AS PI OSLO PA KARL JOHANS GATE 5, NO-0154 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PY 2010 VL 49 IS 3 BP 298 EP 304 DI 10.3109/02841860903584945 PG 7 WC Oncology SC Oncology GA 583EU UT WOS:000276657000004 PM 20397765 ER PT J AU Perlis, RH AF Perlis, Roy H. TI Irritability in depression can be a symptom of mixed depression Reply SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM rperlis@partners.org 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 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD JAN PY 2010 VL 121 IS 1 BP 80 EP 80 DI 10.1111/j.1600-0447.2009.01440.x PG 1 WC Psychiatry SC Psychiatry GA 532SH UT WOS:000272769400015 ER PT B AU Zhu, JM Kennedy, DN Cao, XD AF Zhu, Jinmin Kennedy, David N. Cao, Xiaoding BA Xia, Y Cao, X Wu, G Cheng, J BF Xia, Y Cao, X Wu, G Cheng, J TI Neural Transmission of Acupuncture Signal SO ACUPUNCTURE THERAPY FOR NEUROLOGICAL DISEASES: A NEUROBIOLOGICAL VIEW LA English DT Article; Book Chapter DE acupuncture signal; afferent nerves; autonomic nervous system; central nervous system; transmission ID CONTROLLED-TRIAL; FUNCTIONAL MRI; HUMAN BRAIN; STIMULATION; FMRI; ELECTROACUPUNCTURE; ACTIVATION; ANALGESIA; MECHANISMS; ACUPOINTS AB Acupuncture, one of the most prevalent methodologies of Traditional Chinese Medicine (TCM), has been used in Asian countries for curing numerous diseases for thousands of years. However, the true mechanisms underlying the effectiveness of acupuncture are still under debating. The meridian model based on TCM has been used so far, for guiding the practice of acupuncture. In this model, acupuncture is believed to treat the diseased organ of the patient by balancing the Yin and Yang conditions that are regulated by an energy substance (Qi) flowing constantly through the whole meridian, a network connecting all the organs of the body. Therefore, in the acupuncture treatment, it is crucial to select special acupoint(s) along the meridian that links the diseased organs, as well as to modulate the Qi flowing in the meridian through the induction of the needling sensation (De-Qi). On the other hand, a neurobiological model established in the recent decades, has supported the notion that an important mechanism of acupuncture in curing diseases is mediated by the nervous system. Stimulation by needles at acupoints is considered to initiate acupuncture signals through the nerve fibers (e.g., A(beta) and A(delta)) innervated at the deep tissue near the acupoints. The acupuncture signal is transmitted through the central nervous system, which activates and integrates with the neurons located in broad areas, such as those in the cortex, limbic system, brainstem, spinal cord, which in turn, regulate other systems. The nerve-mediated model provides us a better explanation regarding the biological mechanisms of acupuncture signal transmission in the body which has been broadly documented by both in vivo and in vitro studies under controlled conditions. In this chapter, we will review in particular, the research concerning the influence of acupuncture-elicited signals in the nervous system and how the neural pathways mediate the therapeutic effects of acupuncture. C1 [Zhu, Jinmin; Kennedy, David N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Cao, Xiaoding] Fudan Univ, Shanghai Med Coll, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Cao, Xiaoding] Fudan Univ, Shanghai Med Coll, Dept Integrat Med & Neurobiol, Shanghai 200032, Peoples R China. RP Zhu, JM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. EM jzhy2@partners.org; dave@nmr.mgh.harvard.edu; xdcao@shmu.edu.cn NR 46 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY BN 978-3-642-10855-6 PY 2010 BP 81 EP 103 DI 10.1007/978-3-642-10857-0_3 D2 10.1007/978-3-642-10857-0 PG 23 WC Medicine, Research & Experimental; Neurosciences SC Research & Experimental Medicine; Neurosciences & Neurology GA BQH11 UT WOS:000280966400003 ER PT B AU Fujikawa, DG AF Fujikawa, Denson G. BE Fujikawa, DG TI Acute Neuronal Injury The Role of Excitotoxic Programmed Cell Death Mechanisms Introduction SO ACUTE NEURONAL INJURY: THE ROLE OF EXCITOTOXIC PROGRAMMED CELL DEATH MECHANISMS LA English DT Editorial Material; Book Chapter ID ELECTRON-MICROSCOPIC FINDINGS; HYPOGLYCEMIC BRAIN-DAMAGE; INTERNUCLEOSOMAL DNA CLEAVAGE; POLY(ADP-RIBOSE) PAR POLYMER; INDUCED STATUS EPILEPTICUS; APOPTOSIS-INDUCING FACTOR; CEREBRAL-ISCHEMIA; GLUTAMATE NEUROTOXICITY; TEMPORAL EVOLUTION; GLOBAL-ISCHEMIA C1 [Fujikawa, Denson G.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. RP Fujikawa, DG (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. EM dfujikaw@ucla.edu; dfujikaw@ucla.edu NR 63 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-73225-1 PY 2010 BP 1 EP 6 DI 10.1007/978-0-387-73226-8_1 D2 10.1007/978-0-387-73226-8 PG 6 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA BMT69 UT WOS:000273556000001 ER PT B AU Fujikawa, DG AF Fujikawa, Denson G. BE Fujikawa, DG TI Age-Dependence of Neuronal Apoptosis and of Caspase Activation SO ACUTE NEURONAL INJURY: THE ROLE OF EXCITOTOXIC PROGRAMMED CELL DEATH MECHANISMS LA English DT Article; Book Chapter ID PROGRAMMED CELL-DEATH; INTERNUCLEOSOMAL DNA CLEAVAGE; ELECTRON-MICROSCOPIC FINDINGS; POLY(ADP-RIBOSE) PAR POLYMER; INDUCED STATUS EPILEPTICUS; HYPOGLYCEMIC BRAIN-DAMAGE; CYTOCHROME-C; TEMPORAL EVOLUTION; CALPAIN ACTIVATION; CEREBRAL-ISCHEMIA C1 [Fujikawa, Denson G.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. RP Fujikawa, DG (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. EM dfujikaw@ucla.edu; dfujikaw@ucla.edu NR 58 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-73225-1 PY 2010 BP 67 EP 77 DI 10.1007/978-0-387-73226-8_4 D2 10.1007/978-0-387-73226-8 PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA BMT69 UT WOS:000273556000004 ER PT B AU Liu, C Signore, AP Cao, GD Chen, J AF Liu, Can Signore, Armando P. Cao, Guodong Chen, Jun BE Fujikawa, DG TI Apoptosis-Inducing Factor Translocation to Nuclei After Transient Global Ischemia SO ACUTE NEURONAL INJURY: THE ROLE OF EXCITOTOXIC PROGRAMMED CELL DEATH MECHANISMS LA English DT Article; Book Chapter ID FOCAL CEREBRAL-ISCHEMIA; NEURONAL CELL-DEATH; SUBSEQUENT DNA FRAGMENTATION; OXYGEN-GLUCOSE DEPRIVATION; NEONATAL HYPOXIA-ISCHEMIA; X-LINKED INHIBITOR; POLY(ADP-RIBOSE) POLYMERASE; CYTOCHROME-C; MITOCHONDRIAL RELEASE; CALPAIN INHIBITOR C1 [Liu, Can; Signore, Armando P.; Cao, Guodong; Chen, Jun] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Liu, Can; Chen, Jun] Fudan Univ, Sch Med, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Cao, Guodong; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Educ & Clin Ctr, Pittsburgh, PA 15261 USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. EM chenj2@upmc.edu NR 79 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-73225-1 PY 2010 BP 131 EP 144 DI 10.1007/978-0-387-73226-8_9 D2 10.1007/978-0-387-73226-8 PG 14 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA BMT69 UT WOS:000273556000009 ER PT B AU Fujikawa, DG AF Fujikawa, Denson G. BE Fujikawa, DG TI Activation of Caspase-Independent Programmed Pathways in Seizure-Induced Neuronal Necrosis SO ACUTE NEURONAL INJURY: THE ROLE OF EXCITOTOXIC PROGRAMMED CELL DEATH MECHANISMS LA English DT Article; Book Chapter ID INDUCED STATUS EPILEPTICUS; EXTRACELLULAR AMINO-ACIDS; CELL-DEATH MECHANISMS; INTERNUCLEOSOMAL DNA CLEAVAGE; ELECTRON-MICROSCOPIC FINDINGS; POLY(ADP-RIBOSE) PAR POLYMER; PILOCARPINE-INDUCED SEIZURES; HYPOGLYCEMIC BRAIN-DAMAGE; NMDA RECEPTOR ANTAGONIST; FREELY MOVING RATS C1 [Fujikawa, Denson G.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. RP Fujikawa, DG (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. EM dfujikaw@ucla.edu; dfujikaw@ucla.edu NR 85 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-73225-1 PY 2010 BP 277 EP 293 DI 10.1007/978-0-387-73226-8_17 D2 10.1007/978-0-387-73226-8 PG 17 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA BMT69 UT WOS:000273556000017 ER PT B AU Fujikawa, DG AF Fujikawa, Denson G. BE Fujikawa, DG TI Acute Neuronal Injury The Role of Excitotoxic Programmed Cell Death Mechanisms Concluding Remarks SO ACUTE NEURONAL INJURY: THE ROLE OF EXCITOTOXIC PROGRAMMED CELL DEATH MECHANISMS LA English DT Editorial Material; Book Chapter ID DNA FRAGMENTATION; APOPTOSIS; NECROSIS; PRIMATES; CALPAIN; ACTIVATION; INHIBITOR; CATHEPSIN; CASPASE; GOLGI C1 [Fujikawa, Denson G.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Fujikawa, Denson G.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. RP Fujikawa, DG (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Neurol, North Hills, CA 91343 USA. NR 18 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-73225-1 PY 2010 BP 295 EP 298 D2 10.1007/978-0-387-73226-8 PG 4 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA BMT69 UT WOS:000273556000018 ER PT J AU Kelly, JF Kahler, CW Humphreys, K AF Kelly, John F. Kahler, Christopher W. Humphreys, Keith TI Assessing why substance use disorder patients drop out from or refuse to attend 12-step mutual-help groups: The "REASONS" questionnaire SO ADDICTION RESEARCH & THEORY LA English DT Article DE Alcoholics Anonymous; self-help; groups; mutual-help; addiction; substance abuse ID ALCOHOL-USE DISORDERS; SELF-HELP; ABUSE PATIENTS; INPATIENT TREATMENT; GROUP INVOLVEMENT; REDUCE DEMAND; RECOVERY; OUTCOMES; PARTICIPATION; INDIVIDUALS AB Substance use disorder (SUD) patients who become involved in 12-step mutual-help groups (MHGs), such as Alcoholics Anonymous, experience better outcomes and have reduced healthcare costs. In spite of this, many do not attend at all and other initial attendees drop out. Reasons for non-attendance and dropout have not been systematically studied, yet such knowledge could enhance the efficiency of twelve-step facilitation (TSF) efforts or help clinicians decide which patients might prefer non-12-step MHGs (e.g., SMART Recovery). This study developed and tested a measure of reasons for non-participation and dropout from 12-step MHGs. Items were generated and clustered into eight domains using a rational keying approach. Male veterans (N = 60; M age = 49; 41% African American) undergoing SUD treatment were asked to complete a brief assessment about prior MHG experiences. Psychometric analyses produced a 24-item measure containing seven internally consistent, face-valid, subscales. Co-morbid psychiatric issues and, to a lesser degree, spiritual concerns, were found to be particularly important dimensions relating to this phenomenon. The measure could serve as a useful screening tool for barriers to 12-step participation and subsequently focus TSF efforts or inform referral to non-12 step MHGs.70% luminal narrowing) as compared with 0% in controls. Conclusion: Young, asymptomatic, HIV-infected men with long-standing HIV disease demonstrate an increased prevalence and degree of coronary atherosclerosis compared with non-HIV-infected patients. Both traditional and nontraditional risk factors contribute to atherosclerotic disease in HIV-infected patients. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Lo, Janet; Wei, Jeffrey; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Abbara, Suhny] Massachusetts Gen Hosp, Cardiovasc Imaging Sect, Dept Radiol, Boston, MA 02114 USA. [Shturman, Leon; Soni, Anand; Rocha-Filho, Jose A.; Nasir, Khurram] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Shturman, Leon; Soni, Anand; Rocha-Filho, Jose A.; Nasir, Khurram] Harvard Univ, Sch Med, Boston, MA USA. [Nasir, Khurram] Boston Med Ctr, Dept Internal Med, Boston, MA USA. RP Lo, J (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM jlo@partners.org FU Bristol Myers Squibb, Inc; NIH [K23 HL092792, K24 DK064545, F32 HL088991, T32 HL076136, M01 RR01066-25S1] FX We wish to thank the participants of this study and the Nursing and Bionutrition Staff of the Massachusetts General Hospital and Massachusetts Institute of Technology General Clinical Research Centers. Principal contributions of authors are study conception (J.L., S.G.), study design (J.L., S.A., A.S., K.N., S.G.), participant recruitment (J.L., J.W), history-taking and physical examination O.L.), data acquisition and database management O.L., J.W), cardiac imaging data acquisition and analysis (S.A., L.S., A.S., J.R.), statistical analysis and interpretation J.L., S.G.), drafting of the manuscript U.L., S.G.), critical revision of manuscript U.L., S.A., L.S.JR., K.N., J.W, S.G.), and Supervision of study (S.G.). The funding was received from Bristol Myers Squibb, Inc., NIH K23 HL092792 (J.L.), K24 DK064545 (S.K.G.), F32 HL088991 (J.L.), T32 HL076136 (L.S., A.S. and K.N.), and M01 RR01066-25S1. Funding sources had no role in the design of the study, data analysis or the writing of the manuscript. NR 42 TC 137 Z9 137 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN PY 2010 VL 24 IS 2 BP 243 EP 253 DI 10.1097/QAD.0b013e328333ea9e PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 544SR UT WOS:000273680100009 PM 19996940 ER PT J AU Bassett, IV Regan, S Chetty, S Giddy, J Uhler, LM Holst, H Ross, D Katz, JN Walensky, RP Freedberg, KA Losina, E AF Bassett, Ingrid V. Regan, Susan Chetty, Senica Giddy, Janet Uhler, Lauren M. Holst, Helga Ross, Douglas Katz, Jeffrey N. Walensky, Rochelle P. Freedberg, Kenneth A. Losina, Elena TI Who starts antiretroviral therapy in Durban, South Africa? ... not everyone who should SO AIDS LA English DT Article DE HIV-1; HIV testing; linkage to care; loss to care; South Africa ID TREATMENT PROGRAMS; TREATMENT SERVICE; INCOME COUNTRIES; EARLY MORTALITY; FOLLOW-UP; HIV CARE; ADULTS; DISCLOSURE; SETTINGS; GENDER AB Objective: To evaluate rates of antiretroviral therapy (ART) initiation within 12 months of a new HIV diagnosis in Durban, South Africa. Design: Prospective observational cohort. Methods: Adults (>= 18 years) were enrolled before HIV testing at two outpatient clinics into the South African Test, Identify and Link cohort. Both sites offer comprehensive HIV care. HIV test results, CD4 cell counts, dates of ART initiation and dates of death were collected from medical records and 12-month patient/family interviews were conducted. ART eligibility was defined as a CD4 cell count less than 200 cells/mu l within 90 days of HIV diagnosis. The primary endpoint was ART initiation within 12 months for ART-eligible subjects. Results: From November 2006 to October 2008, 1474 newly diagnosed HIV-infected outpatients were enrolled, 1012 (691%) of whom underwent CD4 cell count testing within 90 days. The median CD4 cell count was 159 cells/mu l (interquartile range 65299). Of those who underwent CD4 cell count testing, 538 (53%) were ART-eligible. Only 210 (39%) eligible enrollees were known to have initiated ART within 12 months. Among ART-eligible subjects, there were 108 known deaths; 82% occurred before ART initiation or with unknown ART initiation status. Men rate ratio (RR) 1.3, 95% confidence interval (CI) 1.1-1.51 and subjects without an HIV-infected family member/friend (RR 1.3, 95% CI 1.1-1.7) were more likely not to start ART. Conclusion: Less than half of ART-eligible subjects started ART within 12 months. Substantial attrition and mortality follow HIV diagnosis before ART initiation in Durban, South Africa. Major efforts directed towards earlier HIV diagnosis, effective linkage to care and timely ART initiation are urgently needed. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Bassett, Ingrid V.; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bassett, Ingrid V.; Regan, Susan; Uhler, Lauren M.; Walensky, Rochelle P.; Freedberg, Kenneth A.; Losina, Elena] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Chetty, Senica; Giddy, Janet; Holst, Helga] McCord Hosp, Durban, South Africa. [Ross, Douglas] St Marys Hosp, Durban, South Africa. [Walensky, Rochelle P.] Boston Univ, Sch Publ Hlth, Div Infect Dis, Boston, MA USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.; Losina, Elena] Boston Univ, Sch Publ Hlth, Brigham & Womens Hosp, Harvard Ctr AIDS Res CFAR, Boston, MA USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Bassett, IV (reprint author), 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ibassett@partners.org FU National Institutes of Health [K23 AI068458, R01 AI058736, K24 AI062476, R01 MH073445, P30 AI42851]; Massachusetts General Hospital; Doris Duke Charitable Foundation FX This study was partly supported by the National Institutes of Health: K23 AI068458; R01 AI058736; K24 AI062476; R01 MH073445; P30 AI42851 (Harvard Center for AIDS Research), Harvard University Program on AIDS, Claflin Distinguished Scholar Award of the Massachusetts General Hospital (I.V.B.) and The Doris Duke Charitable Foundation, Clinical Scientist Development Award (R.P.W). NR 27 TC 82 Z9 83 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN PY 2010 VL 24 SU 1 BP S37 EP S44 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 544SS UT WOS:000273680200005 PM 20023438 ER PT J AU Reisner, SL Mimiaga, MJ Bland, S Skeer, M Cranston, K Isenberg, D Driscoll, M Mayer, KH AF Reisner, Sari L. Mimiaga, Matthew J. Bland, Sean Skeer, Margie Cranston, Kevin Isenberg, Deborah Driscoll, Maura Mayer, Kenneth H. TI Problematic alcohol use and HIV risk among Black men who have sex with men in Massachusetts SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE MSM; alcohol; African American; Black; HIV; STD ID AFRICAN-AMERICAN MEN; NATIONAL EPIDEMIOLOGIC SURVEY; HOMOSEXUALLY ACTIVE MEN; SUBSTANCE USE DISORDERS; MAJOR DEPRESSION; CAGE QUESTIONNAIRE; PROBLEM DRINKING; UNITED-STATES; BISEXUAL MEN; DRUG-USE AB This analysis was designed to explore the frequency of problem drinking and its role in potentiating HIV risk among a community-recruited sample of Black men who have sex with men (MSM) in Massachusetts. Black MSM (n=197) recruited via modified respondent-driven sampling between January and July 2008 completed an interviewer-administered survey, including HIV sexual behavior, the Center for Epidemiologic Studies Depression Scale (CES-D), and the CAGE alcohol screener. Bivariate and multivariable logistic regression procedures examined the association of behavioral HIV-risk factors and other psychosocial variables with problematic alcohol use (CAGE score 3 or 4). Overall, 29% of the sample was found to abuse alcohol. In a multivariable model adjusting for demographic and behavioral variables, factors associated with increased odds of problem drinking were: (1) depressive symptoms (CES-D 16+ ); (2) one or more episodes of serodiscordant unprotected anal sex during last sexual encounter with a casual male partner; and (3) one or more episodes of unprotected anal or vaginal sex with a female partner in the past 12 months. Black MSM who engaged in HIV risk behaviors may be more likely to have concurrent problematic alcohol use. HIV prevention interventions with Black MSM may benefit from incorporating screening and/or treatment for alcohol problems, as well as screening for co-morbid depressive symptoms. C1 [Reisner, Sari L.; Mimiaga, Matthew J.; Bland, Sean; Skeer, Margie; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA 02215 USA. [Reisner, Sari L.; Mimiaga, Matthew J.; Skeer, Margie] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Cranston, Kevin; Isenberg, Deborah; Driscoll, Maura] Massachusetts Dept Publ Hlth, Boston, MA USA. [Mayer, Kenneth H.] Miriam Hosp, Brown Med Sch, Providence, RI 02906 USA. RP Reisner, SL (reprint author), Fenway Hlth, Fenway Inst, 1340 Boylston St,8th Floor, Boston, MA 02215 USA. EM sreisner@fenwayhealth.org NR 69 TC 20 Z9 20 U1 15 U2 25 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 PY 2010 VL 22 IS 5 BP 577 EP 587 AR PII 922244221 DI 10.1080/09540120903311482 PG 11 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 597PG UT WOS:000277770000007 PM 20336557 ER PT J AU Mimiaga, MJ Safren, SA Dvoryak, S Reisner, SL Needle, R Woody, G AF Mimiaga, Matthew J. Safren, Steven A. Dvoryak, Sergiy Reisner, Sari L. Needle, Richard Woody, George TI "We fear the police, and the police fear us": structural and individual barriers and facilitators to HIV medication adherence among injection drug users in Kiev, Ukraine SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE HIV; ARV; IDU; Ukraine; opioid substitution therapy; adherence ID ANTIRETROVIRAL THERAPY HAART; ACCESS; METHADONE AB Ukraine has one of the most severe HIV/AIDS epidemics in Europe, with an estimated 1.63% of the population living with HIV/AIDS in 2007. Injection drug use (IDU) remains the predominant mode of transmission in Kiev - the capital and largest city. Prior reports suggest that the HIV infection rate among IDUs in Kiev reaches 33%, and many have poor and inequitable access to highly active antiretroviral therapy (HAART). Among those with access to HAART, little is understood about barriers and facilitators to HAART medication adherence. In May 2009, two semi-structured focus groups were conducted with HIV-infected IDUs seeking treatment at the City AIDS Center, Kiev. The goal was to use this information to adapt and tailor, to Ukrainian culture, an evidence-based intervention for improving adherence to HAART. All 16 participants attributed HIV infection to IDU. Their average age was 31.6 (SD=7.0), average time with HIV 5.7 years (SD=4.0), average time on HAART 2.5 years (SD=1.7), average time as IDU 14.6 years (SD=6.8), and 88% were on opioid substitution therapy. The most salient themes related to adherence barriers included: (1) harassment and discrimination by police; (2) opioid dependence; (3) complexity of drug regimen; (4) side effects; (5) forgetting; (6) co-occurring mental health problems; and (7) HIV stigma. Facilitators of adherence included: (1) cues for pill taking; (2) support and reminders from family, significant other, and friends; (3) opioid substitution therapy; and (4) wanting improved health. Additional factors explored included: (1) knowledge about HAART; (2) storage of medications; and (3) IDU and sexual risk behaviors. Findings highlighted structural and individual barriers to adherence. At the structural level, police discrimination and harassment was reported to be a major barrier to adherence to opioid substitution therapy and HAART. Privacy and stigma were barriers at the individual level. Recommendations for adherence interventions included education, training, and identification cards to show police that medication was for treatment of HIV, not for abuse; and involving family members and other systems of support for HIV treatment. C1 [Mimiaga, Matthew J.; Safren, Steven A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Mimiaga, Matthew J.; Safren, Steven A.; Reisner, Sari L.] Fenway Inst, Boston, MA USA. [Dvoryak, Sergiy] Ukrainian Inst Publ Hlth Policy, Kiev, Ukraine. [Reisner, Sari L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Needle, Richard] Pangaea Global AIDS Fdn, San Francisco, CA USA. [Woody, George] Univ Penn, Philadelphia, PA 19104 USA. [Woody, George] Treatment Res Inst, Philadelphia, PA USA. RP Mimiaga, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. EM mmimiaga@partners.org FU NIDA NIH HHS [K05 DA017009, K05DA17009, P60 DA005186, P60-DA-005186-22, R21 DA021073, R21DA021073] NR 23 TC 45 Z9 45 U1 0 U2 12 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 PY 2010 VL 22 IS 11 BP 1305 EP 1313 AR PII 924492984 DI 10.1080/09540121003758515 PG 9 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 660YH UT WOS:000282684800001 PM 20640954 ER PT J AU Holman, AG Mefford, ME O'Connor, N Gabuzda, D AF Holman, Alexander G. Mefford, Megan E. O'Connor, Niall Gabuzda, Dana TI HIVBrainSeqDB: a database of annotated HIV envelope sequences from brain and other anatomical sites SO AIDS RESEARCH AND THERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CENTRAL-NERVOUS-SYSTEM; IN-VIVO; AIDS; TISSUES; REPLICATION; TROPISM; BLOOD; MODEL; ENV AB Background: The population of HIV replicating within a host consists of independently evolving and interacting sub-populations that can be genetically distinct within anatomical compartments. HIV replicating within the brain causes neurocognitive disorders in up to 20-30% of infected individuals and is a viral sanctuary site for the development of drug resistance. The primary determinant of HIV neurotropism is macrophage tropism, which is primarily determined by the viral envelope (env) gene. However, studies of genetic aspects of HIV replicating in the brain are hindered because existing repositories of HIV sequences are not focused on neurotropic virus nor annotated with neurocognitive and neuropathological status. To address this need, we constructed the HIV Brain Sequence Database. Results: The HIV Brain Sequence Database is a public database of HIV envelope sequences, directly sequenced from brain and other tissues from the same patients. Sequences are annotated with clinical data including viral load, CD4 count, antiretroviral status, neurocognitive impairment, and neuropathological diagnosis, all curated from the original publication. Tissue source is coded using an anatomical ontology, the Foundational Model of Anatomy, to capture the maximum level of detail available, while maintaining ontological relationships between tissues and their subparts. 44 tissue types are represented within the database, grouped into 4 categories: (i) brain, brainstem, and spinal cord; (ii) meninges, choroid plexus, and CSF; (iii) blood and lymphoid; and (iv) other (bone marrow, colon, lung, liver, etc). Patient coding is correlated across studies, allowing sequences from the same patient to be grouped to increase statistical power. Using Cytoscape, we visualized relationships between studies, patients and sequences, illustrating interconnections between studies and the varying depth of sequencing, patient number, and tissue representation across studies. Currently, the database contains 2517 envelope sequences from 90 patients, obtained from 22 published studies. 1272 sequences are from brain; the remaining 1245 are from blood, lymph node, spleen, bone marrow, colon, lung and other non-brain tissues. The database interface utilizes a faceted interface, allowing real-time combination of multiple search parameters to assemble a meta-dataset, which can be downloaded for further analysis. Conclusions: This online resource, which is publicly available at http://www.HIVBrainSeqDB.org, will greatly facilitate analysis of the genetic aspects of HIV macrophage tropism, HIV compartmentalization and evolution within the brain and other tissue reservoirs, and the relationship of these findings to HIV-associated neurological disorders and other clinical consequences of HIV infection. C1 [Holman, Alexander G.; Mefford, Megan E.; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [O'Connor, Niall] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02115 USA. [Gabuzda, Dana] Harvard Univ, Dept Neurol, Sch Med, Boston, MA USA. RP Gabuzda, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM dana_gabuzda@dfci.harvard.edu FU ARRA, NIH/NIMH [3ROI MH83588-12S1, MH83588]; NIH [1F31NS060611-01]; Harvard Center for AIDS Research; DFCI/Harvard Center for Cancer Research; NIH through the NIMH Institute [U01MH083501, R24MH59724, U01MH083507, R24 NS45491, 5U01MH083500, NS 38841, U01MH083506, R24MH59745, U01MH083545, N01MH32002]; NIH through the NINDS Institute [U01MH083501, R24MH59724, U01MH083507, R24 NS45491, 5U01MH083500, NS 38841, U01MH083506, R24MH59745, U01MH083545, N01MH32002] FX This work was supported by an ARRA supplement NIH/NIMH #3ROI MH83588-12S1 and the parent grant MH83588. MEM was supported in part by NIH fellowship 1F31NS060611-01. Core facilities were supported by the Harvard Center for AIDS Research and DFCI/Harvard Center for Cancer Research grants. The NNTC was supported by NIH funding through the NIMH and NINDS Institutes by the following grants: Manhattan HIV Brain Bank U01MH083501, R24MH59724 Texas NeuroAIDS Research Center U01MH083507, R24 NS45491 National Neurological AIDS Bank 5U01MH083500, NS 38841 California NeuroAIDS Tissue Network U01MH083506, R24MH59745, Statistics and Data Coordinating Center U01MH083545, N01MH32002. The funders and NNTC had no role in study design, data analysis, or preparation and submission of the publication. NR 34 TC 14 Z9 14 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 43 DI 10.1186/1742-6405-7-43 PG 12 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700043 PM 21156070 ER PT J AU Ivers, LC Chang, YC Jerome, JG Freedberg, KA AF Ivers, Louise C. Chang, Yuchiao Jerome, J. Gregory Freedberg, Kenneth A. TI Food assistance is associated with improved body mass index, food security and attendance at clinic in an HIV program in central Haiti: a prospective observational cohort study SO AIDS RESEARCH AND THERAPY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; INFECTED INDIVIDUALS; INSECURITY; AFRICA; SUPPLEMENTATION; ADHERENCE; NUTRITION; MORTALITY; ADULTS; CARE AB Background: Few data are available to guide programmatic solutions to the overlapping problems of undernutrition and HIV infection. We evaluated the impact of food assistance on patient outcomes in a comprehensive HIV program in central Haiti in a prospective observational cohort study. Methods: Adults with HIV infection were eligible for monthly food rations if they had any one of: tuberculosis, body mass index (BMI) <18.5kg/m(2), CD4 cell count <350/mm(3) (in the prior 3 months) or severe socio-economic conditions. A total of 600 individuals (300 eligible and 300 ineligible for food assistance) were interviewed before rations were distributed, at 6 months and at 12 months. Data collected included demographics, BMI and food insecurity score (range 0 - 20). Results: At 6- and 12-month time-points, 488 and 340 subjects were eligible for analysis. Multivariable analysis demonstrated that at 6 months, food security significantly improved in those who received food assistance versus who did not (-3.55 vs -0.16; P < 0.0001); BMI decreased significantly less in the food assistance group than in the non-food group (-0.20 vs -0.66; P = 0.020). At 12 months, food assistance was associated with improved food security (-3.49 vs -1.89, P = 0.011) and BMI (0.22 vs -0.67, P = 0.036). Food assistance was associated with improved adherence to monthly clinic visits at both 6 (P < 0.001) and 12 months (P = 0.033). Conclusions: Food assistance was associated with improved food security, increased BMI, and improved adherence to clinic visits at 6 and 12 months among people living with HIV in Haiti and should be part of routine care where HIV and food insecurity overlap. C1 [Ivers, Louise C.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Ivers, Louise C.] Partners Hlth, Boston, MA USA. [Ivers, Louise C.; Chang, Yuchiao; Freedberg, Kenneth A.] Harvard Univ, Ctr AIDS Res, Cambridge, MA 02138 USA. [Ivers, Louise C.; Chang, Yuchiao; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Jerome, J. Gregory] Zanmi Lasante, Cange, Haiti. RP Ivers, LC (reprint author), Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. EM livers@pih.org FU National Institute of Allergy and Infectious Disease [K23 AI063998, K24 AI062476]; Harvard Center for AIDS Research [P30 AI060354-02S1]; Johnson and Johnson Foundation FX This work was supported in part by National Institute of Allergy and Infectious Disease (K23 AI063998 to LCI; K24 AI062476 to KAF), by the Harvard Center for AIDS Research (P30 AI060354-02S1) and by the Johnson and Johnson Foundation. NR 34 TC 35 Z9 35 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 33 DI 10.1186/1742-6405-7-33 PG 8 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700033 PM 20796284 ER PT J AU Mayer, KH Skeer, M Mimiaga, MJ AF Mayer, Kenneth H. Skeer, Margie Mimiaga, Matthew J. TI Biomedical Approaches to HIV Prevention SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE Alcohol and other drug use, abuse and dependence; human immunodeficiency virus (HIV); HIV prevention; risk factors; sexual behavior; treatment ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; TENOFOVIR DISOPROXIL FUMARATE; SEXUALLY-TRANSMITTED-DISEASES; HETEROSEXUAL TRANSMISSION; ANTIRETROVIRAL THERAPY; MALE CIRCUMCISION; POSTEXPOSURE PROPHYLAXIS; RISK BEHAVIORS; HOMOSEXUAL-MEN AB People who use and abuse alcohol and other drugs are an important population to target for HIV prevention because they are more likely to engage in sexual behaviors that increase their likelihood of acquiring or transmitting HIV A variety of biomedical approaches to HIV prevention have been evaluated or currently are being studied. These approaches include an anti-HIV vaccine; topical protection treatments; and additional biomedical and barrier approaches, such as controlling sexually transmitted diseases, male circumcision, diaphragm use, and substance abuse treatment. The article also reviews topical versus oral antiretrovirals to prevent HIV transmission, antiretroviral treatment as prevention, and the role of alcohol and other drug use in HIV prevention. C1 [Mayer, Kenneth H.] Miriam Hosp, Div Infect Dis, Providence, RI 02906 USA. [Mayer, Kenneth H.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Mayer, Kenneth H.; Skeer, Margie; Mimiaga, Matthew J.] Fenway Inst, Boston, MA USA. [Skeer, Margie] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA 02138 USA. RP Mayer, KH (reprint author), Miriam Hosp, Div Infect Dis, Providence, RI 02906 USA. NR 75 TC 2 Z9 2 U1 1 U2 2 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2010 VL 33 IS 3 BP 195 EP 202 PG 8 WC Substance Abuse SC Substance Abuse GA 663BO UT WOS:000282858200004 PM 23584061 ER PT J AU Sutherland, ER Camargo, CA Busse, WW Meltzer, EO Ortega, HG Yancey, SW Emmett, AH Stempel, DA AF Sutherland, E. Rand Camargo, Carlos A., Jr. Busse, William W. Meltzer, Eli O. Ortega, Hector G. Yancey, Steven W. Emmett, Amanda H. Stempel, David A. TI Comparative effect of body mass index on response to asthma controller therapy SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Review DE Asthma; body mass index; clinical trial; controller therapy; fluticasone propionate; inhaled corticosteroids; montelukast; obese; overweight ID AIRWAY HYPERRESPONSIVENESS; PERSISTENT ASTHMA; OBESITY; MONTELUKAST; FLUTICASONE; TRIAL; RISK; BECLOMETHASONE; SEVERITY; ADULTS AB Increases in body mass index (BMI) are reported to influence asthma severity and response to treatment. This analysis was designed to explore whether increasing BMI altered the comparative response to treatment with either fluticasone propionate (FP) or montelukast. Two double-blind, randomized, parallel-group trials of 12-weeks duration comparing FP, 88 micrograms, twice daily or montelukast, 10 mg, daily Were evaluated. Subjects with mild-moderate persistent asthma were retrospectively stratified by BMI of <20 kg/m(2) (underweight), 20-24.9 kg/m(2) (normal Weight), 25-29.9 kg/m(2) (overweight), and >= 30 kg/m(2) (obese). Outcomes included mean changes in forced expiratory volume in 1 second (FEV) and morning peak flow, daily albuterol use, and daily symptom scores. There were 1052 subjects evenly distributed between FP and montelukast by baseline parameters, including BMI. FP was statistically superior to montelukast for all BMI categories of normal, overweight, and obese subjects for FEV(1) (p < 0.008), morning peak flow (p < 0.002), albuterol use (p < 0.02), and symptom scores (p < 0.05). FP produced a significantly greater clinical response for normal, overweight, and obese subjects compared with montelukast. Irrespective of BMT, FP appears to be the more effective asthma controller therapy. (Allergy Asthma Proc 31:20-25, 201.0; doi: 10.2500/aap.2010.31.3307) C1 [Ortega, Hector G.; Yancey, Steven W.; Emmett, Amanda H.; Stempel, David A.] GlaxoSmithKline Inc, Med Dev Ctr, Res Triangle Pk, NC 27709 USA. [Sutherland, E. Rand] Natl Jewish Hlth, Dept Med, Denver, CO USA. [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Busse, William W.] Univ Wisconsin, Dept Med, Madison, WI USA. [Meltzer, Eli O.] Allergy & Asthma Med Grp & Res Ctr, San Diego, CA USA. RP Stempel, DA (reprint author), GlaxoSmithKline Inc, Med Dev Ctr, 5 Moore Dr,POB 13398, Res Triangle Pk, NC 27709 USA. EM david.a.stempel@gsk.com FU GlaxoSmithKline FX Meltzer has received grant support from GlaxoSmithKline. S. Yancey,A. Emmett, atid D. Stempel are all employees of GlaxoSmithKline. H. Ortega is an employee and stock holder of GlaxoSmithKline NR 27 TC 22 Z9 22 U1 1 U2 3 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JAN-FEB PY 2010 VL 31 IS 1 BP 20 EP 25 DI 10.2500/aap.2010.31.3307 PG 6 WC Allergy SC Allergy GA 564CG UT WOS:000275188800004 PM 20167142 ER PT J AU Rafi, A Do, LT Katz, R Sheinkopf, LE Simons, CW Klaustermeyer, W AF Rafi, Asif Do, LanAnh T. Katz, Roger Sheinkopf, Lee E. Simons, Caroline Watson Klaustermeyer, William TI Effects of omalizumab in patients with food allergy SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article; Proceedings Paper CT 64th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 14-18, 2008 CL Philadelphia, PA SP Amer Acad Allergy, Asthma & Immunol DE Anti-IgE; asthma; biologic therapeutic; food allergy; IgE; omalizumab; peanut; prospective; treatment ID CHRONIC URTICARIA; ASTHMA AB Omalizumab is a novel therapy approved for treating patients with moderate to severe persistent allergic asthma with a serum IgE ranging from 30 to 700 IU/mL. We examined the efficacy of omalizumab as a treatment for IgE-mediated food allergy. An Institutional Review Board-approved prospective pilot study was performed to assess the efficacy of omalizumab in 22 patients with persistent asthma and concomitant IgE-mediated food allergy. All patients showed skin test positivity to foods and experienced allergic food reactions based on history. Patients were interviewed on unintentional and/or unauthorized exposures to sensitized foods, Thirteen female and nine male patients (range, 4-66 years: old; mean, 38 years) were evaluated in a private practice setting. Mean IgE level was 1120.74 IU/mL. Sensitized allergens included fish, shellfish, peanuts, tree nuts, egg, soybean, and wheat. All 22 (100%) patients maintained significant improvement as shown by a decrease/lack of clinical symptoms on reexposure to sensitized foods. Clinical improvement by the sixth dosage of omalizumab (150-300 mg q. 2-4 weeks) was noted by history and physical examination. Eight patients noted a decrease in their food-induced atopic dermatitis, 13 patients noted a decrease in their food-induced asthma symptoms, 3 patients noted a decrease in their food-induced urticaria, 6 patients noted a decrease in their food-induced rhinosinusitis symptoms, and 9 patients showed efficacy for angioedema and/or anaphylaxis. While treating asthma patients with omalizumab, patients subjectively observed a reduction in their concomitant IgE-mediated food allergy symptoms. (Allergy Asthma Proc 31:76-83, 2010; doi: 10.2500/aap.2010.31.3304) C1 [Rafi, Asif; Simons, Caroline Watson; Klaustermeyer, William] Univ Calif Los Angeles, VA Greater Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Do, LanAnh T.; Katz, Roger; Sheinkopf, Lee E.] Allergy Asthma Care Ctr Inc, Los Angeles, CA USA. RP Rafi, A (reprint author), Univ Calif Los Angeles, VA Greater Angeles Healthcare Syst, 11301 Wilshire Blvd,111R, Los Angeles, CA 90073 USA. EM asifrafi1@yahoo.com NR 13 TC 23 Z9 24 U1 1 U2 4 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JAN-FEB PY 2010 VL 31 IS 1 BP 76 EP 83 DI 10.2500/aap.2010.31.3304 PG 8 WC Allergy SC Allergy GA 564CG UT WOS:000275188800010 PM 20167148 ER PT B AU Ballen, K AF Ballen, Karen BE Lazarus, HM Laughlin, MJ TI Update on Umbilical Cord Blood Transplantation SO ALLOGENEIC STEM CELL TRANSPLANTATION, SECOND EDITION SE Contemporary Hematology LA English DT Article; Book Chapter ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW-TRANSPLANTATION; TREATMENT-RELATED MORTALITY; VERSUS-HOST-DISEASE; UNRELATED DONORS; ADULT PATIENTS; ACUTE-LEUKEMIA; MYOCARDIAL-INFARCTION; PEDIATRIC-PATIENTS; PERIPHERAL-BLOOD C1 Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. RP Ballen, K (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. NR 58 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND BN 978-1-934115-33-6 J9 CONTEMP HEMATOL PY 2010 BP 363 EP 374 DI 10.1007/978-1-59745-478-0_20 D2 10.1007/978-1-59745-478-0 PG 12 WC Hematology; Medicine, General & Internal SC Hematology; General & Internal Medicine GA BNS22 UT WOS:000275376700020 ER PT B AU Cutler, C Ho, VT Antin, JH AF Cutler, Corey Ho, Vincent T. Antin, Joseph H. BE Lazarus, HM Laughlin, MJ TI Acute Graft Versus Host Disease: Prophylaxis SO ALLOGENEIC STEM CELL TRANSPLANTATION, SECOND EDITION SE Contemporary Hematology LA English DT Article; Book Chapter ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; UNRELATED DONOR TRANSPLANTATION; MONOCLONAL-ANTIBODY OKT3; HLA-IDENTICAL SIBLINGS; HUMAN DENDRITIC CELLS; MYCOPHENOLATE-MOFETIL; PERIPHERAL-BLOOD; RANDOMIZED-TRIAL; ACUTE-LEUKEMIA C1 [Cutler, Corey; Ho, Vincent T.; Antin, Joseph H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Cutler, Corey; Ho, Vincent T.; Antin, Joseph H.] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cutler, C (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 75 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND BN 978-1-934115-33-6 J9 CONTEMP HEMATOL PY 2010 BP 565 EP 576 DI 10.1007/978-1-59745-478-0_32 D2 10.1007/978-1-59745-478-0 PG 12 WC Hematology; Medicine, General & Internal SC Hematology; General & Internal Medicine GA BNS22 UT WOS:000275376700032 ER PT J AU Mittelman, M AF Mittelman, Michele TI OUR NATION'S HEALTH DEPENDS ON EXPANDING THE NURSING PROFESSION SO ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE LA English DT Editorial Material C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mittelman, M (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM Michele@innovisionhm.com NR 14 TC 0 Z9 0 U1 0 U2 0 PU INNOVISION COMMUNICATIONS PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1078-6791 J9 ALTERN THER HEALTH M JI Altern. Ther. Health Med. PD JAN-FEB PY 2010 VL 16 IS 1 SI SI BP 12 EP 14 PG 3 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 633GE UT WOS:000280487200002 PM 20085172 ER PT J AU Chao, LL Buckley, ST Kornak, J Schuff, N Madison, C Yaffe, K Miller, BL Kramer, JH Weiner, MW AF Chao, Linda L. Buckley, Shannon T. Kornak, John Schuff, Norbert Madison, Catherine Yaffe, Kristine Miller, Bruce L. Kramer, Joel H. Weiner, Michael W. TI ASL Perfusion MRI Predicts Cognitive Decline and Conversion From MCI to Dementia SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE mild cognitive impairment; dementia; cognitive and functional decline; ASL perfusion MRI; hippocampal volume ID CEREBRAL-BLOOD-FLOW; EARLY ALZHEIMERS-DISEASE; POSITRON-EMISSION-TOMOGRAPHY; EPISODIC MEMORY DEFICIT; CLINICAL DEMENTIA; RECOGNITION MEMORY; FUNCTIONAL STATUS; FDG-PET; IMPAIRMENT; BRAIN AB We compared the predictive value of cerebral perfusion as measured by arterial-spin labeling magnetic resonance imaging (ASL-MRI) with MRI-derived hippocampal volume for determining future cognitive and functional decline and subsequent conversion from mild cognitive impairment to dementia. Forty-eight mild cognitive impairment subjects received structural and ASL-MRI scans at baseline and clinical and neuropsychologic assessments annually. Thirteen subjects became demented during the period of longitudinal observation (2.7 +/- 1.0 y). Cox regression analyses suggest that baseline hippocampal volume [relative risk (RR) = 0.99, P = 0.004], baseline right inferior parietal (RR = 0.64, P = 0.01) and right middle frontal (RR = 0.73, P = 0.01) perfusion were associated with conversion to dementia. Results from linear mixed effects modeling suggest that baseline perfusion from the right precuneus predicted subsequent declines in Clinical Dementia Rating Sum of Boxes (P = 0.002), Functional Activates Questionnaire (P = 0.01), and selective attention (ie, Stroop switching, P = 0.009) whereas baseline perfusion from the right middle frontal cortex predicted subsequent episodic memory decline (ie, total recognition discriminability score from the California Verbal Learning Test, P = 0.03). These results suggest that hypoperfusion as detected by ASL-MRI can predict subsequent clinical, functional, and cognitive decline and may be useful for identifying candidates for future Alzheimer disease treatment trials. C1 [Chao, Linda L.; Buckley, Shannon T.; Schuff, Norbert; Weiner, Michael W.] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Chao, Linda L.; Kornak, John; Schuff, Norbert; Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Chao, Linda L.; Yaffe, Kristine; Weiner, Michael W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Kornak, John; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine; Miller, Bruce L.; Kramer, Joel H.; Weiner, Michael W.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Madison, Catherine] Calif Pacific Med Ctr, Dept Neurol, San Francisco, CA USA. RP Chao, LL (reprint author), 4150 Clement St 114M, San Francisco, CA 94121 USA. EM linda.chao@ucsf.edu FU NIH NIA [NIA R01 AG010897] FX Supported by NIH NIA R01 AG010897. NR 66 TC 67 Z9 69 U1 3 U2 15 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 JAN-MAR PY 2010 VL 24 IS 1 BP 19 EP 27 DI 10.1097/WAD.0b013e3181b4f736 PG 9 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 564FC UT WOS:000275197700003 PM 20220321 ER PT J AU Pihlajamaki, M O'Keefe, K Bertram, L Tanzi, RE Dickerson, BC Blacker, D Albert, MS Sperling, RA AF Pihlajamaki, Maija O'Keefe, Kelly Bertram, Lars Tanzi, Rudolph E. Dickerson, Bradford C. Blacker, Deborah Albert, Marilyn S. Sperling, Reisa A. TI Evidence of Altered Posteromedial Cortical fMRI Activity in Subjects at Risk for Alzheimer Disease SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; apolipoprotein E (APOE); cognitive aging; functional magnetic resonance imaging (fMRI); mild cognitive impairment (MCI); memory ID MILD COGNITIVE IMPAIRMENT; RESTING-STATE NETWORKS; APOLIPOPROTEIN-E; HIPPOCAMPAL ACTIVATION; POSTERIOR CINGULATE; BRAIN ACTIVATION; FUNCTIONAL MRI; DEFAULT-MODE; MEMORY; DEMENTIA AB The posteromedial cortices and other regions of the "default network'' are particularly vulnerable to the pathology of Alzheimer disease (AD). In this study, we performed functional magnetic resonance imaging (fMRI) to investigate whether the presence of apolipoprotein E (APOE) epsilon 4 allele and degree of memory impairment were associated with the dysfunction of these brain regions. Seventy-five elderly subjects ranging from cognitively normal to mild AD, divided into epsilon 4 carriers and noncarriers, underwent fMRI during a memory-encoding task. Across all subjects, posteromedial and ventral anterior cingulate cortices (key components of the default network) as well as right middle and inferior prefrontal regions demonstrated reduced task-induced deactivation in the epsilon 4 carriers relative to noncarriers. Even among cognitively normal subjects, epsilon 4 carriers demonstrated reduced posteromedial deactivation compared with the noncarriers in the same regions which demonstrated failure of deactivation in AD patients. Greater failure of posteromedial deactivation was related to worse memory performance (delayed recall) across all subjects and within the range of cognitively normal subjects. In summary, the posteromedial cortical fMRI response pattern is modulated both by the presence of APOE epsilon 4 and episodic memory capability. Altered fMRI activity of the posteromedial areas of the brain default network may be an early indicator of risk for AD. C1 [Pihlajamaki, Maija] Univ Kuopio, Inst Clin Med, Neurol Unit, FIN-70211 Kuopio, Finland. [Pihlajamaki, Maija; O'Keefe, Kelly; Sperling, Reisa A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol,Memory Disorders Unit, Boston, MA 02115 USA. [Pihlajamaki, Maija; O'Keefe, Kelly; Blacker, Deborah; Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Bertram, Lars; Tanzi, Rudolph E.; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dickerson, Bradford C.; Sperling, Reisa A.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Albert, Marilyn S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Pihlajamaki, M (reprint author), Univ Kuopio, Inst Clin Med, Neurol Unit, POB 1627, FIN-70211 Kuopio, Finland. EM Maija.Pihlajamaki@uku.fi RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X FU Academy of Finland [108188, 214050]; NINDS [K23-NS02189]; NIA [R01 AG027435, PO1-AG04953, P50-AG00513421] FX Supported by Academy of Finland grants # 108188 and # 214050 (M. P.), NINDS K23-NS02189 (R. S.), NIA R01 AG027435 (R. S.), NIA PO1-AG04953 (D.B./M.A./R.S.), and NIA P50-AG00513421 (R. S.). NR 54 TC 31 Z9 32 U1 1 U2 6 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 JAN-MAR PY 2010 VL 24 IS 1 BP 28 EP 36 DI 10.1097/WAD.0b013e3181a785c9 PG 9 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 564FC UT WOS:000275197700004 PM 19571734 ER PT J AU D'Amico, AV Braccioforte, MH Moran, BJ Chen, MH AF D'Amico, Anthony V. Braccioforte, Michelle H. Moran, Brian J. Chen, Ming-Hui TI Luteinizing-hormone Releasing Hormone Therapy and the Risk of Death From Alzheimer Disease SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; hormone therapy; prostate cancer ID PROSTATE-CANCER; COMPETING RISK; DEPOSITION; DEMENTIA AB Purpose: We evaluated the risk of death from Alzheimer disease (AD) in men with prostate cancer undergoing treatment with or without a luteinizing-hormone releasing hormone (LHRH) agonist. Methods: Between 1997 and 2007, 6,647 men were treated with brachytherapy for prostate cancer with (N = 1,700) or without (N = 4,947) LHRH agonist therapy. Competing risks multivariable regression was performed to assess whether the use of a LHRH agonist was associated with the risk of death from AD adjusting for the presence of mild AD and age at presentation and known prostate cancer prognostic factors. Results: After a median follow-up of 4.1 years, 1.2% (81/6,647) of the study cohort died from AD accounting for 16% (81/506) of all observed mortality. There was a significant reduction in the risk of death from AD in men who were treated with a LHRH agonist for a median of 4.0 months as compared with those who were not [adjusted hazard ratio: 0.45 (95% confidence interval, 0.25-0.83); P = 0.01]. Conclusions: LHRH agonist use as compared with no use in men with prostate cancer was associated with a decreased risk of death from AD. C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Braccioforte, Michelle H.; Moran, Brian J.] Prostate Canc Fdn Chicago, Dept Radiat Oncol, Westmont, IL USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02215 USA. EM adamico@partners.org NR 26 TC 13 Z9 14 U1 0 U2 3 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 JAN-MAR PY 2010 VL 24 IS 1 BP 85 EP 89 DI 10.1097/WAD.0b013e31819cb8f4 PG 5 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 564FC UT WOS:000275197700012 PM 20556875 ER PT J AU Dickerson, BC AF Dickerson, Bradford C. TI Advances in quantitative magnetic resonance imaging-based biomarkers for Alzheimer disease SO ALZHEIMERS RESEARCH & THERAPY LA English DT Editorial Material AB A critical goal of Alzheimer disease research is to identify disease biomarkers that can be used in clinical trials to assist in the adjudication of treatment effects. While clinical validation remains a goal for many potential Alzheimer disease biomarkers, the rapid proliferation of markers has sparked comparative efforts as well. New data acquisition methods and sophisticated image-processing algorithms are poised to make a substantial impact on our ability to make precise measurements of the structure and function of regions within the living human brain and their connections and chemical composition. This commentary provides a perspective on a recently published paper and how it illustrates progress and challenges in the field. C1 [Dickerson, Bradford C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Alzheimers Dis Res Ctr, Dept Neurol,Frontotemporal Dementia Unit, Charlestown, MA 02129 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Alzheimers Dis Res Ctr, Frontotemporal Dementia Unit,Dept Psychiat, Charlestown, MA 02129 USA. [Dickerson, Bradford C.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Dickerson, BC (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Alzheimers Dis Res Ctr, Dept Neurol,Frontotemporal Dementia Unit, 149 13th St, Charlestown, MA 02129 USA. EM bradd@nmr.mgh.harvard.edu FU NIA NIH HHS [R01 AG029411] NR 19 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PY 2010 VL 2 IS 4 AR UNSP 21 DI 10.1186/alzrt45 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V25RC UT WOS:000208494100002 PM 20619002 ER PT J AU Sperling, R Johnson, K AF Sperling, Reisa Johnson, Keith TI Pro: Can biomarkers be gold standards in Alzheimer's disease? SO ALZHEIMERS RESEARCH & THERAPY LA English DT Editorial Material AB Recent advances in biomarkers for Alzheimer's disease (AD) now allow the visualization of one of the hallmark pathologies of AD in vivo, and combination biomarker profiles can now approximate the diagnostic accuracy of autopsy in patients with dementia. Biomarkers are already employed in clinical trials in prodromal AD for both subject selection and in monitoring therapeutic response. Ultimately the greatest utility of biomarkers may be in the preclinical stages of AD, to identify and track progression of the disease prior to significant cognitive impairment, at the point when disease-modifying therapies are likely to be most efficacious. C1 [Sperling, Reisa; Johnson, Keith] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Sperling, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Brigham & Womens Hosp, Longwood Ave, Boston, MA 02115 USA. EM rsperling@rics.bwh.harvard.edu NR 15 TC 8 Z9 9 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PY 2010 VL 2 IS 3 AR 17 DI 10.1186/alzrt41 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V25RB UT WOS:000208494000006 PM 20587006 ER PT J AU Tan, ZS Seshadri, S AF Tan, Zaldy S. Seshadri, Sudha TI Inflammation in the Alzheimer's disease cascade: culprit or innocent bystander? SO ALZHEIMERS RESEARCH & THERAPY LA English DT Editorial Material AB The strongest known risk factors for late-onset Alzheimer disease (LOAD) remain a positive family history and the APOE epsilon 4 allele. van Exel and colleagues used these known risk factors to identify high- and low-risk samples of middle-aged persons in whom they compared levels of inflammatory and vascular risk factors. They observed that, compared with controls, middle-aged off spring of families with a parental history of LOAD had higher blood pressures, lower ankle-brachial indices (measure of peripheral atherosclerosis), and increased production of proinflammatory cytokines in lipopolysaccharide-stimulated whole blood samples, associations that were independent of APOE genotype. This study adds to the growing body of evidence linking inflammatory mechanisms to Alzheimer disease risk and, especially when considered in light of the recently described association of genetic variation in the complement receptor 1 (CR1) gene with LOAD, suggests that inflammatory biomarkers (whether causal or incidental) could be measured and perhaps used to risk-stratify middle-aged persons for early preventive and therapeutic interventions. C1 [Tan, Zaldy S.] Brigham & Womens Hosp, Geriatr Res Educ & Clin Ctr, VA Boston Healthcare Syst, Div Aging,Dept Med, Boston, MA 02120 USA. [Tan, Zaldy S.] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Tan, ZS (reprint author), Brigham & Womens Hosp, Geriatr Res Educ & Clin Ctr, VA Boston Healthcare Syst, Div Aging,Dept Med, 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. EM ztan@hms.harvard.edu OI Seshadri, Sudha/0000-0001-6135-2622 NR 23 TC 15 Z9 16 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PY 2010 VL 2 IS 2 AR 6 DI 10.1186/alzrt29 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V25RA UT WOS:000208493900003 PM 20388190 ER PT B AU Fazeli, P Nachtigall, LB AF Fazeli, Pouneh Nachtigall, Lisa B. BE Santoro, NF NealPerry, G TI Hyperprolactinemia and Pituitary Causes of Amenorrhea SO AMENORRHEA: A CASE-BASED, CLINICAL GUIDE SE Contemporary Endocrinology LA English DT Article; Book Chapter ID CARDIAC-VALVE REGURGITATION; PROLACTIN SECRETION; LYMPHOCYTIC HYPOPHYSITIS; TRICUSPID REGURGITATION; DOPAMINE AGONISTS; SHEEHANS-SYNDROME; HEART-DISEASE; BRAIN-TUMORS; HYPOPITUITARISM; GALACTORRHEA C1 [Nachtigall, Lisa B.] Massachusetts Gen Hosp, Neuroendocrine Clin Ctr Unit, Boston, MA 02114 USA. [Fazeli, Pouneh; Nachtigall, Lisa B.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Fazeli, Pouneh] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Nachtigall, LB (reprint author), Massachusetts Gen Hosp, Neuroendocrine Clin Ctr Unit, Boston, MA 02114 USA. EM lnachtigall@partners.org NR 63 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-60327-863-8 J9 CONTEMP ENDOCRINOL S PY 2010 BP 83 EP 100 DI 10.1007/978-1-60327-864-5_6 D2 10.1007/978-1-60327-864-5 PG 18 WC Endocrinology & Metabolism; Obstetrics & Gynecology SC Endocrinology & Metabolism; Obstetrics & Gynecology GA BRH74 UT WOS:000282725300006 ER PT J AU Harkness, JR Sabatine, MS Braunwald, E Morrow, DA Sloan, S Wiviott, SD Giugliano, RP Antman, EM Cannon, CP Scirica, BM AF Harkness, James R. Sabatine, Marc S. Braunwald, Eugene Morrow, David A. Sloan, Sarah Wiviott, Stephen D. Giugliano, Robert P. Antman, Elliott M. Cannon, Christopher P. Scirica, Benjamin M. TI Extent of ST-segment resolution after fibrinolysis adds improved risk stratification to clinical risk score for ST-segment elevation myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID SINGLE ELECTROCARDIOGRAPHIC LEAD; STRONG PREDICTOR; THERAPY; REPERFUSION; THROMBOLYSIS; MORTALITY; TRIAL; RECLASSIFICATION; ANGIOPLASTY; CLOPIDOGREL AB Background The TIMI risk score (TRS) for ST-segment elevation myocardial infarction (STEMI) is a convenient validated clinical risk score for predicting mortality. Although not part of the risk score, ST-segment resolution (STRes) may provide a simple method of risk stratification based on the response to reperfusion. We sought to determine whether STRes provides incremental risk stratification to the TIMI risk score. Methods The Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infraction (CLARITY-TIMI 28) trial randomized STEMI patients receiving fibrinolysis to clopidogrel or placebo. A total of 2,340 patients had electrocardiograms (ECGs) valid to calculate STRes at 90 minutes, which was defined as complete (>70%), partial (30%-70%), or no resolution (30%). TRS was defined as low (0-2), medium (3-4), and high (>= 5). Clinical follow-up was through 30 days. Results were validated in 2,743 patients from the ExTRACT-TIMI 25 study. Results The degree of STRes at 90 minutes after fibrinolysis correlated in a stepwise fashion with death or heart failure (5.1% complete STRes, 8.9% partial STRes, 13.4% no STRes, P < .001). Furthermore, the degree of STRes provided a consistent and significant gradient of risk across all risk score categories (low, medium, or high) and significantly improved the discriminatory ability of TIMI risk score to predict death or heart failure (c-statistic 0.69 for TIMI risk score alone and 0.74 with STRes added to the model, P < .001). With the inclusion of STRes to the TIMI risk score, 913 patients (39%) were reclassified to higher or lower risk groups, and the net reclassification improvement (NRI) was highly significant (P < .001). In the ExTRACT-TIMI 25 trial, addition of the STRes improved also the c-statistic (P = .012) and NRI (P < .001). Conclusions The extent of STRes based on routinely obtained ECGs is an independent predictor of death and heart failure when used together with the TIMI risk score and significantly improves the ability to risk stratify patients after fibrinolysis. (Am Heart J 2010; 159: 55-62.) C1 [Harkness, James R.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Harkness, JR (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. NR 29 TC 4 Z9 4 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 JAN PY 2010 VL 159 IS 1 BP 55 EP 62 DI 10.1016/j.ahj.2009.10.033 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 536NO UT WOS:000273051300008 PM 20102867 ER PT J AU Steinman, MA Schillinger, D AF Steinman, Michael A. Schillinger, Dean TI Drug Detailing in Academic Medical Centers: Regulating for the Right Reasons, with the Right Evidence, at the Right Time SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID PROMOTION; INDUSTRY C1 [Steinman, Michael A.; Schillinger, Dean] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Steinman, Michael A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Schillinger, Dean] San Francisco Gen Hosp, San Francisco, CA USA. RP Steinman, MA (reprint author), 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. EM mike.steinman@ucsf.edu FU NCRR NIH HHS [UL1 RR024131]; NIA NIH HHS [K23 AG030999] NR 11 TC 3 Z9 3 U1 0 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 1 BP 21 EP 23 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 543WX UT WOS:000273611700008 PM 20077331 ER PT J AU Koski, G AF Koski, Greg TI "Rethinking Research Ethics," Again: Casuistry, Phronesis, and the Continuing Challenges of Human Research SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Koski, Greg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Koski, Greg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Koski, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Mongan Inst Hlth Policy, 32 Fruit St, Boston, MA 02114 USA. EM gkoski@partners.org NR 6 TC 0 Z9 0 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 10 BP 37 EP 39 AR PII 927986017 DI 10.1080/15265161.2010.526444 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 664OI UT WOS:000282971200009 PM 20945265 ER PT J AU Scripko, PD Greer, DM AF Scripko, Patricia Diane Greer, David Matthew TI Practical Considerations for Reviving the CPR/DNR Conversation SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID CARDIOPULMONARY-RESUSCITATION; CARE C1 [Scripko, Patricia Diane] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA. [Greer, David Matthew] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Scripko, PD (reprint author), Cleveland Clin, Lerner Coll Med, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM pscripko@gmail.com NR 10 TC 1 Z9 1 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 1 BP 74 EP 75 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 543WX UT WOS:000273611700026 PM 20077349 ER PT J AU Gabayan, GZ Derose, SF Asch, SM Chiu, VY Glenn, SC Mangione, CM Sun, BC AF Gabayan, Gelareh Z. Derose, Stephen F. Asch, Steven M. Chiu, Vicki Y. Glenn, Sungching C. Mangione, Carol M. Sun, Benjamin C. TI Predictors of Short-Term (Seven-Day) Cardiac Outcomes After Emergency Department Visit for Syncope SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RISK STRATIFICATION; PROSPECTIVE VALIDATION; EXTERNAL VALIDATION; RULE; SCORE; PROGNOSIS; ADMISSION AB Syncope is a common reason for emergency department (ED) visits, and patients are often admitted to exclude syncope of cardiovascular origin. Population-based data on patterns and predictors of cardiac outcomes may improve decision-making. Our objective was to identify patterns and predictors of short-term cardiac outcomes in ED patients with syncope. Administrative data from an integrated health system of 11 Southern California EDs were used to identify cardiac outcomes after ED presentation for syncope from January 1, 2002, to December 31, 2005. Syncope and cause of death were identified by codes from the International Classification of Disease, Ninth Revision. Cardiac outcomes included cardiac death and hospitalization or procedure consistent with ischemic heart disease, valvular disease, or arrhythmia. Predictors of cardiac outcomes were identified through multivariate logistic regression. There were 35,330 adult subjects who accounted for 39,943 ED visits for syncope. Risk of cardiac outcome sharply decreased following the 7 days after syncope. A 7-day cardiac outcome occurred in 893 cases (3%). Positive predictors of 7-day cardiac outcomes included age >= 60 years, male gender, congestive heart failure, ischemic heart disease, cardiac arrhythmia, and valvular heart disease. Negative predictors included dementia, pacemaker, coronary revascularization, and cerebrovascular disease. There was an age-dependent relation between 7-day cardiac outcomes and arrhythmia and valvular disease, with younger patients (<60 years of age) having greater risk of an event compared to their same-age counterparts. In conclusion, ED decision-making should focus on risk of cardiac event in the first 7 days after syncope and special attention should be given to younger patients with cardiac co-morbidities. Published by Elsevier Inc. (Am J Cardiol 2010;105:82-86) C1 [Gabayan, Gelareh Z.; Asch, Steven M.; Sun, Benjamin C.] Univ Calif Los Angeles, Dept Med, Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90024 USA. [Derose, Stephen F.; Chiu, Vicki Y.; Glenn, Sungching C.] Kasier Permanente So Calif, Dept Res & Evaluat, Pasadena, CA USA. RP Gabayan, GZ (reprint author), Univ Calif Los Angeles, Dept Med, Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90024 USA. EM Gelareh@gabayan.com RI Max, Mad/E-5238-2010 OI Max, Mad/0000-0001-6966-6829 FU Greater Los Angeles Veteran's Affairs Health Services Research and Development Fellowship, Los Angeles, California; American Geriatrics Society New York [20051687]; New York Dennis Jahnigen Career Development Award; University of California, Los Angeles [AG 01-004]; National Institutes of Aging [K12]; UCLA Older Americans Independence Center, NIH/NIA [P30-AG028748] FX Dr. Gabayan is supported by a Greater Los Angeles Veteran's Affairs Health Services Research and Development Fellowship, Los Angeles, California. This research was also supported by Grant 20051687 to Dr. Sun from the American Geriatrics Society New York, New York Dennis Jahnigen Career Development Award and Grant AG 01-004 to Dr. Sun from the University of California, Los Angeles, National Institutes of Aging K12 Mentored Clinical Scientist Development Program in Geriatrics. Los Angeles, California. Dr. Sun also received support from the UCLA Older Americans Independence Center, NIH/NIA Grant P30-AG028748, and the content does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. NR 18 TC 9 Z9 9 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 JAN 1 PY 2010 VL 105 IS 1 BP 82 EP 86 DI 10.1016/j.amjcard.2009.08.654 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602JU UT WOS:000278136200014 PM 20102895 ER PT J AU Scragg, RK Camargo, CA Simpson, RU AF Scragg, Robert K. Camargo, Carlos A., Jr. Simpson, Robert U. TI Relation of Serum 25-Hydroxyvitamin D to Heart Rate and Cardiac Work (from the National Health and Nutrition Examination Surveys) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID MYOCARDIAL BLOOD-FLOW; VITAMIN-D; CARDIOVASCULAR-DISEASE; DOUBLE PRODUCT; US ADULTS; ALL-CAUSE; PRESSURE; RISK; INFARCTION; MORTALITY AB Vitamin D may protect against cardiovascular disease, but its association with cardiac function is unclear. The aim of this study was to examine the associations of serum 25-hydroxyvitamin D (25[OH]D) with heart rate, systolic blood pressure, and the rate pressure product (RPP). Data analyses were carried out on 27,153 participants aged >= 20 years, with measurements of serum 25(OH)D, heart rate (from radial pulse), and systolic blood pressure, in the National Health and Nutrition, Examination Surveys (NHANES) carried out from 1988 to 1994 and from 2001 to 2006. RPP was calculated as heart rate times systolic blood pressure. Results were adjusted for age, gender, race or ethnicity, body mass index, physical activity, tobacco smoking, co-morbidities, and blood pressure treatment. Compared to participants with 25(OH)D >= 35 ng/ml, the adjusted mean +/- SE heart rate was significantly (p <0.001) higher, by 2.1 +/- 0.6 beats/min, in participants with 25(OH)D <10.0 ng/ml, while mean systolic blood pressure was 1.9 +/- 0.8 mm Hg higher (p <0.05) for participants with 25(OH)D <10.0 ng/ml and 1.7 +/- 0.6 mm Hg higher (p <0.01) for those with 25(OH)D of 10.0 to 14.9 ng/ml. As a consequence, adjusted mean RPP was 408 +/- 110 beats/min . mm Hg higher (p <0.001) for participants with 25(OH)D <10.0 ng/ml and 245 +/- 80 beats/min . mm Hg higher (p <0.01) for participants with 25(OH)D of 10.0 to 14.9 ng/ml, compared to those with 25(OH)D 35 ng/ml. In conclusion, these results show that low serum 25(OH)D levels are associated with increased heart rate, systolic blood pressure, and RPP and suggest that low vitamin D status may increase cardiac work. Vitamin D intervention studies are required to confirm these findings. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:122-128) C1 [Scragg, Robert K.] Univ Auckland, Auckland 1, New Zealand. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Simpson, Robert U.] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Scragg, RK (reprint author), Univ Auckland, Auckland 1, New Zealand. EM r.scragg@auckland.ac.nz OI Scragg, Robert/0000-0003-0013-2620 FU Health Research Council of New Zealand, Auckland, New Zealand; Massachusetts General Hospital Center for D-Receptor Activation Research, Boston, Massachusetts FX Dr. Scragg was supported by Health Research Council of New Zealand, Auckland, New Zealand. Dr. Camargo was supported by the Massachusetts General Hospital Center for D-Receptor Activation Research, Boston, Massachusetts. NR 30 TC 29 Z9 33 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 JAN 1 PY 2010 VL 105 IS 1 BP 122 EP 128 DI 10.1016/j.amjcard.2009.08.661 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602JU UT WOS:000278136200022 PM 20102903 ER PT J AU Aljaroudi, W Hermann, D Hage, F Heo, J Iskandrian, AE AF Aljaroudi, Wael Hermann, Daniel Hage, Fadi Heo, Jaekyeong Iskandrian, Ami E. TI Safety of Regadenoson in Patients with End-Stage Renal Disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ADENOSINE; AGONIST; SPECT AB Regadenoson is a selective A(2A) receptor agonist that was recently approved by the Food and Drug Administration for vasodilator stress myocardial perfusion imaging. Because the drug is cleared by renal excretion, its safety in patients with end-stage renal disease (ESRD) needs to be determined. We studied 277 consecutive patients with ESRD who had undergone regadenoson stress gated single photon emission computed tomography myocardial perfusion imaging and compared their side effect profile and safety outcome to those of 134 patients with normal kidney function. The ESRD group included 164 men (59%) and the control group included 73 men (54%; p = NS). The patients with ESRD were younger than the controls (52 11 years vs 61 +/- 12 years; p <0.001). The myocardial perfusion imaging findings were abnormal in 53 patients (19%) with ESRD and in 24 patients in the control group (18%; p = NS). The left ventricular ejection fraction was 57 +/- 12% in the ESRD group and 64 +/- 12% in the control group (p <0.001). The changes in heart rate and systolic blood pressure (from baseline to peak stress) were 20 +/- 12 beats/min versus 22 +/- 13 beats/min and -11 +/- 24 mm Hg versus 12 +/- 23 mm Hg in the ESRD and control groups, respectively (p = NS for both). Very few patients in either group reported symptoms during the stress test. No medication-related hospitalizations, serious events, or death occurred in either group within 30 days of the study. In conclusion, this is the first study to document the safety of regadenoson in a large number of patients with ESRD. The drug was well tolerated, and the hemodynamic and side effect profiles were similar to those of patients with normal renal function. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010; 105:133-135) C1 [Aljaroudi, Wael; Hage, Fadi; Heo, Jaekyeong; Iskandrian, Ami E.] Univ Alabama, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hermann, Daniel] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Hage, Fadi] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Aljaroudi, W (reprint author), Univ Alabama, Div Cardiovasc Dis, Birmingham, AL 35294 USA. EM waljaroudi@cardmail.dom.uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 14 TC 23 Z9 23 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 JAN 1 PY 2010 VL 105 IS 1 BP 133 EP 135 DI 10.1016/j.amjcard.2009.08.663 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602JU UT WOS:000278136200024 PM 20102905 ER PT J AU Ademi, Z Liew, D Hollingsworth, B Steg, PG Bhatt, DL Reid, CM AF Ademi, Zanfina Liew, Danny Hollingsworth, Bruce Steg, Ph. Gabriel Bhatt, Deepak L. Reid, Christopher M. CA REACH Registry Investigators TI Predictors of Annual Pharmaceutical Costs in Australia for Community-Based Individuals with, or at Risk of, Cardiovascular Disease Analysis of Australian Data from the REACH Registry SO AMERICAN JOURNAL OF CARDIOVASCULAR DRUGS LA English DT Article ID HEALTH-CARE COSTS; SERVICES USE; HYPERTENSION; OBESITY; ATHEROTHROMBOSIS; PREVALENCE; CORONARY; IMPACT; AGE AB Background: Cardiovascular disease (CVD) remains a leading cause of death across the world and poses a significant economic burden. Research regarding per-person use and cost of cardiovascular pharmaceuticals in Australia, as well as potential predictors of pharmaceutical costs in populations using the 'bottom up' costing approach, is limited. Previous studies have adopted 'top down' costing approaches and have been based largely on hypothetical examples and considered only inpatient settings. Objective: To determine the distribution of pharmaceutical costs (from a governmental perspective) related to each cardiovascular risk factor for individuals with, or at high risk of, CVD by analysing data for Australian participants enrolled in the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Methods: 2873 participants were recruited for the REACH Registry through 273 general (primary care) practices in Australia. Included among data collected at baseline was a cardiovascular medicines review. Average weighted costs per person were estimated using Government-reimbursed prices (2007). Annual costs were stratified by sex, age, disease group and other co-morbidities. A multivariate linear regression model was utilized to reveal the predictors of the pharmaceutical costs. Results: The average annual median cost of cardiovascular pharmaceuticals per person was Australian dollars ($A)1310. Use of lipid-lowering agents, non-aspirin (acetylsalicylic acid) antiplatelet agents and thiazolidinediones (glitazones) added significantly to the average annual per-person costs. The multivariate regression model showed that the predictors of annual pharmaceutical costs were dyslipidemia (beta coefficient value [marginal annual cost associated with a condition] $A691; p < 0.001), hypertension ($A346; p < 0.001), vascular disease ($A340; p < 0.001), diabetes mellitus ($A298; p < 0.001), and obesity ($A52; p = 0.03). The same predictors, together with sex, were shown to have an impact on the number of medicines used. Conclusions: Among community-based Australians with, or at risk of, CVD, independent drivers of annual cardiovascular pharmaceutical costs are dyslipidemia (which accounts for half of per-person costs), followed by hypertension, established CVD, and diabetes. Obesity also independently adds to the cost of cardiovascular pharmaceuticals in community-based Australians with, or at risk of, CVD. C1 [Ademi, Zanfina; Reid, Christopher M.] Monash Univ, Ctr Cardiovasc Res & Educ Therapeut, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Liew, Danny] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic, Australia. [Hollingsworth, Bruce] Monash Univ, Ctr Hlth Econ, Melbourne, Vic 3004, Australia. [Steg, Ph. Gabriel] Univ Paris 07, INSERM, U698, Paris, France. [Steg, Ph. Gabriel] AP HP, Paris, France. [Bhatt, Deepak L.] Brigham & Womens Hosp, Integrated Intervent Cardiovasc Program, Boston, MA 02115 USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. RP Ademi, Z (reprint author), Monash Univ, Alfred Hosp, Sch Publ Hlth & Prevent Med, Dept Epidemiol & Prevent Med, Commercial Rd, Melbourne, Vic 3004, Australia. EM Zanfina.Ademi@med.monash.edu.au; Chris.Reid@med.monash.edu.au OI Hollingsworth, Bruce/0000-0002-4314-6523; Liew, Danny/0000-0002-0131-623X FU sanofi-aventis; BMS; Eisai; Ethicon; Heartscape; The Medicines Company FX No sources of funding were used to assist in the preparation of this study. Gabriel Steg has acted as a consultant/advisory board member for Astellas, Bayer, AstraZeneca, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Endotis Pharma, GlaxoSmithKline (GSK), Medtronic, Merck Sharp & Dohme, Nycomed, sanofi-aventis, Servier, and The Medicines Company; has received speaker's bureau honoraria from BI, BMS, GSK, Medtronic, Nycomed, sanofi-aventis, and Servier; and has received grants from sanofi-aventis. Deepak Bhatt has acted as a consultant/advisory board member for Arena, Astellas, AstraZeneca, Bayer, BMS, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Parineenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, Scios, Takeda, The Medicines Company, TNS Healthcare, and Vertex; has received honoraria from AstraZeneca, BMS, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Millennium, Paringenix, PDL, sanofi-aventis, Schering Plough, and The Medicines Company; and has received research grants from BMS, Eisai, Ethicon, Heartscape, sanofi-aventis, and The Medicines Company. The other authors have no conflicts of interest that are directly relevant to the content of this study. NR 39 TC 7 Z9 7 U1 0 U2 8 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 1175-3277 J9 AM J CARDIOVASC DRUG JI Am. J. Cardiovasc. Drugs PY 2010 VL 10 IS 2 BP 85 EP 94 PG 10 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 584MS UT WOS:000276756800002 PM 20334445 ER PT J AU Alora-Palli, MB Perkins, AC Van Cotti, A Kimball, AB AF Alora-Palli, Maria B. Perkins, Alexis C. Van Cotti, Alicia Kimball, Alexandra B. TI Efficacy and Tolerability of a Cosmetically Acceptable Coal Tar Solution in the Treatment of Moderate Plaque Psoriasis A Controlled Comparison with Calcipotriene (Calcipotriol) Cream SO AMERICAN JOURNAL OF CLINICAL DERMATOLOGY LA English DT Article ID QUALITY-OF-LIFE; THERAPY; EXOREX; ADULTS AB Background: Topical coal tar is a well known and effective treatment for psoriasis, but the messiness, staining, odor, and inconvenience associated with its use make patient satisfaction and compliance a challenge. Objective: To determine the efficacy, patient tolerability, and cosmetic acceptability of a new topical liquor carbonis distillate (LCD) 15% solution compared with calcipotriene (calcipotriol) cream in patients with moderate, chronic plaque psoriasis. Study Design: A randomized, single-blind, active-controlled, parallel-group, clinical trial consisting of a 12-week treatment phase and a 6-week post-treatment follow-up phase. Setting: Outpatient dermatology research unit in an academic hospital. Patients: Sixty adults with moderate, chronic plaque psoriasis (3-15% body surface area affected) not receiving other psoriasis therapies. Intervention: Patients were randomized to apply either an LCD 15% solution (Psorent (R)) or a commercially available calcipotriene 0.005% cream (Dovonex (R)) to their psoriasis areas (excluding the head) twice daily at home for 12 weeks. Assessments: A blinded investigator evaluated the patients' psoriasis using a modified Psoriasis Area and Severity Index (PASI) that excluded the head, and a Physician's Global Assessment (PGA) scale at weeks 0 (baseline), 2, 4, 8, and 12 (end of treatment), and 18 (6 weeks after treatment was withdrawn). Patients assessed their psoriasis symptoms and quality of life and completed a cosmetic acceptability survey about their medication. Outcome Measures: The changes in the baseline PASI scores after 12 weeks of treatment were compared between LCD and calcipotriene groups. Additional comparisons were performed for success rates during treatment (PASI 75 and PASI 50), changes in PGA scores, patient-reported psoriasis symptom scores, patients' quality-of-life scores, and recurrence rates during post-treatment follow-up. Results: Both treatment groups showed improvement in psoriasis severity and quality of life. However, the LCD group had greater mean reductions in PASI scores: 58% vs 37% in the calcipotriene group (p <0.05) at week 12. Additionally, the LCD group had more patients (14/27) with absent or minimal psoriasis on the PGA scale than the calcipotriene group (6/28) by the end of treatment (p <0.05). LCD-treated patients also maintained their improvement better than calcipotriene-treated patients through week 18 after treatment was withdrawn for 6 weeks. Both treatments were well tolerated and cosmetically acceptable to patients. Conclusion: The newly formulated LCD solution, applied twice daily at home for 12 weeks, was more effective and as well tolerated and cosmetically acceptable as the calcipotriene cream over 12 weeks of treatment and 6 weeks of follow-up. The LCD solution is a patient-accepted and effective corticosteroid-sparing treatment alternative for psoriasis patients. C1 [Kimball, Alexandra B.] Massachusetts Gen Hosp, Clin Unit Res Trials Skin, Boston, MA 02114 USA. [Perkins, Alexis C.] Univ Massachusetts, Worcester, MA 01605 USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Clin Unit Res Trials Skin, 50 Staniford St,Suite 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org FU NeoStrata Company, Inc FX This study was supported by a grant from NeoStrata Company, Inc. The authors wish to acknowledge Dror Rom, PhD, Prosoft Software, Inc., for his contribution to the statistical analysis. Dr Kimball was a consultant for NeoStrata Company, Inc. at the time of the study. The other authors have no conflicts of interest that are directly relevant to the content of this study. NR 25 TC 5 Z9 6 U1 0 U2 2 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 1175-0561 J9 AM J CLIN DERMATOL JI Am. J. Clin. Dermatol. PY 2010 VL 11 IS 4 BP 275 EP 283 PG 9 WC Dermatology SC Dermatology GA 616PU UT WOS:000279222100005 PM 20513160 ER PT J AU Geyer, JT Ferry, JA Longtine, JA Flotte, TJ Harris, NL Zukerberg, LR AF Geyer, Julia Turbiner Ferry, Judith A. Longtine, Janina A. Flotte, Thomas J. Harris, Nancy L. Zukerberg, Lawrence R. TI Characteristics of Cutaneous Marginal Zone Lymphomas With Marked Plasmacytic Differentiation and a T Cell-Rich Background SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Marginal zone lymphoma; Skin; Plasmacytic differentiation; T-cell predominance; IgH rearrangement ID EPSTEIN-BARR-VIRUS; LARGE B-CELLS; EXTRAMEDULLARY PLASMACYTOMA; EUROPEAN-ORGANIZATION; EORTC CLASSIFICATION; BORRELIA-BURGDORFERI; SKIN; INFECTION; FEATURES; PROLIFERATIONS AB Primary cutaneous marginal zone lymphoma (MZL) is a common B-cell lymphoma of skin and is characterized by an infiltrate of neoplastic marginal zone B cells typically within the marginal zones of reactive lymphoid follicles and the interfollicular region. However, in our experience, many cases have underemphasized features such as marked plasmacytic differentiation and/or a prominent T-cell component, which may obscure the neoplastic B cells and lead to misdiagnosis We wanted to draw attention to these features and have studied 15 cases of MZL with marked plasmacytic differentiation, 10 of which had numerous T cells, some with cytologic atypia, and few B cells in the interfollicular region. Plasma cells were monotypic in all cases by in situ hybridization. By polymerase chain reaction, 6 of 8 T cell-rich cases had an IGH gene rearrangement, and none were clonal for T-cell receptor gene We discuss the terminology, morphologic features, molecular profile, behavior, and differential diagnosis of cutaneous MZL. C1 [Geyer, Julia Turbiner; Ferry, Judith A.; Flotte, Thomas J.; Harris, Nancy L.; Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Longtine, Janina A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Zukerberg, LR (reprint author), Massachusetts Gen Hosp, Pathol Dept Warren 2, 55 Fruit St, Boston, MA 02114 USA. NR 37 TC 14 Z9 14 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2010 VL 133 IS 1 BP 59 EP 69 DI 10.1309/AJCPW64FFBTTPKFN PG 11 WC Pathology SC Pathology GA 534RC UT WOS:000272914000007 PM 20023259 ER PT J AU Chang, G Meadows, ME Jones, JA Antin, JH Orav, EJ AF Chang, Grace Meadows, Mary-Ellen Jones, Jennifer A. Antin, Joseph H. Orav, E. John TI Substance Use and Survival after Treatment for Chronic Myelogenous Leukemia (CML) or Myelodysplastic Syndrome (MDS) SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE Cancer; cocaine use disorders; stem cell transplantation; survival ID NATIONAL EPIDEMIOLOGIC SURVEY; STEM-CELL TRANSPLANTATION; CANCER-PATIENTS; UNITED-STATES; PREVALENCE; DIAGNOSIS; ALCOHOL; HEALTH; ABUSE; LIFE AB Background: Patients' substance use problems are a particularly understudied aspect of psychosocial variables in cancer treatment. Objectives: The specific hypothesis tested was that lifetime substance use disorders increased the risk of adverse outcome, in the context of other psychosocial and clinical characteristics demonstrated in other studies to have an impact on treatment outcome. Method: Prospective cohort study of 106 adults with chronic myelogenous leukemia or primary myelodysplastic syndrome. None satisfied criteria for current substance abuse or dependence, but the lifetime rates of substance use disorders in this sample were 28% for alcohol, 12% for cannabis, and 9% for cocaine. Results: Participants received treatment as directed by their physicians, and were followed until death or the end of the study (median 1.5 years). Twenty-eight died. Multivariate survival analysis identified three predictors of outcome: lifetime cocaine use, associated with a six-fold increased risk of death (p = .04), and two protective variables, baseline hemoglobin (p = .002) and estimated intelligence quotient (IQ) (p = .04). Conclusion: The results of this study highlight the potential significance of substance use disorders, and lifetime cocaine diagnoses in particular, on treatment outcome for people with chronic myelogenous leukemia or myelodysplastic syndrome. Whereas neither lifetime alcohol nor cannabis use were associated with survival on either the univariate or multivariate models of survival, lifetime cocaine diagnoses were associated with significant six-fold increased risk of death (p = .04). C1 [Chang, Grace; Jones, Jennifer A.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Chang, Grace; Meadows, Mary-Ellen] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Meadows, Mary-Ellen] Brigham & Womens Hosp, Dept Neurol, Div Cognit & Behav Neurol, Boston, MA 02115 USA. [Antin, Joseph H.; Orav, E. John] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Antin, Joseph H.] Brigham & Womens Hosp, Div Hematol Malignancies, Dept Adult Oncol, Boston, MA 02115 USA. [Orav, E. John] Brigham & Womens Hosp, Dept Gen Med & Primary Care, Boston, MA 02115 USA. [Antin, Joseph H.] Dana Farber Canc Ctr, Dept Adult Oncol, Div Hematol Malignancies, Boston, MA USA. RP Chang, G (reprint author), Brigham & Womens Hosp, Dept Psychiat, 221 Longwood Ave, Boston, MA 02115 USA. EM gchang@partners.org FU NCI NIH HHS [P01 CA142106, P01 CA142106-06A1]; NIAAA NIH HHS [K24 AA000289, K24 AA00289] NR 29 TC 5 Z9 6 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD JAN PY 2010 VL 36 IS 1 BP 1 EP 6 DI 10.3109/00952990903490758 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 559VB UT WOS:000274855000001 PM 20141389 ER PT J AU Fee, C Metlay, JP Camargo, CA Maselli, JH Gonzales, R AF Fee, Christopher Metlay, Joshua P. Camargo, Carlos A., Jr. Maselli, Judith H. Gonzales, Ralph TI ED antibiotic use for acute respiratory illnesses since pneumonia performance measure inception SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; EMERGENCY-DEPARTMENTS; CORE MEASURES; INFECTIONS AB Objective: The study aimed to determine if emergency department (ED) administered antibiotics for patients discharged home with nonpneumonia acute respiratory tract infections (ARIs) have increased since national pneumonia performance measure implementation, including antibiotic administration within 4 hours of arrival. Methods: Design: Time series analysis. Setting: Six university and 7 Veterans Administration EDs participating in the Improving Antibiotic Use for Acute Care Treatment (IMPAACT) trial (randomized educational intervention to reduce antibiotics for bronchitis). Participants: Randomly selected adult (age > 18 years) ED visits for acute cough, diagnosed with nonpneumonia ARIs, discharged home during winters (November-February) of 2003 to 2007. Main outcome: Time trend in ED-administered antibiotics, adjusted for patient demographics, comorbidities, vital signs, ED length of stay, IMPAACT intervention status, geographic region, Veterans Administration/university setting, and site and provider level clustering. Results: Six thousand four hundred seventy-six met study criteria. Three hundred ninety-four (6.1%) received ED-administered antibiotics. Emergency department administered antibiotics did not increase across the study period among all IMPAACT sites (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.76-1.01) after adjusting for age, congestive heart failure history, temperature higher than 100 F, heart rate more than 100, blood cultures obtained, diagnoses, and ED length of stay. The ED-administered antibiotic rate decreased at IMPAACT intervention (OR, 0.80; 95% CI, 0.69-0.93) but not nonintervention sites (OR, 1.04; 95% CI, 0.91-1.19). Adjusted proportions receiving ED-administered antibiotics were 6.1% (95% CI, 2.7%-13.2%) for 2003 to 2004; 4.8% (95% CI, 2.2%-10.0%) for 2004 to 2005; 4.6% (95% CI, 2.7%-7.8%) for 2005 to 2006; and 4.2% (95% CI, 2.2%-8.0%) for 2006 to 2007. Conclusions: Emergency department administered antibiotics did not increase for patients with acute cough discharged home with nonpneumonia ARIs since pneumonia antibiotic timing performance measure implementation in these academic EDs. (C) 2010 Elsevier Inc. All rights reserved. C1 [Fee, Christopher] UCSF, Med Ctr, Dept Emergency Med, San Francisco, CA 94143 USA. [Metlay, Joshua P.] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Metlay, Joshua P.] VA Med Ctr, Philadelphia, PA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Gonzales, Ralph] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94118 USA. RP Fee, C (reprint author), UCSF, Med Ctr, Dept Emergency Med, Box 0208, San Francisco, CA 94143 USA. EM christopher.fee@ucsfmedctr.org FU Translating Research into Practice initiative; Agency for Healthcare Research and Quality, Rockville, Maryland [1 R01 HS013915]; Health Services Research and Development Office of the Department of Veterans Affairs, Washington, D.C. [AVA-03-239] FX This study was funded by the Translating Research into Practice initiative, jointly sponsored by the Agency for Healthcare Research and Quality, Rockville, Maryland (1 R01 HS013915) and the Health Services Research and Development Office of the Department of Veterans Affairs, Washington, D.C. (AVA-03-239). The funding agencies had no role in the design and conduct of the study; collection management, analysis, and interpretation of the data; or preparation, review, or approval of the article. NR 13 TC 3 Z9 3 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 0735-6757 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JAN PY 2010 VL 28 IS 1 BP 23 EP 31 DI 10.1016/j.ajem.2008.09.023 PG 9 WC Emergency Medicine SC Emergency Medicine GA 609QI UT WOS:000278671800005 PM 20006197 ER PT J AU Ginde, AA Espinola, JA Sullivan, AF Blum, FC Camargo, CA AF Ginde, Adit A. Espinola, Janice A. Sullivan, Ashley F. Blum, Frederick C. Camargo, Carlos A., Jr. TI Use of midlevel providers in US EDs, 1993 to 2005: implications for the workforce SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID EMERGENCY-DEPARTMENT; NURSE-PRACTITIONERS; PHYSICIAN ASSISTANTS; FAST-TRACK; MEDICINE AB Objective: The aim of the study was to evaluate use of physician assistants (PAs) and nurse practitioners (NPs) in US emergency departments (EDs). Methods: We analyzed visits from the 1993 to 2005 National Hospital Ambulatory Medical Care Survey, seen by midlevel provider (MLP), and compared characteristics of MLP visits to those seen by physicians only. Results: From 1993 to 2005, 5.2% (95% CI, 4.6%-5.8%) of US ED visits were seen by PAs and 1.7% (95% CI, 1.5%-2.0%) by NPs. During the study period, PA visits rose from 2.9% to 9.1%, whereas NP visits rose from 1.1% to 3.8% (both P(trend) < .001). Compared to physician only visits, those seen only by MLPs arrived by ambulance less frequently (6.0% vs 15%), had lower urgent acuity (37% vs 59%), and were admitted less often (3.0% vs 13%). Conclusions: Midlevel provider use has increased in US EDs. Their involvement in some urgent visits and those requiring admission suggests that the role of MLPs extends beyond minor presentations. (C) 2010 Elsevier Inc. All rights reserved. C1 [Ginde, Adit A.] Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO 80045 USA. [Espinola, Janice A.; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Blum, Frederick C.] W Virginia Univ, Sch Med, Dept Emergency Med, Morgantown, WV 26506 USA. RP Ginde, AA (reprint author), Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO 80045 USA. EM adit.ginde@ucdenver.edu RI Siry, Bonnie/D-7189-2017 NR 10 TC 11 Z9 11 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 0735-6757 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JAN PY 2010 VL 28 IS 1 BP 90 EP 94 DI 10.1016/j.ajem.2008.09.028 PG 5 WC Emergency Medicine SC Emergency Medicine GA 609QI UT WOS:000278671800017 PM 20006209 ER PT J AU Peralta, CA Adeney, KL Shlipak, MG Jacobs, D Duprez, D Bluemke, D Polak, J Psaty, B Kestenbaum, BR AF Peralta, Carmen A. Adeney, Kathryn L. Shlipak, Michael G. Jacobs, David, Jr. Duprez, Daniel Bluemke, David Polak, Joseph Psaty, Bruce Kestenbaum, Bryan R. TI Structural and Functional Vascular Alterations and Incident Hypertension in Normotensive Adults SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arteries; elasticity; hypertension ID INTIMA-MEDIA THICKNESS; PULSE CONTOUR ANALYSIS; ARTERIAL COMPLIANCE; BLOOD-PRESSURE; INDEPENDENT PREDICTOR; SERUM CREATININE; WAVE VELOCITY; NORMAL VALUES; ATHEROSCLEROSIS; DISEASE AB Vascular abnormalities may exist before clinical hypertension. Using Poisson regression, the authors studied the association of coronary artery calcium (CAC), common carotid intima-media thickness (CIMT), aortic distensibility, and large and small arterial elasticity with incident hypertension among 2,512 normotensive US adults free of cardiovascular disease. Incidence rate ratios for incident hypertension (blood pressure >= 140/90 mm Hg or new antihypertensive medication) were calculated. Increased CAC was associated with incident hypertension in demographics-adjusted models (incidence rate ratio (IRR) = 1.35, 95% confidence interval (CI): 1.04, 1.75; IRR = 1.35, 95% CI: 1.02, 1.78; and IRR = 1.59, 95% CI: 1.12, 2.25 for CAC scores of 30-99, 100-399, and >= 400, respectively) but was attenuated after further adjustment. Increased common CIMT was associated with incident hypertension (IRR = 1.77, 95% CI: 1.28, 2.46 for quintile 4; IRR = 1.80, 95% CI: 1.28, 2.53 for quintile 5). Participants with the lowest, compared with the highest, aortic distensibility had an increased risk of hypertension (IRR = 1.75, 95% CI: 1.10, 2.79), as did those with the lowest large arterial elasticity (IRR = 1.49, 95% CI: 1.11, 1.99). Lower small arterial elasticity was incrementally associated with incident hypertension starting at quintile 2 (IRR = 2.01, 95% CI: 1.39, 2.91; IRR = 2.47, 95% CI: 1.71, 3.57; IRR = 2.73, 95% CI: 1.88, 3.95; and IRR = 2.85, 95% CI: 1.95, 4.16). Structural and functional vascular abnormalities are independent predictors of incident hypertension. These findings are important for understanding the pathogenesis of hypertension. C1 [Peralta, Carmen A.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Peralta, Carmen A.; Shlipak, Michael G.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Adeney, Kathryn L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Jacobs, David, Jr.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Duprez, Daniel] Univ Minnesota, Div Cardiovasc, Sch Med, Minneapolis, MN 55455 USA. [Bluemke, David] NIH, Bethesda, MD 20892 USA. [Polak, Joseph] Tufts Univ, Dept Radiol, Boston, MA 02111 USA. [Psaty, Bruce] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Kestenbaum, Bryan R.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. RP Peralta, CA (reprint author), VA Med Ctr, Gen Internal Med Sect 111A1, 4150 Clement St, San Francisco, CA 94124 USA. EM carmenalicia.peralta@ucsf.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169]; National Center for Research Resources [KL2 RR024130] FX This work was supported by contracts (N01-HC-95159 through N01-HC-95165 and N01-HC-95169) from the National Heart, Lung, and Blood Institute. This work was also funded by the National Center for Research Resources (KL2 RR024130 to C. A. P.). NR 28 TC 48 Z9 51 U1 0 U2 2 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 JAN 1 PY 2010 VL 171 IS 1 BP 63 EP 71 DI 10.1093/aje/kwp319 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 537KT UT WOS:000273112500008 PM 19951938 ER PT J AU Cole, SR Jacobson, LP Tien, PC Kingsley, L Chmiel, JS Anastos, K AF Cole, Stephen R. Jacobson, Lisa P. Tien, Phyllis C. Kingsley, Lawrence Chmiel, Joan S. Anastos, Kathryn TI Using Marginal Structural Measurement-Error Models to Estimate the Long-term Effect of Antiretroviral Therapy on Incident AIDS or Death SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE acquired immunodeficiency syndrome; bias (epidemiology); cohort studies; confounding factors (epidemiology); epidemiologic measurements; HIV; pharmacoepidemiology; selection bias ID HUMAN-IMMUNODEFICIENCY-VIRUS; LOGISTIC-REGRESSION; CLINICAL-COHORT; EPIDEMIOLOGIC RESEARCH; BAYESIAN PERSPECTIVES; SURVIVAL ANALYSIS; CAUSAL INFERENCE; CONTROLLED-TRIAL; VIRAL LOAD; HIV AB To estimate the net effect of imperfectly measured highly active antiretroviral therapy on incident acquired immunodeficiency syndrome or death, the authors combined inverse probability-of-treatment-and-censoring weighted estimation of a marginal structural Cox model with regression-calibration methods. Between 1995 and 2007, 950 human immunodeficiency virus-positive men and women were followed in 2 US cohort studies. During 4,054 person-years, 374 initiated highly active antiretroviral therapy, 211 developed acquired immunodeficiency syndrome or died, and 173 dropped out. Accounting for measured confounders and determinants of dropout, the weighted hazard ratio for acquired immunodeficiency syndrome or death comparing use of highly active antiretroviral therapy in the prior 2 years with no therapy was 0.36 (95% confidence limits: 0.21, 0.61). This association was relatively constant over follow-up (P = 0.19) and stronger than crude or adjusted hazard ratios of 0.75 and 0.95, respectively. Accounting for measurement error in reported exposure using external validation data on 331 men and women provided a hazard ratio of 0.17, with bias shifted from the hazard ratio to the estimate of precision as seen by the 2.5-fold wider confidence limits (95% confidence limits: 0.06, 0.43). Marginal structural measurement-error models can simultaneously account for 3 major sources of bias in epidemiologic research: validated exposure measurement error, measured selection bias, and measured time-fixed and time-varying confounding. C1 [Cole, Stephen R.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Tien, Phyllis C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Tien, Phyllis C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Kingsley, Lawrence] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [Chmiel, Joan S.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Anastos, Kathryn] Montefiore Med Ctr, Bronx, NY 10467 USA. [Anastos, Kathryn] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Cole, SR (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, MacGavran Greenberg Hall,CB 7435, Chapel Hill, NC 27599 USA. EM cole@unc.edu FU National Institutes of Health [R03-AI-071763, R01-AA-017594, P30-AI-50410]; National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources [UL1 RR024131]; MACS [UO1-AI-35042, 5-MO1-RR-00722, UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041] FX Dr. Stephen Cole's work was partially supported by National Institutes of Health grants R03-AI-071763, R01-AA-017594, and P30-AI-50410. The Women's Interagency HIV Study is funded by the National Institute of Allergy and Infectious Diseases (grants UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (grant UO1-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI grant UL1 RR024131). MACS is funded by grants UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041 from the National Institutes of Health. NR 59 TC 11 Z9 11 U1 0 U2 2 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 JAN 1 PY 2010 VL 171 IS 1 BP 113 EP 122 DI 10.1093/aje/kwp329 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 537KT UT WOS:000273112500013 PM 19934191 ER PT J AU Granito, A Yang, WH Muratori, L Lim, MJ Nakajima, A Ferri, S Pappas, G Quarneti, C Bianchi, FB Bloch, DB Muratori, P AF Granito, Alessandro Yang, Wei-Hong Muratori, Luigi Lim, Mark J. Nakajima, Ayako Ferri, Silvia Pappas, Georgios Quarneti, Chiara Bianchi, Francesco B. Bloch, Donald B. Muratori, Paolo TI PML Nuclear Body Component Sp140 Is a Novel Autoantigen in Primary Biliary Cirrhosis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID PROMYELOCYTIC LEUKEMIA PROTEIN; ANTINUCLEAR ANTIBODIES; ANTI-SP100 ANTIBODIES; CLINICAL-SIGNIFICANCE; AUTOIMMUNE HEPATITIS; CELL EPITOPE; RISK-FACTORS; AUTOANTIBODIES; BODIES; DOTS AB OBJECTIVES: Some patients with primary biliary cirrhosis (PBC) have antinuclear antibodies (ANAs). These ANAs include the "multiple nuclear dots" (MND) staining pattern, targeting promyelocytic leukemia protein (PML) nuclear body (NB) components, such as "speckled 100-kD" protein (Sp100) and PML. A new PML NB protein, designated as Sp140, was identified using serum from a PBC patient. The aim of this study was to analyze the immune response against Sp140 protein in PBC patients. METHODS: We studied 135 PBC patients and 157 pathological controls with type 1 autoimmune hepatitis, primary sclerosing cholangitis, and systemic lupus erythematosus. We used indirect immunofluorescence and a neuroblastoma cell line expressing Sp140 for detecting anti-Sp140 antibodies, and a commercially available immunoblot for detecting anti-Sp100 and anti-PML antibodies. RESULTS: Anti-Sp140 antibodies were present in 20 (15%) PBC patients but not in control samples, with a higher frequency in antimitochondrial antibody (AMA)-negative cases (53 vs. 9%, P<0.0001). Anti-Sp140 antibodies were found together with anti-Sp100 antibodies in all but one case (19 of 20, 90%) and with anti-PML antibodies in 12 (60%) cases. Anti-Sp140 positivity was not associated with a specific clinical feature of PBC. CONCLUSIONS: Our study identifies Sp140 as a new, highly specific autoantigen in PBC for the first time. The very frequent coexistence of anti-Sp140, anti-Sp100 and anti-PML antibodies suggests that the NB is a multiantigenic complex in PBC and enhances the diagnostic significance of these reactivities, which are particularly useful in AMA-negative cases. C1 [Granito, Alessandro; Muratori, Luigi; Ferri, Silvia; Pappas, Georgios; Quarneti, Chiara; Bianchi, Francesco B.; Muratori, Paolo] Alma Mater Studiorum Univ Bologna, Dipartimento Med Clin, I-40138 Bologna, Italy. [Yang, Wei-Hong; Bloch, Donald B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Yang, Wei-Hong; Bloch, Donald B.] Massachusetts Gen Hosp, Gen Med Serv, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Lim, Mark J.] AmberGen Inc, Watertown, MA USA. [Nakajima, Ayako] Tokyo Womens Med Coll, Inst Rheumatol, Tokyo 162, Japan. RP Granito, A (reprint author), Alma Mater Studiorum Univ Bologna, Dipartimento Med Clin, S Orsola Malpighi Hosp, Padigli 11,Via Massarenti 9, I-40138 Bologna, Italy. EM alessandro.granito@unibo.it RI Muratori, Luigi/I-3181-2012; OI Granito, Alessandro/0000-0002-0637-739X FU National Institutes of Health [DK-051179] FX The screening of the North-American cohort was supported by a grant from the National Institutes of Health (DK-051179). NR 47 TC 30 Z9 32 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JAN PY 2010 VL 105 IS 1 BP 125 EP 131 DI 10.1038/ajg.2009.596 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 548VG UT WOS:000273996200018 PM 19861957 ER PT J AU Mimiaga, MJ Reisner, SL Goldhammer, H Tetu, AM Belanoff, C Mayer, KH AF Mimiaga, Matthew J. Reisner, Sari L. Goldhammer, Hilary Tetu, Ashley M. Belanoff, Candice Mayer, Kenneth H. TI Sources of Human Immunodeficiency Virus and Sexually Transmitted Disease Information and Responses to Prevention Messages Among Massachusetts Men Who Have Sex With Men SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE Human Immunodeficency Virus; Sexually Transmitted Disease; Prevention; Men Who Have Sex With Men; Media Messages; Respondent-Driven Sampling; Prevention Research ID ACTIVE ANTIRETROVIRAL THERAPY; SOCIAL MARKETING CAMPAIGN; HIV-INFECTION; RISK BEHAVIORS; HIDDEN POPULATIONS; HOMOSEXUAL-MEN; YOUNG MEN; DRUG-USE; HIV/AIDS; GAY AB Purpose. Sexually transmitted disease (STD) rates have continued to increase among men who have sex with men (MSM). The present study used qualitative methods to assess sources of human immunodeficiency virus (HIV)/STD information and responses to HIV/STD prevention messages among MSM. This was done to understand how to design more effective media campaigns on HIV/STD prevention and testing for this population. Design. One-on-one semistructured, qualitative interviews and a brief demographic written survey were conducted. Setting. A Massachusetts community-based organisation specializing in HIV/AIDS healthcare. Participants. A novel, modified, respondent-driven sampling method was used to recruit a diverse sample of 50 Massachusetts MSM between January and April 2005; qualitative interviews were conducted until redundancy in responses was achieved. Method. Qualitative data were analyzed using content analysis. NVIVO software was used to organize transcripts, identify themes, and report frequency of responses. Results. Respondents reported having derived information on sexual health from multiple media sources. Direct outreach, gay- and HIV-centered organizations, print and broadcast media, public transportation ads, and the Internet held the greatest potential for dissemination. Primary care providers were also frequently seen as trusted sources of HIV/STD prevention information. Ideas for content often included having "people just like you" in ads. Conclusion. Health message that focus on getting tested for HIV and STDs, practicing safe sex, incorporating straightforward and accurate information on prevention may be the most acceptable to MSM. Providers should be proactive in disseminating information about HIV/STD prevention. (Am J Health Promot 2010;24[3]:170-177.) C1 [Mimiaga, Matthew J.; Reisner, Sari L.; Goldhammer, Hilary; Tetu, Ashley M.; Mayer, Kenneth H.] Fenway Community Hlth, Fenway Inst, Boston, MA 02199 USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Tetu, Ashley M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Belanoff, Candice] 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 02199 USA. EM mmimiaga@fenwayhealth.org RI Paparello, Joel/F-7521-2011; OI Belanoff, Candice/0000-0002-2491-7548 NR 50 TC 2 Z9 2 U1 2 U2 3 PU AMER JOURNAL HEALTH PROMOTION INC PI TROY PA PO BOX 1254, TROY, MI 48099-1254 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD JAN-FEB PY 2010 VL 24 IS 3 BP 170 EP 177 DI 10.4278/ajhp.08042841 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 549KE UT WOS:000274046500003 PM 20073382 ER PT J AU Sobota, A Graham, DA Heeney, MM Neufeld, EJ AF Sobota, Amy Graham, Dionne A. Heeney, Matthew M. Neufeld, Ellis J. TI Corticosteroids for acute chest syndrome in children with sickle cell disease: Variation in use and association with length of stay and readmission SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID UNITED-STATES; INPATIENT MANAGEMENT; ASTHMA; DEXAMETHASONE; TRANSFUSION; DIAGNOSIS; ANEMIA; PAIN; CARE AB Acute chest syndrome (ACS) causes significant morbidity and mortality in sickle cell disease. The role of corticosteroids is unclear. The objectives of our study were to examine the variation between hospitals in their use of corticosteroids for ACS, describe characteristics associated with corticosteroids, and investigate the association between corticosteroids, length of stay, and readmission. We performed a retrospective examination of 5,247 hospitalizations for ACS between January 1, 2004, and June 30, 2008, at 32 hospitals in the Pediatric Health Information System database. We used multivariate regression to examine the variability in the use of corticosteroids adjusting for hospital case mix, identify factors associated with corticosteroid use, and evaluate the association of corticosteroids with length of stay and 3-day readmission rates controlling for propensity score. Corticosteroid use varied greatly by hospital (10-86% among all patients, 18-92% in patients with asthma). Treatment with corticosteroids was associated with comorbid asthma (OR 3.9, 95% CI: 3.2-4.8), inhaled steroids (OR 1.4, 95% CI: 1.1-1.7), bronchodilators (OR 3.2, 95% CI: 2.5-4.2), nitric oxide (OR 2.4, 95% CI: 1.2-5.0), oxygen (OR 2.3, 95% CI: 1.8-2.9), ICU (OR 1.7, 95% CI 1.3-2.3), ventilation (OR 2.0, 95% CI: 1.4-2.8), APR-DRG severity level (OR 1.4, 95% CI: 1.2-1.6), and discharge year (OR 0.86, 95% CI: 0.80-0.92). Corticosteroids were associated with an increased length of stay (25%, 95% CI: 14-38%) and a higher 3-day readmission rate (OR 2.3, 95% CI: 1.6-3.4), adjusted for confounding. Hospitals vary greatly in the use of corticosteroids for ACS, even in patients with asthma. Clear evidence of the efficacy and toxicity of corticosteroid treatment in ACS may reduce variation in care. Am. J. Hematol. 85:24-28, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Sobota, Amy; Heeney, Matthew M.; Neufeld, Ellis J.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Sobota, Amy; Heeney, Matthew M.; Neufeld, Ellis J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sobota, Amy; Graham, Dionne A.; Heeney, Matthew M.; Neufeld, Ellis J.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Graham, Dionne A.] Childrens Hosp, Clin Res Program, Boston, MA 02115 USA. [Sobota, Amy] Harvard Pediat Hlth Serv Res Fellowship, Boston, MA USA. RP Sobota, A (reprint author), 300 Longwood Ave AU-522, Boston, MA 02115 USA. EM amy.sobota@childrens.harvard.edu RI Neufeld, Ellis/F-9331-2011; Heeney, Matthew/J-6838-2015 OI Heeney, Matthew/0000-0002-1104-6843 FU AHRQ (Harvard Pediatric Health Services Research Fellowship) [T32 NRSA: HS000063]; Harvard Blood Scholars Program [K12 HL087164]; NIH [K24 HI-004184] FX Contract grant sponsor: AHRQ (Harvard Pediatric Health Services Research Fellowship); Contract grant number: T32 NRSA: HS000063; Contract grant sponsor: Harvard Blood Scholars Program; Contract grant number: K12 HL087164; Contract grant sponsor: NIH Contract grant number: K24 HI-004184. NR 23 TC 29 Z9 30 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JAN PY 2010 VL 85 IS 1 BP 24 EP 28 DI 10.1002/ajh.21565 PG 5 WC Hematology SC Hematology GA 542NO UT WOS:000273501200006 PM 19957348 ER PT J AU Axon, RN Zhao, YM Egede, LE AF Axon, R. Neal Zhao, Yumin Egede, Leonard E. TI Association of Depressive Symptoms With All-Cause and Ischemic Heart Disease Mortality in Adults With Self-Reported Hypertension SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; depression; epidemiology; hypertension; mortality ID NATIONAL DEATH INDEX; MAJOR DEPRESSION; UNITED-STATES; OLDER-ADULTS; RISK-FACTOR; CARDIOVASCULAR HEALTH; BLOOD-PRESSURE; FOLLOW-UP; PREVALENCE; TRIAL AB BACKGROUND Hypertension (HTN) is a prevalent and important risk factor for both cardiovascular and all-cause mortality. Depression is often present in hypertensive patients and has also been associated with increased mortality risk. The aim of this study was to evaluate the association of depressive symptoms with all-cause mortality and ischemic heart disease (IHD) mortality among adults with self-reported HTN. METHODS We studied 10,025 participants in the National Health and Nutrition Epidemiologic Follow-up Study (NHANES 1) who were alive and interviewed in 1982 and had complete data for the Center for Epidemiologic Studies Depression Scale (CES-D). Four groups were identified based screening status at initial interview: (i) no HTN, no depression (reference group); (ii) HTN, no depression; (iii) no HTN, depression; and (iv) both HTN and depression. Cox proportional hazards regression was used to calculate multivariate-adjusted hazard ratios (HRs) of death for each group. RESULTS Over an average of 8 years (83,943 person-years) of follow-up, patients with both self-reported HTN and depressive symptoms had the highest multivariate-adjusted HR for all-cause mortality at 1.39 (95% confidence interval (CI) 1.14,1.69) as well as for IHD mortality at 1.59 (95% CI 1.08, 2.34). In post hoc analysis, nondepressed hypertensive patients had significantly lower adjusted HR for all-cause mortality compared to depressed hypertensive patients (HR 0.85; 95% CI 0.73-1.00), but the HR for IHD mortality was not significant (HR 0.87,95% CI 0.63-1.20). CONCLUSION Comorbid depressive symptoms are associated with increased all-cause mortality in patients with self-reported HTN. C1 [Axon, R. Neal; Zhao, Yumin; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Axon, R. Neal; Egede, Leonard E.] Ralph Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Axon, RN (reprint author), Med Univ S Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. EM axon@musc.edu FU Department of Veterans Affairs Research Enhancement FX Dr Axon and Dr Egede receive funding support from the Department of Veterans Affairs Research Enhancement Award Program. NR 45 TC 20 Z9 21 U1 1 U2 6 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 JAN PY 2010 VL 23 IS 1 BP 30 EP 37 DI 10.1038/ajh.2009.199 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 533NS UT WOS:000272831400006 PM 19893497 ER PT J AU Maciejewski, ML Bryson, CL Perkins, M Blough, DK Cunningham, FE Fortney, JC Krein, SL Stroupe, KT Sharp, ND Liu, CF AF Maciejewski, Matthew L. Bryson, Chris L. Perkins, Mark Blough, David K. Cunningham, Francesca E. Fortney, John C. Krein, Sarah L. Stroupe, Kevin T. Sharp, Nancy D. Liu, Chuan-Fen TI Increasing Copayments and Adherence to Diabetes, Hypertension, and Hyperlipidemic Medications SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID INCENTIVE-BASED FORMULARIES; OF-VETERANS-AFFAIRS; PRESCRIPTION DRUGS; MANAGED CARE; LONG-TERM; ANTIHYPERTENSIVE MEDICATION; PHARMACY BENEFITS; LONGITUDINAL DATA; RISK ADJUSTMENT; STATIN THERAPY AB Objective: To examine the impact of a medication copayment increase on adherence to diabetes, hypertension, and hyperlipidemic medications. Study Design: Retrospective pre-post observational study. Methods: This study compared medication adherence at 4 Veterans Affairs medical centers between veterans who were exempt from copayments and propensity-matched veterans who were not exempt. The diabetes sample included 1069 exempt veterans and 1069 nonexempt veterans, the hypertension sample included 3545 exempt veterans and 3545 nonexempt veterans, and the sample of veterans taking statins included 2029 exempt veterans and 2029 nonexempt veterans. The main outcome measure was medication adherence 12 months before and 23 months after the copayment increase. Adherence differences were assessed in a difference-in-difference approach by using generalized estimating equations that controlled for time, copayment exemption, an interaction between time and copayment exemption, and patient demographics, site, and other factors. Results: Adherence to all medications increased in the short term for all veterans, but then declined in the longer term (February-December 2003). The change in adherence between the preperiod and the postperiod was significantly different for exempt and nonexempt veterans in all 3 cohorts, and nonadherence increased over time for veterans required to pay copayments. The impact of the copayment increase was particularly adverse for veterans with diabetes who were required to pay copayments. Conclusion: A $5 copayment increase (from $2 to $7) adversely impacted medication adherence for veterans subject to copayments taking oral hypoglycemic agents, antihypertensive medications, or statins. (Am J Manag Care. 2010; 16(1): e20-e34) C1 [Maciejewski, Matthew L.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care 152, Durham, NC 27705 USA. [Maciejewski, Matthew L.] Duke Univ, Div Gen Internal Med, Durham, NC USA. [Bryson, Chris L.; Perkins, Mark; Sharp, Nancy D.; Liu, Chuan-Fen] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Bryson, Chris L.] Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. [Blough, David K.] Univ Washington, Pharmaceut Outcomes Res & Policy Program, Seattle, WA 98195 USA. [Sharp, Nancy D.; Liu, Chuan-Fen] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Cunningham, Francesca E.] Dept Vet Affairs, Pharm Benefits Management Strateg Healthcare Grp, Hines, IL USA. [Cunningham, Francesca E.] Univ Illinois, Dept Pharm Practice, Chicago, IL USA. [Fortney, John C.] Cent Arkansas Vet Healthcare Syst, Ctr Mental Healthcare & Outcomes Res, Little Rock, AR USA. [Fortney, John C.] Univ Arkansas, Dept Psychiat & Behav Sci, Little Rock, AR 72204 USA. [Fortney, John C.] Univ Arkansas, Dept Hlth Policy & Management, Little Rock, AR 72204 USA. [Krein, Sarah L.] VA Ann Arbor Healthcare Syst, Ctr Clin Management Res, Ann Arbor, MI USA. [Krein, Sarah L.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Stroupe, Kevin T.] Hines VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Stroupe, Kevin T.] Northwestern Univ, Inst Healthcare Studies, Evanston, IL USA. RP Maciejewski, ML (reprint author), Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care 152, 508 Fulton St, Durham, NC 27705 USA. EM matthew.maciejewski@va.gov RI Krein, Sarah/E-2742-2014 OI Krein, Sarah/0000-0003-2111-8131 FU Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs [HR 03-200] FX This work was supported by the Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs, project number HR 03-200. The views expressed are those of the authors and do not reflect the views of the Department of Veterans Affairs. NR 56 TC 36 Z9 37 U1 1 U2 5 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD JAN PY 2010 VL 16 IS 1 BP E20 EP E34 PG 15 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 549TQ UT WOS:000274077600011 PM 20059288 ER PT J AU Hopkins, E Lin, AE Krepkovich, KE Axelrad, ME Sol-Church, K Stabley, DL Hossain, J Gripp, KW AF Hopkins, Elizabeth Lin, Angela E. Krepkovich, Katherine E. Axelrad, Marni E. Sol-Church, Katia Stabley, Deborah L. Hossain, Jobayer Gripp, Karen W. TI Living With Costello Syndrome: Quality of Life Issues in Older Individuals SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE multiple congenital anomalies/mental retardation (MCA/MR) syndrome; genetic counseling; qualitative research; Ras/MAPK pathway syndrome ID PHENOTYPE; MUTATIONS; FEATURES AB Clinical and molecular analyses of Costello syndrome are proceeding at a rapid pace, including the delineation of the adult phenotype. We designed a two-part survey in order to describe the quality of life (QoL) of older individuals with Costello syndrome. The survey consisted of the Costello syndrome quality of life (CSQoL): Caregiver Questionnaire, to obtain objective information such as skills, activities, and medical issues from caregivers; and the CSQoL:Self-Questionnaire assessing subjective information including self-esteem, life satisfaction, and interpersonal relations from affected individuals. Thirteen of 18 (72%) individuals with Costello syndrome (age 16-34 years, mean 22 years) and caregiver pairs responded. The data were analyzed to study day-to-day life, and to determine potential impediments on QoL for older individuals with Costello syndrome. The CSQoL:Caregiver total scores were significantly lower than the CSQoL:Self total scores as demonstrated by the Wilcoxon Signed Ranks Test (P < 0.008). The CSQoL:Caregiver total scores appear negatively correlated with total number of medical issues (r = - 0.549; P = 0.065). No association was found between the CSQoL:Self scores and total number of medical issues (r = - 0.107; P = 0. 769). Four impediments to QoL for individuals with Costello syndrome were identified: relationships outside of their immediate circle of family and friends, lack of independence, male gender, and the presence of major medical issues. This information may be useful to the families and health care professionals of adults with Costello syndrome. As a measurable characteristic, QoL may have utility as a metric in future therapeutic trials. (C) 2009 Wiley-Liss, Inc. C1 [Hopkins, Elizabeth; Gripp, Karen W.] Alfred I duPont Hosp Children, Div Med Genet, Nemours Childrens Clin, Wilmington, DE 19803 USA. [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA USA. [Krepkovich, Katherine E.] Boston Univ, Sch Med, Ctr Human Genet, Boston, MA 02118 USA. [Axelrad, Marni E.] Texas Childrens Hosp, Baylor Coll Med, Psychol Serv, Houston, TX 77030 USA. RP Hopkins, E (reprint author), Alfred I duPont Hosp Children, Div Med Genet, Nemours Childrens Clin, 1600 Rockland Rd, Wilmington, DE 19803 USA. EM ehopkins@nemours.org NR 20 TC 4 Z9 4 U1 1 U2 4 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 JAN PY 2010 VL 152A IS 1 BP 84 EP 90 DI 10.1002/ajmg.a.33147 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 544SV UT WOS:000273680500008 PM 20034064 ER PT J AU Fan, JB Ionita-Laza, I McQueen, MB Devlin, B Purcell, S Faraone, SV Allen, MH Bowden, CL Calabrese, JR Fossey, MD Friedman, ES Gyulai, L Hauser, P Ketter, TB Marangell, LB Miklowitz, DJ Nierenberg, AA Patel, JK Sachs, GS Thase, ME Molay, FB Escamilla, MA Nimgaonkar, VL Sklar, P Laird, NM Smoller, JW AF Fan, Jinbo Ionita-Laza, Iuliana McQueen, Matthew B. Devlin, Bernie Purcell, Shaun Faraone, Stephen V. Allen, Michael H. Bowden, Charles L. Calabrese, Joseph R. Fossey, Mark D. Friedman, Edward S. Gyulai, Laszlo Hauser, Peter Ketter, Terence B. Marangell, Lauren B. Miklowitz, David J. Nierenberg, Andrew A. Patel, Jayendra K. Sachs, Gary S. Thase, Michael E. Molay, Francine B. Escamilla, Michael A. Nimgaonkar, Vishwajit L. Sklar, Pamela Laird, Nan M. Smoller, Jordan W. TI Linkage Disequilibrium Mapping of The Chromosome 6q21-22.31 Bipolar I Disorder Susceptibility Locus SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE bipolar disorder; genetic; association; SLC22A16; 6q ID WHOLE-GENOME ASSOCIATION; SEROTONIN TRANSPORTER; NATIONAL-INSTITUTE; GENE POLYMORPHISMS; WIDE ASSOCIATION; CANDIDATE GENES; PEDIGREES; FAMILY; DISEASE; SAMPLE AB We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium. mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder. (C) 2009 Wiley-Liss, Inc. C1 [Fan, Jinbo; Purcell, Shaun; Sklar, Pamela; Smoller, Jordan W.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Boston, MA USA. [Ionita-Laza, Iuliana; Laird, Nan M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [McQueen, Matthew B.] Univ Colorado, Inst Behav Genet, Dept Psychol, Boulder, CO 80309 USA. [Devlin, Bernie; Friedman, Edward S.; Nimgaonkar, Vishwajit L.] Univ Pittsburgh, Sch Med, Dept Psychiat & Human Genet, Pittsburgh, PA USA. [Purcell, Shaun; Sklar, Pamela; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Purcell, Shaun; Nierenberg, Andrew A.; Sachs, Gary S.; Molay, Francine B.; Sklar, Pamela; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY USA. [Allen, Michael H.] Univ Colorado Denver, Dept Psychiat, Denver, CO USA. [Bowden, Charles L.; Escamilla, Michael A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Calabrese, Joseph R.] Case Western Reserve Univ, Dept Psychiat, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Fossey, Mark D.] Univ Oklahoma, Tulsa Med Coll, Dept Psychiat, Tulsa, OK USA. [Fossey, Mark D.] Laureate Psychiat Clin & Hosp, Tulsa, OK USA. [Gyulai, Laszlo; Thase, Michael E.] Univ Penn Hlth Syst, Dept Psychiat, Philadelphia, PA USA. [Hauser, Peter] Portland VA Med Ctr, Portland, OR USA. [Ketter, Terence B.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Marangell, Lauren B.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Miklowitz, David J.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Patel, Jayendra K.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Escamilla, Michael A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cell & Struct Biol, San Antonio, TX 78229 USA. [Marangell, Lauren B.] Baylor Coll Med, Houston, TX 77030 USA. RP Smoller, JW (reprint author), Simches Res Bldg,185 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM jsmoller@hms.harvard.edu RI Allen, Michael/A-8776-2011; OI Faraone, Stephen/0000-0002-9217-3982 FU National Institute of Mental Health [MH063445, MH067288, MH63420]; National Institute of Mental Health (NIMH) [1Z01MH002810-01]; National Institutes of Health [N01MH80001]; A. King Trust; NARSAD; [N01-MH-80001] FX Raymnd DePaulo, Jr., M.D., Dean F. MacKinnon, M.D., Francis M. Mondimore, M.D., James B. Potash, M.D., Peter P. Zandi, Ph.D, Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini M.D.,Ph.D.; University of California at Irvine, CA, R01 MH60068, William Byerley M.D., and Mark Vawter M.D.; University of Iowa, IA, R01 MH059548, William Coryell M.D., and Raymond Crowe M.D.; University of Chicago, IL, R01 MH59535, Elliot Gershon, M.D., Judith Badner Ph.D., Francis McMahon M.D., Chunyu Liu Ph.D., Alan Sanders M.D., Maria Caserta, Steven Dinwiddie M.D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, M.D., Rebecca McKinney, B.A.; Rush University, IL, R01 MH059556, William Scheftner M.D., Howard M. Kravitz, D.O., M.P.H., Diana Marta, B.S., Annette Vaughn-Brown, MSN, RN, and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis 35 J. McMahon, M.D., Layla Kassem, PsyD, Sevilla Detera-Wadleigh, Ph.D, Lisa Austin, Ph.D, Dennis L. Murphy, M.D. NR 36 TC 8 Z9 8 U1 2 U2 3 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 JAN PY 2010 VL 153B IS 1 BP 29 EP 37 DI 10.1002/ajmg.b.30942 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500004 PM 19308960 ER PT J AU Thermenos, HW Goldstein, JM Milanovic, SM Whitfield-Gabrieli, S Makris, N LaViolette, P Koch, JK Faraone, SV Tsuang, MT Buka, SL Seidman, LJ AF Thermenos, Heidi W. Goldstein, Jill M. Milanovic, Snezana M. Whitfield-Gabrieli, Susan Makris, Nikos LaViolette, Peter Koch, Jennifer K. Faraone, Stephen V. Tsuang, Ming T. Buka, Stephen L. Seidman, Larry J. TI An fMRI Study of Working Memory in Persons With Bipolar Disorder or at Genetic Risk for Bipolar Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE bipolar disorder; genetics; functional MRI; working memory; insula; frontopolar cortex ID ANTERIOR PREFRONTAL CORTEX; FUNCTIONAL MRI; I DISORDER; EUTHYMIC PATIENTS; MAJOR DEPRESSION; ACTIVATION; SCHIZOPHRENIA; TWINS; TASK; ABNORMALITIES AB First-degree relatives of persons with bipolar disorders (BDs) carry elevated risk for the illness, and manifest deficits in attention and memory (possible "endophenotypes"). However, there is only one published functional magnetic resonance imaging (fMRI) study of candidate endophenotypes in BD. We used fMRI to examine brain function in BD and in first-degree relatives performing a 2-back working memory (WM) task, and correlated brain activity with mood measures taken at the scanning session. Subjects (age 32-46) were 19 persons with BD, 18 unmedicated, non-psychotic first-degree relatives (RELs) of persons with BD, and 19 matched controls, ascertained from a long-term follow-up of a prenatal cohort study in New England. fMRI signal during 2-back and 0-back WM tasks was measured on a Siemens 1.5T MR scanner. fMRI data were analyzed using SPM-2. Persons with BD and RELs failed to suppress activation in the left anterior insula (BA 13) during WM, whereas controls suppressed activation. Compared to controls, RELs also failed to suppress activation in the orbitofrontal cortex (OFC) and superior parietal cortex. Controls and RELs exhibited greater activation than BD individuals in the left frontopolar cortex (BA 10) during WM. Results remained significant after controlling for confounders except for mild attenuation of OFC findings. Significant correlations between brain activity, mood, and WM suggest that activity in WM circuits is affected by activity in emotion-regulatory circuits. Persons with BD and RELs exhibit altered activity in the frontopolar cortex and insula, which may represent biomarkers of genetic risk for BD. (C) 2009 Wiley-Liss, Inc. C1 [Thermenos, Heidi W.; Milanovic, Snezana M.; Koch, Jennifer K.; Tsuang, Ming T.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Mental Hlth Ctr,Div Publ Psychiat,B, Boston, MA 02115 USA. [Goldstein, Jill M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Goldstein, Jill M.] Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Med, Connors Ctr Womens Hlth & Gender Biol,Div Womens, Boston, MA 02115 USA. [Thermenos, Heidi W.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Athinoula A Martinos Ctr B, Boston, MA 02115 USA. [Goldstein, Jill M.; Milanovic, Snezana M.; Makris, Nikos; LaViolette, Peter; Tsuang, Ming T.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Whitfield-Gabrieli, Susan] MIT, Harvard Mit Div Hlth Sci & Technol, Dept Brain & Cognit Sci, Boston, MA USA. [Makris, Nikos] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Morphometr Anal, Dept Neurol & Radiol Serv,Athinoula A Martinos Ct, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Med Genet Res Program, Dept Psychiat & Behav Sci, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. [Tsuang, Ming T.] Univ Calif San Diego, Ctr Behav Genom, Dept Psychiat, La Jolla, CA 92093 USA. [Buka, Stephen L.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. RP Thermenos, HW (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,2nd Floor,Room 2602E,13th St, Charlestown, MA 02129 USA. EM hthermen@bidmc.harvard.edu RI Buka, Stephen/H-7335-2014; OI Buka, Stephen/0000-0002-8578-9308; Faraone, Stephen/0000-0002-9217-3982 FU National Institute of Mental Health [MH-63951, MH-56956, MH-50647]; The Stanley Medical Research Institute; NARSAD; Clinical Research Training Program in Biological and Social Psychiatry [MH-16259]; Institutional Training Grant, "Training in Psychiatric Genetics," [R25 MH 60485]; Harvard Medical School; Stanley Medical Research Institute; NIMH RO1s [MH-63951, MH-50647, MH 56956, MH-43518]; Poitras Center for Affective Disorders Research; National Center for Research Resources [P41RR14075]; MIND Institute FX Grant sponsor: National Institute of Mental Health; Grant numbers: MH-63951, MH-56956, MH-50647; Grant sponsor: The Stanley Medical Research Institute.; This research was supported by two NARSAD Independent Investigator Awards to L.J.S. including support from Donald and Jean Stone, the Clinical Research Training Program in Biological and Social Psychiatry MH-16259 (H.W.T., Training PI: Stuart T. Hauser, MD, PhD); Institutional Training Grant, "Training in Psychiatric Genetics," R25 MH 60485 (H.W.T., Training PI: Stephen V. Faraone, PhD); Peter B. Livingston Fellowship Fund, Harvard Medical School (H.W.T.); Stanley Medical Research Institute (S.L.B., L.J.S.); NIMH RO1s MH 56956 (J.M.G.); MH-63951 (L.J.S.); MH-43518 (M.T.T., L.J.S.); MH-50647 (M.T.T., J.M.G.); and the Poitras Center for Affective Disorders Research (S.W.G.). This work was also supported in part by the National Center for Research Resources (P41RR14075) and the MIND Institute (L.J.S.). We thank the patients with bipolar disorder, their family members, control subjects, and the following project staff for their generous contributions to the study: Lindsay Barker, Ariel Brown, Jennifer Burbridge, PhD, Lisa Denny, MD, JoAnn Donatelli, PhD, Christine Fetterer, William S. Kremen, PhD, Elizabeth Olson, Anne Peters, Kathleen Rhodes, William S. Stone, PhD, Lynda Tucker, and Tami Wilson. Dr. Thernienos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 55 TC 48 Z9 50 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN PY 2010 VL 153B IS 1 BP 120 EP 131 DI 10.1002/ajmg.b.30964 PG 12 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500014 PM 19418510 ER PT J AU Fukumoto, N Fujii, T Combarros, O Kamboh, MI Tsai, SJ Matsushita, S Nacmias, B Comings, DE Arboleda, H Ingelsson, M Hyman, BT Akatsu, H Grupe, A Nishimura, AL Zatz, M Mattila, KM Rinne, J Goto, Y Asada, T Nakamura, S Kunugi, H AF Fukumoto, Noriko Fujii, Takashi Combarros, Onofre Kamboh, M. Ilyas Tsai, Shin-Jen Matsushita, Sachio Nacmias, Benedetta Comings, David E. Arboleda, Humberto Ingelsson, Martin Hyman, Bradley T. Akatsu, Hiroyasu Grupe, Andrew Nishimura, Agnes Lumi Zatz, Mayana Mattila, Kari M. Rinne, Juha Goto, Yu-ichi Asada, Takashi Nakamura, Shun Kunugi, Hiroshi TI Sexually Dimorphic Effect of the Val66Met Polymorphism of BDNF on Susceptibility to Alzheimer's Disease: New Data and Meta-Analysis SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE Alzheimer's disease (AD); brain-derived neurotrophic factor (BDNF); meta-analysis; polymorphism; sex difference ID NEUROTROPHIC FACTOR GENE; PARKINSONS-DISEASE; GENDER-DIFFERENCES; BRAIN MORPHOLOGY; DECREASED-LEVELS; ASSOCIATION; VARIANTS; SCHIZOPHRENIA; CHINESE; ALLELE AB Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (RDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD. (C) 2009 Wiley-Liss, Inc. C1 [Fujii, Takashi; Kunugi, Hiroshi] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mental Disorder Res, Kodaira, Tokyo 1878502, Japan. [Fukumoto, Noriko; Nakamura, Shun] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Biochem & Cellular Biol, Kodaira, Tokyo 1878502, Japan. [Combarros, Onofre] Univ Hosp Marques de Valdecilla, Neurol Serv, Santander, Spain. [Kamboh, M. Ilyas] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Tsai, Shin-Jen] Taipei Vet Gen Hosp, Dept Psychiat, Taipei, Taiwan. [Matsushita, Sachio] Natl Hosp Org, Kurihama Alcoholism Ctr, Kanagawa, Japan. [Nacmias, Benedetta] Dept Neurol & Psychiat Sci, Florence, Italy. [Comings, David E.] Carlsbad Sci Fdn, City Hope Med Ctr Emeritus, Dept Med Genet, Monrovia, CA USA. [Arboleda, Humberto] Univ Nacl Colombia, Sch Med, Inst Genet, Neurosci Res Grp, Bogota, Colombia. [Ingelsson, Martin] Uppsala Univ, Dept Publ Hlth Mol Geriatr, Uppsala, Sweden. [Hyman, Bradley T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. [Akatsu, Hiroyasu] Fukushimura Hosp, Choju Med Inst, Aichi, Japan. [Grupe, Andrew] CNS Res Celera Diagnost, Alameda, CA USA. [Nishimura, Agnes Lumi; Zatz, Mayana] Univ Sao Paulo, Inst Biosci, Human Genome Res Ctr, Dept Biol, Sao Paulo, Brazil. [Mattila, Kari M.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Mattila, Kari M.] Tampere Univ Hosp, Ctr Lab Med, Tampere, Finland. [Rinne, Juha] Univ Turku, Turku PET Ctr, Turku, Finland. [Goto, Yu-ichi] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mental Retardat & Birth Defect Res, Kodaira, Tokyo 1878502, Japan. [Asada, Takashi] Univ Tsukuba, Inst Clin Med, Dept Psychiat, Tsukuba, Ibaraki 305, Japan. RP Kunugi, H (reprint author), Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mental Disorder Res, Kodaira, Tokyo 1878502, Japan. EM hkunugi@ncnp.go.jp RI Nishimura, Agnes/B-2905-2011; Cetgen, Inct/I-2412-2013; Zatz, Mayana/M-5338-2015; OI Zatz, Mayana/0000-0003-3970-8025; Kunugi, Hiroshi/0000-0002-7209-3790 FU Health and Labor Sciences Research Grants; National Institute of Biomedical Innovation (NIBIO); Japan Society for the Promotion of Science (JSPS) FX Grant sponsor: Health and Labor Sciences Research Grants; Grant sponsor: National Institute of Biomedical Innovation (NIBIO); Grant sponsor: Japan Society for the Promotion of Science (JSPS). NR 52 TC 46 Z9 47 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN PY 2010 VL 153B IS 1 BP 235 EP 242 DI 10.1002/ajmg.b.30986 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500027 PM 19504537 ER PT J AU Hare, E Glahn, DC Dassori, A Raventos, H Nicolini, H Ontiveros, A Medina, R Mendoza, R Jerez, A Munoz, R Almasy, L Escamilla, MA AF Hare, Elizabeth Glahn, David C. Dassori, Albana Raventos, Henriette Nicolini, Humberto Ontiveros, Alfonso Medina, Rolando Mendoza, Rick Jerez, Alvaro Munoz, Rodrigo Almasy, Laura Escamilla, Michael A. TI Heritability of Age of Onset of Psychosis in Schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE schizophrenia; psychosis; heritability; age of onset ID FACTOR A61G POLYMORPHISM; GENOME-WIDE SCAN; GENDER-DIFFERENCES; SCHIZOAFFECTIVE DISORDER; NEUROTROPHIC FACTOR; CHINESE POPULATION; ASCERTAINMENT BIAS; LINKAGE ANALYSIS; SIBLING PAIRS; ANTICIPATION AB Schizophrenia is a genetically complex illness with heterogeneous clinical presentation, including variable age of onset. In this study, the heritability, or proportion of variation in age of onset of psychotic symptoms due to genetic factors, was estimated using a maximum likelihood method. The subjects were 717 members of families with more than one member affected with schizophrenia from Mexican and Central American populations. Age of onset of psychosis was determined by best-estimate consensus diagnosis based on the Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, and each subject's medical records. Mean age of onset was 21.44 years (SD 8.07); 20.55 years for males (SD 6.90), and 22.67 for females (SD 9.34). Variance components were estimated using a polygenic model in the SOLAR software package. The sex of the participant was a significant covariate (P = 0.010) accounting for 0.02 of the total variance in age of onset. The heritability of age of onset of psychosis was 0.33 (SE = 0.09; P = 0.00004). These findings suggest that genetic factors significantly contribute to the age of onset of psychotic symptoms in individuals with schizophrenia and that sex influences this trait as well. (C) 2009 Wiley-Liss, Inc. C1 [Hare, Elizabeth; Dassori, Albana; Medina, Rolando; Escamilla, Michael A.] UT Hlth Sci Ctr, S Texas Psychiat Genet Res Ctr, San Antonio, TX USA. [Glahn, David C.] Yale Univ, Sch Med, Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT USA. [Raventos, Henriette] Univ Costa Rica, Ctr Res Mol Biol, San Jose, Costa Rica. [Nicolini, Humberto] Carracci SC, Med & Family Res Grp, Mexico City, DF, Mexico. [Ontiveros, Alfonso] Inst Informac Invest Salud Mental, Monterrey, Mexico. [Medina, Rolando] S Texas Vet Healthcare Syst, San Antonio, TX USA. [Mendoza, Rick] Univ Calif Los Angeles Harbor, Los Angeles, CA USA. [Jerez, Alvaro] CITACA, Guatemala City, Guatemala. [Munoz, Rodrigo] Family Hlth Ctr San Diego, San Diego, CA USA. [Munoz, Rodrigo; Almasy, Laura] SW Fdn Biomed Res, San Antonio, TX 78284 USA. [Escamilla, Michael A.] Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, S Texas Med Genet Res Grp, Edinburg, TX USA. RP Hare, E (reprint author), 454 Soledad St,Suite 200, San Antonio, TX 78205 USA. EM hare@uthscsa.edu OI Nicolini, Humberto/0000-0003-2494-0067; Raventos, Henriette/0000-0001-9423-8308; Jerez Magana, Alvaro Antonio/0000-0002-1208-3769 NR 55 TC 21 Z9 23 U1 2 U2 3 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 JAN PY 2010 VL 153B IS 1 BP 298 EP 302 DI 10.1002/ajmg.b.30959 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500036 PM 19350535 ER PT J AU Casamassima, F Huang, J Fava, M Sachs, GS Smoller, JW Cassano, GB Lattanzi, L Fagerness, J Stange, JP Perlis, RH AF Casamassima, Francesco Huang, Jie Fava, Maurizio Sachs, Gary S. Smoller, Jordan W. Cassano, Giovanni B. Lattanzi, Lorenzo Fagerness, Jes Stange, Jonathan P. Perlis, Roy H. TI Phenotypic Effects of a Bipolar Liability Gene Among Individuals With Major Depressive Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE CACNA1C; bipolar spectrum; suicidality ID STAR-ASTERISK-D; SEQUENCED TREATMENT ALTERNATIVES; TREATMENT-RESISTANT DEPRESSION; WHOLE-GENOME ASSOCIATION; REPORT QIDS-SR; UNIPOLAR DEPRESSION; SUICIDAL IDEATION; FLUOXETINE TREATMENT; CLINICAL-FEATURES; MOOD SPECTRUM AB Variations in voltage-dependent calcium channel L-type, alpha 1C subunit (CACNA1C) gene have been associated with bipolar disorder in a recent meta-analysis of genome-wide association studies [Ferreira et al., 2008]. The impact of these variations on other psychiatric disorders has not been yet investigated. Caucasian non-Hispanic participants in the STAR(star)D study of treatment for depression for whom DNA was available (N = 1213) were genotyped at two single-nucleotide polymorphisms (SNPs) (rs10848635 and rs1006737) in the CACNA1C gene. We examined putative phenotypic indicators of bipolarity among patients with major depression and elements of longitudinal course suggestive of latent bipolarity. We also considered remission and depression severity following citaloprain treatment. The rs10848635 risk allele was significantly associated with lower levels of baseline agitation (P = 0.03; beta = -0.09). The rs1006737 risk allele was significantly associated with lesser baseline depression severity (P = 0.04; beta = -0.4) and decreased likelihood of insomnia (P = 0.047; beta = -0.22). Both markers were associated with an increased risk of citalopram-emergent suicidality (rs10848635: OR = 1.29, P = 0.04; rs1006737: OR = 1.34, P = 0.02). In this exploratory analysis, treatment-emergent suicidality was associated with two risk alleles in a putative bipolar liability gene. (C) 2009 Wiley-Liss, Inc. C1 [Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Bipolar Clin, Boston, MA 02114 USA. [Casamassima, Francesco; Cassano, Giovanni B.; Lattanzi, Lorenzo] Univ Pisa, Div Psychiat, Pisa, Italy. [Casamassima, Francesco; Fava, Maurizio; Sachs, Gary S.; Stange, Jonathan P.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Huang, Jie; Fava, Maurizio; Sachs, Gary S.; Smoller, Jordan W.; Perlis, Roy H.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Bipolar Clin, 185 Cambridge St, Boston, MA 02114 USA. EM rperlis@partners.org NR 80 TC 29 Z9 31 U1 2 U2 2 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 JAN PY 2010 VL 153B IS 1 BP 303 EP 309 DI 10.1002/ajmg.b.30962 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500037 PM 19388002 ER PT J AU Tsai, HT Caroff, SN Miller, DD McEvoy, J Lieberman, JA North, KE Stroup, TS Sullivan, PF AF Tsai, Huei-Ting Caroff, Stanley N. Miller, Del D. McEvoy, Joseph Lieberman, Jeffrey A. North, Kari E. Stroup, T. Scott Sullivan, Patrick F. TI A Candidate Gene Study of Tardive Dyskinesia in the CATIE Schizophrenia Trial SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE schizophrenia; tardive dyskinesia; antipsychotic medication; adverse drug reaction; genetic; candidate gene association ID RECEPTOR GENE; GENOMEWIDE ASSOCIATION; METAANALYSIS; ANTIPSYCHOTICS; POLYMORPHISMS; METABOLISM; RISK; SET AB Tardive dyskinesia (TD) is a movement disorder characterized by involuntary oro-facial, limb, and truncal movements. As a genetic basis for inter-individual variation is assumed, there have been a sizeable number of candidate gene studies. All subjects met diagnostic criteria for schizophrenia and were randomized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project (CATIE). TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals. Probable TD was defined as meeting Schooler-Kane criteria at any scheduled CATIE visit (207/710 subjects, 29.2%). A total of 128 candidate genes were studied in 710 subjects-2,580 SNPs in 118 candidate genes selected from the literature (e.g., dopamine, serotonin, glutamate, and GABA pathways) and composite genotypes for 10 drug-metabolizing enzymes. No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons. Thus, we found no support for either novel or prior associations from the literature. (C) 2009 Wiley-Liss, Inc. C1 [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Tsai, Huei-Ting; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Tsai, Huei-Ting] NCI, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Caroff, Stanley N.] Univ Penn, Dept Psychiat, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Miller, Del D.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [McEvoy, Joseph] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Lieberman, Jeffrey A.] Columbia Univ, Dept Psychiat, New York, NY USA. [Stroup, T. Scott; Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. RP Sullivan, PF (reprint author), Univ N Carolina, Dept Genet, CB 7264,4109D Neurosci Res Bldg, Chapel Hill, NC 27599 USA. EM pfsulliv@med.unc.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NIMH [N01 MH90001]; [R01s MH074027]; [R01s MH077139]; [R01s MH080403] FX Dr. Sullivan was supported by R01s MH074027, MH077139, and MH080403. The CATIE project was funded by NIMH contract N01 MH90001. We thank Dr. David Goldstein of Duke University for providing genotypes. NR 29 TC 27 Z9 30 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 JAN PY 2010 VL 153B IS 1 BP 336 EP 340 DI 10.1002/ajmg.b.30981 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500043 PM 19475583 ER PT J AU Frayne, SM Miller, DR Sharkansky, EJ Jackson, VW Wang, F Halanych, JH Berlowitz, DR Kader, B Rosen, CS Keane, TM AF Frayne, Susan M. Miller, Donald R. Sharkansky, Erica J. Jackson, Valerie W. Wang, Fei Halanych, Jewell H. Berlowitz, Dan R. Kader, Boris Rosen, Craig S. Keane, Terence M. TI Using Administrative Data to Identify Mental Illness: What Approach Is Best? SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Article DE quality of health care; health services research/methods; algorithms; databases; factual; mental disorders ID VETERANS-AFFAIRS-HOSPITALS; HEALTH-CARE; MEDICAL-RECORD; PSYCHIATRIC DIAGNOSES; DIABETES CARE; SELF-REPORT; DEPRESSION; DISORDERS; OUTPATIENTS; AGREEMENT AB The authors estimated the validity of algorithms for identification of mental health conditions (MHCs) in administrative data for the 133 068 diabetic patients who used Veterans Health Administration (VHA) nationally in 1998 and responded to the 1999 Large Health Survey of Veteran Enrollees. They compared various algorithms for identification of MHCs from International Classification of Diseases, 9th Revision (ICD-9) codes with self-reported depression, posttraumatic stress disorder, or schizophrenia from the survey. Positive predictive value (PPV) and negative predictive value (NPV) for identification of MHC varied by algorithm (0.65-0.86, 0.68-0.77, respectively). PPV was optimized by requiring >= 2 instances of MHC ICD-9 codes or by only accepting codes from mental health visits. NPV was optimized by supplementing VHA data with Medicare data. Findings inform efforts to identify MHC in quality improvement programs that assess health care disparities. When using administrative data in mental health studies, researchers should consider the nature of their research question in choosing algorithms for MHC identification. C1 [Frayne, Susan M.; Jackson, Valerie W.; Rosen, Craig S.] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA 94025 USA. [Frayne, Susan M.] Stanford Univ, Ctr Primary Care & Outcomes Res, Stanford, CA 94305 USA. [Miller, Donald R.; Wang, Fei; Berlowitz, Dan R.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Miller, Donald R.; Wang, Fei; Berlowitz, Dan R.; Kader, Boris] VA Bedford, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Sharkansky, Erica J.; Keane, Terence M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Frayne, Susan M.; Jackson, Valerie W.] Stanford Univ, Div Gen Internal Med, Stanford, CA 94305 USA. [Halanych, Jewell H.] Univ Alabama Birmingham, Birmingham, AL USA. [Keane, Terence M.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Rosen, Craig S.] VA Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA 94025 USA. RP Frayne, SM (reprint author), VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, 795 Willow Rd 152-MPD, Menlo Pk, CA 94025 USA. EM sfrayne@stanford.edu FU Department of Veterans Affairs Health Services Research Development [IIR 20-041, RCD 98-312]; VA Medical Research-Epidemiology FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: This material is based on work supported by the Department of Veterans Affairs Health Services Research & Development, grants IIR 20-041 and RCD 98-312, and by VA Medical Research-Epidemiology. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The funding sources had no role in the study design, data collection, analysis or interpretation, manuscript preparation, or decision to publish the manuscript. NR 47 TC 49 Z9 49 U1 4 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1062-8606 EI 1555-824X J9 AM J MED QUAL JI Am. J. Med. Qual. PD JAN-FEB PY 2010 VL 25 IS 1 BP 42 EP 50 DI 10.1177/1062860609346347 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 538WC UT WOS:000273214000005 PM 19855046 ER PT J AU Mortensen, EM Copeland, LA Pugh, MJ Fine, MJ Nakashima, B Restrepo, MI de Molina, RM Anzueto, A AF Mortensen, Eric M. Copeland, Laurel A. Pugh, Mary Jo Fine, Michael J. Nakashima, Brandy Restrepo, Marcos I. de Molina, Rosa Malo Anzueto, Antonio TI Diagnosis of Pulmonary Malignancy after Hospitalization for Pneumonia SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cancer; Incidence; Pneumonia ID LUNG-CANCER; COMORBIDITY INDEX; VALIDATION; QUALITY; STAGE AB BACKGROUND: Many physicians recommend that patients receive follow-up chest imaging after the diagnosis of pneumonia to ensure that a pulmonary malignancy is not missed. However, there is little research evidence to support this practice. Our aims were to assess the frequency of the diagnosis of Pulmonary malignancy, and to identify risk factors for pulmonary malignancy following hospitalization for pneumonia. METHODS: By excluding patients with a prior diagnosis of pulmonary malignancy, we examined the incidence of a new pulmonary malignancy diagnosis in inpatients aged >= 65 years with a discharge diagnosis of pneumonia in fiscal years 2002-2007, and at least 1 year of Department of Veterans Affairs outpatient care before the index admission. RESULTS: Of 40,744 patients hospitalized with pneumonia, 3760 (9.2%) patients were diagnosed with pulmonary malignancy after their index pneumonia admission. Median time to diagnosis was 297 days, with only 27% diagnosed within 90 days of admission. Factors significantly associated with a new diagnosis of pulmonary malignancy included history of chronic pulmonary disease, any prior malignancy, white race, being married, and tobacco use. Increasing age, Hispanic ethnicity, need for intensive care unit admission, and a history of congestive heart failure, stroke, dementia, or diabetes with complications were associated with a lower incidence of pulmonary malignancy. CONCLUSION: A small, but clinically important, proportion of patients are diagnosed with pulmonary malignancy posthospitalization for pneumonia. Additional research is needed to examine whether previously undiagnosed pulmonary malignancies might be detected at admission, or soon after, for those hospitalized with pneumonia. Published by Elsevier Inc. The American Journal of Medicine (2010) 123, 66-71 C1 [Mortensen, Eric M.; Copeland, Laurel A.; Pugh, Mary Jo; Nakashima, Brandy; Restrepo, Marcos I.; de Molina, Rosa Malo; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, ALMD, VERDICT Res Program, San Antonio, TX 78229 USA. [Mortensen, Eric M.; Copeland, Laurel A.; Pugh, Mary Jo; Nakashima, Brandy; Restrepo, Marcos I.; de Molina, Rosa Malo; Anzueto, Antonio] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. [Mortensen, Eric M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Copeland, Laurel A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Pugh, Mary Jo] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Fine, Michael J.] VA Pittsburg Healthcare Syst, VA Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Fine, Michael J.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15260 USA. [Restrepo, Marcos I.; de Molina, Rosa Malo; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Crit Care Med, San Antonio, TX 78229 USA. RP Mortensen, EM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, ALMD, VERDICT Res Program, 7400 Merton Minter Blvd 11C6, San Antonio, TX 78229 USA. EM mortensene@uthscsa.edu RI Restrepo, Marcos/H-4442-2014; OI Pugh, Mary Jo/0000-0003-4196-7763; Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 FU National Institute of Nursing Research [R01NR010828]; VA Health Services Research and Development program [MRP-05-145]; National Institutes of Health [KL2]; University of Texas Health Science Center at San Antonio FX The project described was supported by Grant Number R01NR010828 from the National Institute of Nursing Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Nursing Research or the National Institutes of Health. This material is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System. Dr Copeland is funded by Merit Review Entry Program grant MRP-05-145 from the VA Health Services Research and Development program. Dr. Restrepo is funded by a KL2 of the National Institutes of Health and the University of Texas Health Science Center at San Antonio. The funding agencies had no role in conducting the study, or role in the preparation, review, or approval of the manuscript. NR 18 TC 21 Z9 21 U1 1 U2 3 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 JAN PY 2010 VL 123 IS 1 BP 66 EP 71 DI 10.1016/j.amjmed.2009.08.009 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 545HC UT WOS:000273722100016 PM 20102994 ER PT J AU Li, M Khan, AM Maderdrut, JL Simon, EE Batuman, V AF Li, Min Khan, Altaf-M. Maderdrut, Jerome L. Simon, Eric E. Batuman, Vecihi TI The Effect of PACAP38 on MyD88-Mediated Signal Transduction in Ischemia-/Hypoxia-Induced Acute Kidney Injury SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Acute kidney injury; Innate immunity; Pituitary adenylate cyclase-activating polypeptide; Proximal tubule cells; Toll-like receptors ID TOLL-LIKE RECEPTORS; ACUTE-RENAL-FAILURE; INNATE IMMUNE-RESPONSE; ISCHEMIA/REPERFUSION INJURY; MACROPHAGES CONTRIBUTE; TUBULAR CELLS; UP-REGULATION; BRAIN-INJURY; PATHWAYS; INFLAMMATION AB Background/Aims: Toll-like receptor 4 (TLR4) and its adaptor protein MyD88 play an important role in ischemia/reperfusion (I/R) injury in the kidney, and pituitary adenylate cyclase-activating polypeptide (PACAP) could ameliorate renal I/R injury. Methods: Primary cultures of proximal tubule epithelial cells (PTEC) were prepared from wild-type and MyD88(-/-) mice, and subjected to hypoxia in vitro. Acute kidney injury (AKI) was induced by I/R in vivo in wild-type mice only. Results: Hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type PTEC, but these responses were markedly blunted in MyD88(-/-) PTEC. Treatment with PACAP38 before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis in both MyD88(+/+) and MyD88(-/-)PTEC cultures. PACAP38 significantly inhibited TLR4/MyD88/TRAF6 as well as TRIF and IRF3 expression in mouse kidney and PTEC, and inhibited the secretion and mRNA expression of cytokines in kidneys from mice after I/R, paralleling the cytokine responses in vitro. Moreover, treatment with PACAP38 protected mice from renal failure, histological damage, neutrophil influx and tubule cell apoptosis after I/R. Conclusion: Our data reveal that the TLR4-mediated cytokine responses to hypoxia are primarily dependent on MyD88 signaling and highlight the pivotal role of MyD88-dependent mechanisms in the coordination of the innate immune responses to ischemic/hypoxic acute renal tubular injury. The renoprotective effect of PACAP in AKI involves both MyD88-dependent and -independent pathways. Copyright (C) 2010 S. Karger AG, Basel C1 [Li, Min; Khan, Altaf-M.; Simon, Eric E.; Batuman, Vecihi] Tulane Univ, Sch Med, Dept Med, Sect Nephrol & Hypertens, New Orleans, LA 70112 USA. [Maderdrut, Jerome L.] Tulane Univ, Sch Med, Dept Med, Peptide Res Lab, New Orleans, LA 70112 USA. [Simon, Eric E.; Batuman, Vecihi] SE Louisiana Vet Hlth Care Syst, US Dept Vet Affairs, New Orleans, LA USA. RP Li, M (reprint author), Tulane Univ, Sch Med, Dept Med, Sect Nephrol & Hypertens, 1430 Tulane Ave,SL-45, New Orleans, LA 70112 USA. EM minlee@tulane.edu OI Batuman, Vecihi/0000-0002-1800-9009 FU Louisiana Board of Regent [013RCEEP-07]; Rudolph Matas Memorial Fund; Dialysis Clinic Inc. FX M.L., J.L.M. and V.B. were supported by the Research Commercialization and Educational Enhancement Program of the Louisiana Board of Regents (013RCEEP-07). V.B. and M.L. were also supported by the Rudolph Matas Memorial Fund and the Dialysis Clinic Inc., and M.L. received additional support from the Arimura Foundation. The authors would like to thank Dr. Eduardo Davila (Louisiana State University Health Sciences Center in New Orleans, La., USA) for providing kidneys from MyD88-/-mice. Data from this research was presented in part at the Annual Meeting of American Society of Nephrology, October 27 to November 1, 2009, in San Diego, Calif., USA. NR 40 TC 11 Z9 12 U1 0 U2 2 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2010 VL 32 IS 6 BP 522 EP 532 DI 10.1159/000321491 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 699OU UT WOS:000285673500002 PM 20980738 ER PT J AU Peralta, CA Risch, N Lin, F Shlipak, MG Reiner, A Ziv, E Tang, H Siscovick, D Bibbins-Domingo, K AF Peralta, Carmen A. Risch, Neil Lin, Feng Shlipak, Michael G. Reiner, Alex Ziv, Elad Tang, Hua Siscovick, David Bibbins-Domingo, Kirsten TI The Association of African Ancestry and Elevated Creatinine in the Coronary Artery Risk Development in Young Adults (CARDIA) Study SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Ancestry; Creatinine; Race; Kidney ID STAGE RENAL-DISEASE; CHRONIC KIDNEY-DISEASE; 9 GENE MYH9; POPULATION-STRUCTURE; RACIAL-DIFFERENCES; SERUM CREATININE; BLOOD-PRESSURE; UNITED-STATES; AMERICANS; ADMIXTURE AB Whether genetic factors account for differences in early kidney disease among blacks in a young healthy population is not well known. We evaluated the association of self-reported race and genetic African ancestry with elevated creatinine (>= 1.3 mg/dl for men, >= 1.1 mg/dl for women) among 3,113 black and white participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 38-50 years. We estimated individual African ancestry using 42 ancestry informative markers. Blacks were more likely to have elevated creatinine than whites, and this effect was more pronounced in men: adjusted odds ratio (AOR) for black versus white men = 7.03, 4.15-11.91; AOR for women = 2.40, 1.15-5.02. Higher African ancestry was independently associated with elevated creatinine among black men (AOR = 1.53,1.08-2.16 per SD increase in African ancestry), but not women. A graded increase in odds of elevated creatinine by African Ancestry was observed among black men compared with white men: AOR = 4.27 (2.26-10.06) for black men with 40-70% African ancestry; AOR = 8.09 (4.19-15.61) for black men with 70-80% African ancestry; AOR = 9.05 (4.81-17.02) for black men with >80% African ancestry. Genetic factors common to African ancestry may be associated with increased risk of early kidney dysfunction in a young, healthy population, particularly among black men. Copyright (C) 2009 S. Karger AG, Basel C1 [Peralta, Carmen A.; Shlipak, Michael G.; Ziv, Elad; Bibbins-Domingo, Kirsten] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Peralta, Carmen A.; Shlipak, Michael G.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Risch, Neil; Lin, Feng; Shlipak, Michael G.; Ziv, Elad; Bibbins-Domingo, Kirsten] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Risch, Neil] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Reiner, Alex; Siscovick, David] Univ Washington, Dept Med, Seattle, WA USA. [Reiner, Alex; Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA USA. [Tang, Hua] Stanford Univ, Palo Alto, CA 94304 USA. [Bibbins-Domingo, Kirsten] San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA 94110 USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco Gen Hosp, Ctr Vulnerable Populat, San Francisco, CA USA. RP Peralta, CA (reprint author), 4150 Clement St,111A1, San Francisco, CA 94121 USA. EM carmenalicia.peralta@ucsf.edu RI Ziv, Elad/L-5396-2014 NR 40 TC 8 Z9 8 U1 1 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2010 VL 31 IS 3 BP 202 EP 208 DI 10.1159/000268955 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 570LE UT WOS:000275678400002 PM 20029176 ER PT J AU Wintermark, M Lev, MH AF Wintermark, M. Lev, M. H. TI FDA Investigates the Safety of Brain Perfusion CT SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Editorial Material ID ACUTE ISCHEMIC-STROKE; TECHNICAL IMPLEMENTATIONS; THEORETIC BASIS; PENUMBRA C1 [Wintermark, M.] Univ Virginia, Neuroradiol Div, Dept Radiol, Charlottesville, VA 22903 USA. [Lev, M. H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Wintermark, M (reprint author), Univ Virginia, Neuroradiol Div, Dept Radiol, Charlottesville, VA 22903 USA. OI Wintermark, Max/0000-0002-6726-3951 NR 18 TC 48 Z9 52 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JAN PY 2010 VL 31 IS 1 BP 2 EP 3 DI 10.3174/ajnr.A1967 PG 2 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 548EY UT WOS:000273943700002 PM 19892810 ER PT J AU Vishwas, MS Chitnis, T Pienaar, R Healy, BC Grant, PE AF Vishwas, M. S. Chitnis, T. Pienaar, R. Healy, B. C. Grant, P. E. TI Tract-Based Analysis of Callosal, Projection, and Association Pathways in Pediatric Patients with Multiple Sclerosis: A Preliminary Study SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID APPEARING WHITE-MATTER; TENSOR IMAGING TRACTOGRAPHY; DIFFUSION-TENSOR; CORPUS-CALLOSUM; IN-VIVO; PYRAMIDAL TRACT; HUMAN BRAIN; DT-MRI; MS; DAMAGE AB BACKGROUND AND PURPOSE: Region-of-interest (ROI) and tract-based diffusion tensor imaging (DTI) analyses have detected increased apparent diffusion coefficients (ADCs) and decreased fractional anisotropy (FA) in callosal and projection systems of adult patients with multiple sclerosis (MS). We explored whether similar changes occur in pediatric patients with MS, assessing 3 major white matter pathways (interhemispheric, projection, and intrahemispheric) in both visibly involved and normal-appearing white matter (NAWM). MATERIALS AND METHODS: DTI datasets from 10 patients with established pediatric MS and 10 age-sex-, and imaging technique-matched controls were analyzed. Tracts were reconstructed by using a fiber assignment by continuous tracking algorithm with a diffusion-weighted imaging mask and a 35 degrees angular threshold. Tracts were selected by using standard ROI placements on color FA maps cross-referenced to b = 0 T2-weighted images for studying white matter pathways. Ten identical ROIs were placed in NAWM on b = 0 T2-weighted images to ensure that both ROIs and resulting tracts passed through NAWM. RESULTS: In pediatric MS, all tracts had higher mean ADC values (P = .002 to P < .04) and lower mean FA(P = .009 to P < .02) than those in healthy controls. Even when the tracts were confined to NAWM, the mean ADC was higher (P < .004 to P < .05) and the mean FA was lower (P = .002 to P < .02). T2 lesion burden correlated with tract-based mean ADC. ROI mean ADC increased, and both tract and 1901 mean FA decreased with increasing T2 lesion burden, however with a statistically nonsignificant correlation. CONCLUSIONS: Increased mean ADC and decreased mean FA occur in all 3 major white matter pathways, both in visibly involved white matter and NAWM in pediatric MS. C1 [Vishwas, M. S.; Pienaar, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Chitnis, T.] Harvard Univ, Sch Med, Partners Pediat Multiple Sclerosis Ctr, Massachusetts Gen Hosp Children, Boston, MA USA. [Healy, B. C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Chitnis, T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Grant, PE (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,13th St,Ste 2301, Charlestown, MA 02129 USA. EM ellen@nmr.mgh.harvard.edu FU Center for Biomedical Imaging; Department of Radiology, Massachusetts General Hospital; National Multiple Sclerosis Society FX We thank Ruopeng Wang and Van J. Wedeen of Athinoula A. Martinos Center for Biomedical Imaging, the Department of Radiology, Massachusetts General Hospital; and the National Multiple Sclerosis Society for funding support (Pediatric MIS Centers of Excellence award to T.C). NR 42 TC 36 Z9 36 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JAN PY 2010 VL 31 IS 1 BP 121 EP 128 DI 10.3174/ajnr.A1776 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 548EY UT WOS:000273943700022 PM 19850763 ER PT J AU Shields, AM LaRue, EM AF Shields, Anne-Marie LaRue, Elizabeth M. TI Transitioning from clinician to clinical research coordinator SO AMERICAN JOURNAL OF NURSING LA English DT Article C1 [Shields, Anne-Marie] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [LaRue, Elizabeth M.] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. RP Shields, AM (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. NR 6 TC 1 Z9 1 U1 0 U2 2 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. PY 2010 SU S BP 26 EP 27 PG 2 WC Nursing SC Nursing GA 549PH UT WOS:000274065600009 ER PT J AU Jakobiec, FA Mehta, M Iwamoto, M Hatton, MP Thakker, M Fay, A AF Jakobiec, Frederick A. Mehta, Manisha Iwamoto, Mami Hatton, Mark P. Thakker, Manoj Fay, Aaron TI Intratarsal Keratinous Cysts of the Meibomian Gland: Distinctive Clinicopathologic and Immunohistochemical Features in 6 Cases SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID VELLUS HAIR CYSTS; STEATOCYSTOMA MULTIPLEX; EPIDERMOID CYST; JUVENILE XANTHOGRANULOMA; CONJUNCTIVAL CYSTS; GARDNERS-SYNDROME; HYBRID CYSTS; CARCINOMA; SIMPLEX; TARSUS AB PURPOSE: To describe 6 patients representing a new entity of Meibomian g and keratinous cysts. DESIGN: Retrospective, interventional, clinicopathologic study. METHODS: Review of clinical histories and findings, histopathologic evaluations, and immunohistochemical studies of the cysts' linings with monoclonal antibodies directed against cytokeratins and cell surface epithelial markers. RESULTS: Six patients with an average age of 62.5 years had noninflamed, upper eyelid nodules fixed to the tarsus. Eyelid eversion revealed a white-yellow nodular bulge in 3 cases, a bluish coloration in 2 cases, and a translucent appearance in 1 case. The cysts were lined by undulating squamous epithelium possessing an inner eosinophilic cuticle that produced a peculiar refractile, strand,like intracavitary keratin. Immunostaining for cytokeratin 17 and carcinoembryonic antigen showed strongly positive results in the Meibomian gland cysts and, by comparison, negative results in cutaneous epidermal cysts. Multiple recurrences occurred after incomplete excisions. CONCLUSIONS: After chalazia and sebaceous cell tumors, Meibomian gland keratinous cysts seem to be the third most common primary intratarsal lesion. Anterior fixation to the tarsus and posterior protrusion beneath the palpebral conjunctiva without inflammation suggest the diagnosis. Histopathologic and immunohistochemical evaluations can distinguish unequivocally the current entity from common epidermal cysts. The optimal treatment consists of an en bloc excision of the cyst with a tarsectomy, or else wide excision with intratarsal cautery of any remnants of the cellular lining. (Am J Ophthalmol 2010, 149:82-94. (c) 2010 by Elsevier Inc. All rights reserved.) C1 [Jakobiec, Frederick A.; Mehta, Manisha] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Mehta, Manisha; Iwamoto, Mami; Hatton, Mark P.; Thakker, Manoj; Fay, Aaron] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Iwamoto, Mami; Hatton, Mark P.] Ophthalm Consultants Boston, Boston, MA USA. [Thakker, Manoj; Fay, Aaron] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 54 TC 19 Z9 19 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JAN PY 2010 VL 149 IS 1 BP 82 EP 94 DI 10.1016/j.ajo.2009.07.033 PG 13 WC Ophthalmology SC Ophthalmology GA 539PY UT WOS:000273270300014 PM 19875094 ER PT J AU Kashino, SS Vallerskog, T Martens, G Troudt, J Keyser, A Taylor, J Izzo, A Kornfeld, H Campos-Neto, A AF Kashino, Suely S. Vallerskog, Therese Martens, Gregory Troudt, JoLynn Keyser, Andrew Taylor, Jenny Izzo, Angelo Kornfeld, Hardy Campos-Neto, Antonio TI Initiation of Acquired Immunity in the Lungs of Mice Lacking Lymph Nodes after Infection with Aerosolized Mycobacterium tuberculosis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID T-CELL RESPONSES; LYMPHOTOXIN-ALPHA; DEFICIENT MICE; TISSUE IBALT; IN-VIVO; EXPRESSION; HOST AB Recent evidence points to lung draining lymph nodes as the site that initiates the immune response in mice infected with aerosolized Mycobacterium tuberculosis. Here we expanded these studies and showed that infection of mice that lack lymph nodes with aerosolized M. tuberculosis results in a massive mononuclear cell infiltrate in the lungs within 14 days postinfection. This infiltration clearly resembles an expansion of the bronchus-associated lymphoid tissue. As expected, no bronchus-associated lymphoid tissue was observed in M. tuberculosis-infected wild-type control mice. Importantly, acquired specific immune response to M. tuberculosis antigens could be detected in lung lymphocytes harvested from mice lacking lymph nodes as early as 14 days postinfection. In addition, the bacterial burden in these mice was indistinguishable from that observed in wild-type C57BL/6 control mice. These results indicate that in the absence of lymph nodes, priming of the immune response occurs in the lung tissues after infection of mice with aerosolized M. tuberculosis and clearly illustrate the enormous plasticity of the immune system to develop resistance to foreign pathogens. (Am J Pathol 2010, 176:198-204; DOI: 10.2353/ajpath.2010.090446) C1 [Kashino, Suely S.; Campos-Neto, Antonio] Forsyth Inst, Boston, MA 02115 USA. [Vallerskog, Therese; Martens, Gregory; Kornfeld, Hardy; Campos-Neto, Antonio] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Troudt, JoLynn; Keyser, Andrew; Taylor, Jenny; Izzo, Angelo] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. RP Campos-Neto, A (reprint author), Forsyth Inst, 140 Fenway, Boston, MA 02115 USA. EM acampos@forsyth.org RI Kashino, Suely/F-4171-2012; McLean, Jennifer/E-9625-2017; Izzo, Angelo/F-1229-2017 OI Izzo, Angelo/0000-0003-3208-2330 FU National Institutes of Health/National Institute of Allergy and Infectious Diseases Tuberculosis Vaccine Testing and Research Materials [HHSN266200400091c]; Diabetes Endocrinology Research Center [DK32520]; National Institutes of Health [R01AI076425, HL081149] FX Experiments performed at Colorado State University were supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases Tuberculosis Vaccine Testing and Research Materials contract (HHSN266200400091c). Experiments performed at University of Massachusetts Medical School core resources were supported by the Diabetes Endocrinology Research Center (DK32520). This work was supported by National Institutes of Health grants R01AI076425 (to A.C.-N.) and HL081149 (to H.K.). NR 25 TC 11 Z9 11 U1 0 U2 1 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 JAN PY 2010 VL 176 IS 1 BP 198 EP 204 DI 10.2353/ajpath.2010.090446 PG 7 WC Pathology SC Pathology GA 550EN UT WOS:000274111200021 PM 20008132 ER PT J AU Sosa, MAG De Gasperi, R Rocher, AB Wang, ACJ Janssen, WGM Flores, T Perez, GM Schmeidler, J Dickstein, DL Hof, PR Elder, GA AF Sosa, Miguel A. Gama De Gasperi, Rita Rocher, Anne B. Wang, Athena Ching-Jung Janssen, William G. M. Flores, Tony Perez, Gissel M. Schmeidler, James Dickstein, Dara L. Hof, Patrick R. Elder, Gregory A. TI Age-Related Vascular Pathology in Transgenic Mice Expressing Presenilin 1-Associated Familial Alzheimer's Disease Mutations SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; BLOOD-VESSELS; MUTANT PRESENILIN-1; NEURONAL EXPRESSION; MOUSE-BRAIN; ADULT MICE; A-BETA; PLAQUES; PROTEIN; GENE AB Mutations in the presenilin 1 (PS1) gene are the most commonly recognized cause of familial Alzheimer's disease (FAD). Besides senile plaques, neurofibrillary tangles, and neuronal loss, Alzheimer's disease (AD) is also accompanied by vascular pathology. Here we describe an age-related vascular pathology in two lines of PS1 FAD-mutant transgenic mice that mimics many features of the vascular pathology seen in AD. The pathology was especially prominent in the microvasculature whose vessels became thinned and irregular with the appearance of many abnormally looped vessels as well as string vessels. Stereologic assessments revealed a reduction of the microvasculature in the hippocampus that was accompanied by hippocampal atrophy. The vascular changes were not congophilic. Yet, despite the lack of congophilia, penetrating vessels at the cortical surface were often abnormal morphologically and microhemorrhages; sometimes occurred. Altered immunostaining of blood vessels with basement membrane-associated antigens was an early feature of the microangiopathy and was associated with thickening of the vascular basal laminae and endothelial cell alterations that were visible ultrastructurally. Interestingly, although the FAD-mutant transgene was expressed in neurons in both lines of mice, there was no detectable expression in vascular endothelial cells or glial cells. These studies thus have implications for the role of neuronal to vascular signaling in the pathogenesis of the vascular pathology associated with AD. (Am J Pathol 2010, 176:353-368; DOI: 10.2353/ajpath.2010.090482) C1 [Elder, Gregory A.] James J Peters VA Med Ctr, Neurol Serv, Bronx, NY 10468 USA. [Sosa, Miguel A. Gama; De Gasperi, Rita; Perez, Gissel M.; Schmeidler, James; Elder, Gregory A.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Rocher, Anne B.; Wang, Athena Ching-Jung; Janssen, William G. M.; Flores, Tony; Dickstein, Dara L.; Hof, Patrick R.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Hof, Patrick R.] Mt Sinai Sch Med, Dept Geriatr & Palliat Care, New York, NY USA. [Elder, Gregory A.] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Dickstein, Dara L.; Hof, Patrick R.] Mt Sinai Sch Med, Computat Neurobiol & Imaging Ctr, New York, NY USA. [Rocher, Anne B.] Boston Univ, Dept Anat & Neurobiol, Boston, MA 02215 USA. RP Elder, GA (reprint author), James J Peters VA Med Ctr, Neurol Serv 3E 16, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM gregory.elder@mssm.edu RI Dickstein, Dara/F-3036-2013 FU National Institute on Aging [AG20139, AG02219, AG05138, AG010491, AG029361]; Alzheimer's Association [IIRG-07-57318]; Department of Veterans Affairs [5I01BX000342-02] FX Supported by the National Institute on Aging (grants AG20139, AG02219, AG05138, AG010491, and AG029361), the Alzheimer's Association (IIRG-07-57318), and a merit award from the Department of Veterans Affairs (5I01BX000342-02). NR 56 TC 29 Z9 29 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JAN PY 2010 VL 176 IS 1 BP 353 EP 368 DI 10.2353/ajpath.2010.090482 PG 16 WC Pathology SC Pathology GA 550EN UT WOS:000274111200035 ER PT J AU Ingmanson, EJ May-Benson, TA Hunnicutt, T Porton, I Weber, MA Pruett, JR Beversdorf, DQ Bauman, ML AF Ingmanson, Ellen J. May-Benson, Teresa A. Hunnicutt, Terri Porton, Ingrid Weber, Martha A. Pruett, John R., Jr. Beversdorf, David Q. Bauman, Margaret L. TI Chimpanzee behavioral anomalies: Possible sensory integration difficulties in a captive individual (Pan troglodytes). SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 79th Annual Meeting of the American-Association-of-Physical-Anthropologists CY APR 14-17, 2010 CL Albuquerque, NM SP Amer Assoc Phys Anthropol C1 [Ingmanson, Ellen J.] Bridgewater State Coll, Dept Anthropol, Bridgewater, MA 02325 USA. [Pruett, John R., Jr.] Washington Univ, Div Child Psychiat, Dept Psychiat, Sch Med, St Louis, MO 63130 USA. [Beversdorf, David Q.] Univ Missouri, Dept Radiol, Columbia, MO 65211 USA. [Beversdorf, David Q.] Univ Missouri, Dept Neurol & Psychol, Columbia, MO 65211 USA. [Beversdorf, David Q.] Univ Missouri, Thompson Ctr, Columbia, MO 65211 USA. [Bauman, Margaret L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RI Beversdorf, David/M-2786-2016 OI Beversdorf, David/0000-0002-0298-0634 NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2010 SU 50 BP 132 EP 133 PG 2 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 565LT UT WOS:000275295200356 ER PT J AU Nakamura, Y Do, JH Yuan, JZ Odinokova, IV Mareninova, O Gukovskaya, AS Pandol, SJ AF Nakamura, Yuji Do, Jae Hyuk Yuan, Jingzhen Odinokova, Irina V. Mareninova, Olga Gukovskaya, Anna S. Pandol, Stephen J. TI Inflammatory cells regulate p53 and caspases in acute pancreatitis SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE pancreatitis; p53; caspases-2; Mdm2; apoptosis ID CERULEIN-INDUCED PANCREATITIS; CYTOCHROME-C RELEASE; INDUCED APOPTOSIS; ACINAR-CELLS; T-CELLS; INHIBITOR; DEATH; ACTIVATION; PROTEIN; COMPLEX AB Nakamura Y, Do JH, Yuan J, Odinokova IV, Mareninova O, Gukovskaya AS, Pandol SJ. Inflammatory cells regulate p53 and caspases in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 298: G92-G100, 2010. First published October 22, 2009; doi:10.1152/ajpgi.00324.2009.-The inflammatory response during pancreatitis regulates necrotic and apoptotic rates of parenchymal cells. Neutrophil depletion by use of anti-polymorphonuclear serum (anti-PMN) increases apoptosis in experimental pancreatitis but the mechanism has not been determined. Our study was designed to investigate signaling mechanisms in pancreatic parenchymal cells regulating death responses with neutrophil depletion. Rats were neutrophil depleted with anti-PMN treatment. Then cerulein pancreatitis was induced, followed by measurements of apoptosis signaling pathways. There was greater activation of executioner caspases-3 in the pancreas with anti-PMN treatment compared with control. There were no differences between these groups of animals in mitochondrial cytochrome c release or in activities of initiator caspase-8 and -9. However, there was greater activation of caspase-2 with anti-PMN treatment during cerulein pancreatitis. The upstream regulation of caspases-2 includes p53, which was increased; the p53 negative regulator, Mdm2, was decreased by anti-PMN treatment during cerulein pancreatitis. In vitro experiments using isolated pancreatic acinar cells a pharmacological inhibitor of Mdm2 increased caspase2/-3 activities, and an inhibitor of p53 decreased these activities during cholecystokinin-8 treatment. Furthermore, experiments using the AR42J cell line Mdm2 small interfering RNA (siRNA) increased caspase-2/-3 activities, and p53 siRNA decreased these activities during cholecystokinin-8 treatment. These results suggest that during acute pancreatitis the inflammatory response inhibits apoptosis. The mechanism of this inhibition involves caspase-2 and its upstream regulation by p53 and Mdm2. Because previous findings indicate that promotion of apoptosis decreases necrosis and severity of pancreatitis, these results suggest that strategies to inhibit Mdm2 or activate p53 will have beneficial effects for treatment of pancreatitis. C1 [Nakamura, Yuji; Do, Jae Hyuk; Yuan, Jingzhen; Odinokova, Irina V.; Mareninova, Olga; Gukovskaya, Anna S.; Pandol, Stephen J.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Nakamura, Yuji; Do, Jae Hyuk; Yuan, Jingzhen; Odinokova, Irina V.; Mareninova, Olga; Gukovskaya, Anna S.; Pandol, Stephen J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Nakamura, Yuji] Keio Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, Tokyo, Japan. [Do, Jae Hyuk] Chung Ang Univ, Sch Med, Dept Internal Med, Div Gastroenterol, Seoul 156756, South Korea. [Odinokova, Irina V.] Russian Acad Sci, Inst Theoret & Expt Biophys, Pushchino 142292, Moscow Region, Russia. RP Pandol, SJ (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 258,Rm 340, Los Angeles, CA 90073 USA. EM stephen.pandol@med.va.gov FU National Institutes of Health (NIH) [5P01AT003960, 2P50AA011999] FX This study was supported by the Department of Veterans Affairs, UCLA Center for Excellence in Pancreatic Diseases [National Institutes of Health (NIH) Grant no. 5P01AT003960], and Southern California Research Center for ALPD and Cirrhosis (NIH Grant no. 2P50AA011999). NR 51 TC 10 Z9 11 U1 0 U2 2 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 JAN PY 2010 VL 298 IS 1 BP G92 EP G100 DI 10.1152/ajpgi.00324.2009 PG 9 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 534VQ UT WOS:000272926000012 PM 19850968 ER PT J AU Ohno, I Eibl, G Odinokova, I Edderkaoui, M Damoiseaux, RD Yazbec, M Abrol, R Goddard, WA Yokosuka, O Pandol, SJ Gukovskaya, AS AF Ohno, Izumi Eibl, Guido Odinokova, Irina Edderkaoui, Mouad Damoiseaux, Robert D. Yazbec, Moussa Abrol, Ravinder Goddard, William A., III Yokosuka, Osamu Pandol, Stephen J. Gukovskaya, Anna S. TI Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE phytochemical; polyphone; mitochondria; proapoptotic protein ID KINASE-C-DELTA; MITOCHONDRIAL PERMEABILITY TRANSITION; LIGAND-INDUCED APOPTOSIS; CYTOCHROME-C; ACINAR-CELLS; PKC-DELTA; MEMBRANE PERMEABILIZATION; CARCINOMA-CELLS; NADPH OXIDASE; ATP LEVELS AB Ohno I, Eibl G, Odinokova I, Edderkaoui M, Damoiseaux RD, Yazbec M, Abrol R, Goddard WA 3rd, Yokosuka O, Pandol SJ, Gukovskaya AS. Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family. Am J Physiol Gastrointest Liver Physiol 298: G63-G73, 2010. First published September 17, 2009; doi:10.1152/ajpgi.00257.2009.-Rottlerin is a polyphenolic compound derived from Mallotus philipinensis. In the present study, we show that rottlerin decreased tumor size and stimulated apoptosis in an orthotopic model of pancreatic cancer with no effect on normal tissues in vivo. Rottlerin also induced apoptosis in pancreatic cancer (PaCa) cell lines by interacting with mitochondria and stimulating cytochrome c release. Immunoprecipitation results indicated that rottlerin disrupts complexes of prosurvival Bcl-xL with Bim and Puma. Furthermore, siRNA knockdown showed that Bim and Puma are necessary for rottlerin to stimulate apoptosis. We also showed that rottlerin and Bcl-2 and Bcl-xL inhibitor BH3I-2' stimulate apoptosis through a common mechanism. They both directly interact with mitochondria, causing increased cytochrome c release and mitochondrial depolarization, and both decrease sequestration of BH3-only proteins by Bcl-xL. However, the effects of rottlerin and BH3I-2' on the complex formation between Bcl-xL and BH3-only proteins are different. BH3I-2' disrupts complexes of Bcl-xL with Bad but not with Bim or Puma, whereas rottlerin had no effect on the Bcl-xL interaction with Bad. Also BH3I-2', but not rottlerin, required Bad to stimulate apoptosis. In conclusion, our results demonstrate that rottlerin has a potent proapoptotic and antitumor activity in pancreatic cancer, which is mediated by disrupting the interaction between prosurvival Bcl-2 proteins and proapoptotic BH3-only proteins. Thus rottlerin represents a promising novel agent for pancreatic cancer treatment. C1 [Gukovskaya, Anna S.] Univ Calif Los Angeles, W Los Angeles VA Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Ohno, Izumi; Odinokova, Irina; Edderkaoui, Mouad; Yazbec, Moussa; Pandol, Stephen J.; Gukovskaya, Anna S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Eibl, Guido] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Odinokova, Irina] Russian Acad Sci, Inst Theoret & Expt Biophys, Pushchino 142292, Russia. [Abrol, Ravinder; Goddard, William A., III] CALTECH, Beckman Inst, Mat & Proc Simulat Ctr, Pasadena, CA 91125 USA. [Ohno, Izumi; Yokosuka, Osamu] Chiba Univ, Grad Sch Med, Dept Med & Clin Oncol, Chiba, Japan. RP Gukovskaya, AS (reprint author), Univ Calif Los Angeles, W Los Angeles VA Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 258,Rm 340, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu RI Damoiseaux, Robert/F-1086-2011; Abrol, Ravinder/B-4980-2010 OI Damoiseaux, Robert/0000-0002-7611-7534; FU Hirshberg Foundation for Pancreatic Cancer Research; NIH [CA119025]; NCCAM [AT003960]; Department of Veterans Affairs Merit Award FX This study was supported by the Hirshberg Foundation for Pancreatic Cancer Research, the NIH grants CA119025 (to A. Gukovskaya.), NCCAM AT003960 (to S. Pandol), and the Department of Veterans Affairs Merit Award (to A. Gukovskaya). NR 48 TC 20 Z9 20 U1 0 U2 1 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 JAN PY 2010 VL 298 IS 1 BP G63 EP G73 DI 10.1152/ajpgi.00257.2009 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 534VQ UT WOS:000272926000009 PM 19762431 ER PT J AU Wang, LX Gourcerol, G Yuan, PQ Wu, SV Million, M Larauche, M Tache, Y AF Wang, Lixin Gourcerol, Guillaume Yuan, Pu-Qing Wu, S. Vincent Million, Mulugeta Larauche, Muriel Tache, Yvette TI Peripheral peptide YY inhibits propulsive colonic motor function through Y-2 receptor in conscious mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE PYY3-36; stress; serotonin; bethanechol ID ENTERIC NERVOUS-SYSTEM; INDUCED ILEAL BRAKE; NEUROPEPTIDE-Y; FOOD-INTAKE; PANCREATIC-POLYPEPTIDE; MYENTERIC NEURONS; FACTOR CRF; RAT COLON; GASTROINTESTINAL-TRACT; INCREASED DEFECATION AB Wang L, Gourcerol G, Yuan P-Q, Wu SV, Million M, Larauche M, Tache Y. Peripheral peptide YY inhibits propulsive colonic motor function through Y-2 receptor in conscious mice. Am J Physiol Gastrointest Liver Physiol 298: G45-G56, 2010. First published November 5, 2009; doi:10.1152/ajpgi.00349.2009.-Peptide YY (PYY) antisecretory effect on intestinal epithelia is well established, whereas less is known about its actions to influence colonic motility in conscious animals. We characterized changes in basal function and stimulated colonic motor function induced by PYY-related peptides in conscious mice. PYY3-36, PYY, and neuropeptide Y (NPY) (8 nmol/kg) injected intraperitoneally inhibited fecal pellet output (FPO) per hour during novel environment stress by 90%, 63%, and 57%, respectively, whereas the Y-1-preferring agonists, [Pro(34)] PYY and [Leu(31), Pro(34)] NPY, had no effect. Corticotrophin-releasing factor 2 receptor antagonist did not alter PYY3-36 inhibitory action. PYY and PYY3-36 significantly reduced restraint-stimulated defecation, and PYY3-36 inhibited high-amplitude distal colonic contractions in restrained conscious mice for 1 h, by intraluminal pressure with the use of a microtransducer. PYY suppression of intraperitoneal 5-hydroxytryptophan induced FPO and diarrhea was blocked by the Y-2 antagonist, BIIE0246, injected intraperitoneally and mimicked by PYY3-36, but not [Leu(31), Pro(34)] NPY. PYY3-36 also inhibited bethanechol-stimulated FPO and diarrhea. PYY3-36 inhibited basal FPO during nocturnal feeding period and light phase in fasted/refed mice for 2-3 h, whereas the reduction of food intake lasted for only 1 h. PYY3-36 delayed gastric emptying after fasting-refeeding by 48% and distal colonic transit time by 104%, whereas [Leu(31), Pro(34)] NPY had no effect. In the proximal and distal colon, higher Y-2 mRNA expression was detected in the mucosa than in muscle layers, and Y-2 immunoreactivity was located in nerve terminals around myenteric neurons. These data established that PYY/PYY3-36 potently inhibits basal and stress/serotonin/cholinergic-stimulated propulsive colonic motor function in conscious mice, likely via Y-2 receptors. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, CURE Digest Dis Res Ctr, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Ctr Neurobiol Stress,Div Digest Dis, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Wang, LX (reprint author), Bldg 115,Rm 117B,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM lixinw@ucla.edu OI Larauche, Muriel/0000-0003-3320-3675 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-57238, DK 41301, DK078676] FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases R01 grant DK-57238 (Y. Tache), Center grant DK 41301 (Peptidomics core and Animal Model core), and DK078676 (M. Million), and VA Senior Career Scientist Award (Y. Tache). NR 69 TC 18 Z9 18 U1 0 U2 2 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 JAN PY 2010 VL 298 IS 1 BP G45 EP G56 DI 10.1152/ajpgi.00349.2009 PG 12 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 534VQ UT WOS:000272926000007 PM 19892938 ER PT J AU Peterfi, Z McGinty, D Sarai, E Szymusiak, R AF Peterfi, Zoltan McGinty, Dennis Sarai, Erzsebet Szymusiak, Ronald TI Growth hormone-releasing hormone activates sleep regulatory neurons of the rat preoptic hypothalamus SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE preoptic area; growth hormone-releasing hormone; somatostatin; octreotide; median preoptic nucleus; ventrolateral preoptic nucleus ID CENTRAL-NERVOUS-SYSTEM; SOMATOSTATIN-CONTAINING NEURONS; WAKING DISCHARGE PATTERNS; SLOW-WAVE SLEEP; MESSENGER-RNA; FACTOR GRF; IMMUNOCYTOCHEMICAL LOCALIZATION; GABAERGIC NEURONS; ULTRADIAN RHYTHM; ARCUATE NUCLEUS AB Peterfi Z, McGinty D, Sarai E, Szymusiak R. Growth hormone-releasing hormone activates sleep regulatory neurons of the rat preoptic hypothalamus. Am J Physiol Regul Integr Comp Physiol 298: R147-R156, 2010. First published November 4, 2009; doi:10.1152/ajpregu.00494.2009.-We examined whether growth hormone-releasing hormone (GHRH) may promote non-rapid eye movement (NREM) sleep via activation of GABAergic neurons in the preoptic area. Male Sprague-Dawley rats were implanted with EEG, EMG electrodes and a unilateral intracerebroventricular cannula. Groups of rats received injections (3 mu l icv) with gonadotropin-releasing hormone (GHRH) (0.1 nmol/100 g body wt) or equal volume of physiological saline at the onset of the dark period and were permitted spontaneous sleep for 90 min. Separate groups of rats were sleep deprived by gentle handling for 90 min, beginning at the time of GHRH or saline injection, at the onset of the dark period. Other groups of rats received intracerebroventricular octreotide (somatostatin analog OCT) injections, intracerebroventricular injection of one of two doses of competitive GHRH antagonist, or intracerebroventricular saline injection at light onset and were then permitted 90 min spontaneous sleep-waking. Rats were killed immediately after the 90-min sleep/wake monitoring period. Brain tissue was processed for immunohistochemistry for c-Fos protein and glutamic acid decarboxylase (GAD). Single c-Fos and dual Fos-GAD cell counts were determined in the median preoptic nucleus (MnPN), and in the core and the extended parts of the ventrolateral preoptic nucleus (cVLPO and exVLPO). Intracerebroventricular GHRH elicited a significant increase in NREM sleep amount. Double-labeled Fos + GAD cell counts were significantly elevated after GHRH injection in the MnPN and VLPO in both undisturbed and sleep-deprived groups. OCT and GHRH antagonist significantly decreased NREM sleep amount compared with control rats. OCT injection increased single c-Fos-labeled cell counts in the MnPN, but not in the VLPO. Double-labeled cell counts were significantly reduced after OCT and the high dose of GHRH antagonist injection in all areas examined. These findings identify GABAergic neurons in the MnPN and VLPO as potential targets of the sleep-regulatory actions of GHRH. C1 [Peterfi, Zoltan; McGinty, Dennis; Sarai, Erzsebet; Szymusiak, Ronald] VA Greater Angeles Healthcare Syst, Res Serv, North Hills, CA 91344 USA. [Peterfi, Zoltan; Szymusiak, Ronald] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Szymusiak, Ronald] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. RP Szymusiak, R (reprint author), VA Greater Angeles Healthcare Syst, Res Serv 151A3, 16111 Plummer St, North Hills, CA 91344 USA. EM rszym@ucla.edu FU Department of Veterans Affairs; National Institutes of Health [MH63323] FX This study is supported by The Department of Veterans Affairs and National Institutes of Health Grant MH63323. NR 66 TC 15 Z9 16 U1 0 U2 4 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 JAN PY 2010 VL 298 IS 1 BP R147 EP R156 DI 10.1152/ajpregu.00494.2009 PG 10 WC Physiology SC Physiology GA 536VF UT WOS:000273071300018 PM 19889861 ER PT J AU Jaimes, EA Hua, P Tian, RX Raij, L AF Jaimes, Edgar A. Hua, Ping Tian, Run-Xia Raij, Leopoldo TI Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin II, and oxidative stress SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE diabetes; prostaglandins; reactive oxygen species; nitric oxide ID NITRIC-OXIDE SYNTHASE; SUPEROXIDE ANION PRODUCTION; TYPE-1 DIABETES-MELLITUS; INTIMA-MEDIA THICKNESS; STAGE RENAL-DISEASE; INSULIN-RESISTANCE; METABOLIC SYNDROME; NEPHROPATHY; KIDNEY; PROGRESSION AB Jaimes EA, Hua P, Tian R-X, Raij L. Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin II, and oxidative stress. Am J Physiol Renal Physiol 298: F125-F132, 2010. First published October 28, 2009; doi:10.1152/ajprenal.00248.2009.-Glomerular endothelial cells (GEC) are strategically situated within the capillary loop and adjacent to the glomerular mesangium. GEC serve as targets of metabolic, biochemical, and hemodynamic signals that regulate the glomerular microcirculation. Unequivocally, hyperglycemia, hypertension, and the local renin-angiotensin system partake in the initiation and progression of diabetic nephropathy (DN). Whether free fatty acids (FFA) and reactive oxygen species (ROS) that have been associated with the endothelial dysfunction of diabetic macrovascular disease also contribute to DN is not known. Since endothelial cells from different organs and from different species may display different phenotypes, we employed human GEC to investigate the effect of high glucose (22.5 mmol/l), FFA (800 mu mol/l), and angiotensin II (ANG II; 10(-7) mol/l) on the genesis of ROS and their effects on endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2), and the synthesis of prostaglandins (PGs). We demonstrated that high glucose but not high FFA increased the expression of a dysfunctional eNOS as well as increased ROS from NADPH oxidase (100%) and likely from uncoupled eNOS. ANG II also induced ROS from NADPH oxidase. High glucose and ANG II upregulated (100%) COX-2 via ROS and significantly increased the synthesis of prostacyclin (PGI(2)) by 300%. In contrast, FFA did not upregulate COX-2 but increased PGI(2) (500%). These novel studies are the first in human GEC that characterize the differential role of FFA, hyperglycemia, and ANG II on the genesis of ROS, COX-2, and PGs and their interplay in the early stages of hyperglcyemia. C1 [Jaimes, Edgar A.; Hua, Ping] Univ Alabama Birmingham, Div Renal, Birmingham, AL 35294 USA. [Jaimes, Edgar A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Tian, Run-Xia; Raij, Leopoldo] Univ Miami, Miller Sch Med, Div Renal, Miami, FL 33136 USA. [Raij, Leopoldo] Miami Vet Affairs Med Ctr, Miami, FL USA. RP Jaimes, EA (reprint author), Univ Alabama Birmingham, Div Renal, 701 19th St S,LHRB 459, Birmingham, AL 35294 USA. EM ejaimes@uab.edu FU Veterans Affairs Merit Review Award; National Institutes of Health Research [DK-063972]; South Florida Veterans Affairs Research Foundation FX These studies were supported by a Veterans Affairs Merit Review Award (E. A. Jaimes), a National Institutes of Health Research Grant (DK-063972 to E. A. Jaimes), and by research funds from the South Florida Veterans Affairs Research Foundation (L. Raij). NR 47 TC 32 Z9 36 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN PY 2010 VL 298 IS 1 BP F125 EP F132 DI 10.1152/ajprenal.00248.2009 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 534VC UT WOS:000272924500016 PM 19864304 ER PT J AU Cheng, EM Cohen, SN Lee, ML Vassar, SD Chen, AY AF Cheng, Eric M. Cohen, Stanley N. Lee, Martin L. Vassar, Stefanie D. Chen, Alex Y. TI Use of Antithrombotic Agents Among US Stroke Survivors, 2000-2006 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID AMERICAN-HEART-ASSOCIATION; TRANSIENT ISCHEMIC ATTACK; ATHEROSCLEROTIC CARDIOVASCULAR-DISEASE; FACTOR SURVEILLANCE SYSTEM; HEALTH-CARE PROFESSIONALS; ASPIRIN USE; MYOCARDIAL-INFARCTION; SECONDARY PREVENTION; SEX-DIFFERENCES; UNITED-STATES AB Background: Secondary stroke prevention guidelines recommend antithrombotic agents such as over-the-counter aspirin, prescription antiplatelet agents, or anticoagulant agents. Purpose: The study was designed to measure whether use of outpatient antithrombotic agents is increasing among stroke survivors. Methods: The sample consisted of 4168 people who self-reported cerebrovascular disease and who participated in the Medical Expenditure Panel Survey, an annual representative sample of the U.S., during the years 2000-2006. Use of antithrombotic agents was calculated from face-to-face interviews about the use of aspirin and from pharmacies about the use of prescription medications. Cochran-Armitage tests were used to detect temporal trends and multivariate models to identify predictors of use of antithrombotic agents. Results: Pooling results across the 7 years, it was found that 57% were taking aspirin, 66% were using any antiplatelet agent, and 75% were using any antithrombotic agent. After excluding people who said aspirin was unsafe, 81% were using any antithrombotic agent. During the study period, use of prescription antiplatelet agents increased (p<0.001) but there was no temporal change in use of antithrombotic agents overall. In multivariate models, being aged >65 years, male gender, non-Hispanic ethnicity, having a usual source of care, and poor or fair health status were associated with use of an antithrombotic agent (p<0.05). Conclusions: Although a high percentage of stroke survivors appear to use an antithrombotic agent, further research should investigate whether and how to improve care among the remaining 20% of stroke survivors, particularly among younger, female, and Hispanic patients. (Am J Prev Med 2010;38(1):47-53) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Cheng, Eric M.; Vassar, Stefanie D.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, Los Angeles, CA 90073 USA. [Cheng, Eric M.; Vassar, Stefanie D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Hlth Serv Res Program, Los Angeles, CA 90095 USA. [Lee, Martin L.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Chen, Alex Y.] Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA 90033 USA. [Cheng, Eric M.; Lee, Martin L.] VA Greater Los Angeles Healthcare Syst, HSR&D Ctr Excellence, Sepulveda, CA USA. [Cohen, Stanley N.] Nevada Neurosci Inst Sunrise, Stroke Prevent Program, Las Vegas, NV USA. RP Cheng, EM (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Neurol, 11301 Wilshire Blvd,Bldg 500,ML 127, Los Angeles, CA 90073 USA. EM eric.cheng@va.gov FU NIH/National Institute of Neurological Disorders and Stroke (NINDS) [K23NS058571]; UCLA/DREW Project EXPORT, National Center on Minority Health and Health Disparities (NCMHD) [P20MD000148/P20MD000182-06]; American Heart Association (AHA) through funding for the AHA/Pharmaceutical Roundtable Outcomes Research Center at UCLA; NIH/National Institute of Child Health and Human Development (NICHD) [K23HD047270]; Veterans Administration; Boeringer Ingelheim speakers bureau FX SNC has received speaking fees from the Boeringer Ingelheim speakers bureau. NR 31 TC 4 Z9 4 U1 1 U2 2 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 JAN PY 2010 VL 38 IS 1 BP 47 EP 53 DI 10.1016/j.amepre.2009.08.029 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 541KL UT WOS:000273413800006 PM 20117556 ER PT J AU Grelotti, DJ Kanayama, G Pope, HG AF Grelotti, David J. Kanayama, Gen Pope, Harrison G., Jr. TI Remission of Persistent Methamphetamine-Induced Psychosis After Electroconvulsive Therapy: Presentation of a Case and Review of the Literature SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID DEFICIT-HYPERACTIVITY DISORDER; LONG-TERM ABSTINENCE; SPONTANEOUS RECURRENCE; BRAIN CATECHOLAMINES; ACUTE EXACERBATION; CLINICAL-FEATURES; USERS; AMPHETAMINE; JAPAN; METHYLPHENIDATE AB Illicit methamphetamine abuse represents a major problem in many countries worldwide, including the United States. Prolonged regular smoking or injection of methamphetamine can cause a psychosis, typically characterized by paranoid delusions and auditory hallucinations and often associated with disturbances in mood. These symptoms may persist long after methamphetamine is discontinued and may prove refractory to antipsychotic medications. The authors describe a patient who developed a typical methamphetamine psychosis that persisted despite months of abstinence from methamphetamine and weeks of treatment with antipsychotic medication but that responded promptly to electroconvulsive therapy (ECT) on two separate occasions: on initial presentation and again a year later when the patient relapsed into methamphetamine abuse and developed psychosis again. The authors review the large international literature on methamphetamine psychosis, much of which is from Japan and has not previously been summarized in English. Persistent methamphetamine psychosis has been widely reported in Japan for more than 50 years but is rarely discussed in the American literature, possibly because some such cases are misdiagnosed in the United States as primary psychotic disorders. Given the growing public health problem of methamphetamine abuse in the United States, the distinction between persistent methamphetamine psychosis and a primary psychotic disorder has grown increasingly important. Thus, American clinicians should be alert to the possibility of methamphetamine psychosis and may wish to consider ECT in refractory cases. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Pope, Harrison G., Jr.] McLean Hosp, Biol Psychiat Lab, Belmont, MA 02178 USA. RP Pope, HG (reprint author), McLean Hosp, Biol Psychiat Lab, 115 Mill St, Belmont, MA 02178 USA. EM hpope@mclean.harvard.edu NR 65 TC 28 Z9 29 U1 4 U2 4 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 JAN PY 2010 VL 167 IS 1 BP 17 EP 23 DI 10.1176/appi.ajp.2009.08111695 PG 7 WC Psychiatry SC Psychiatry GA 543KL UT WOS:000273575900006 PM 20068123 ER PT J AU Valera, EM Brown, A Biederman, J Faraone, SV Makris, N Monuteaux, MC Whitfield-Gabrieli, S Vitulano, M Schiller, M Seidman, LJ AF Valera, Eve M. Brown, Ariel Biederman, Joseph Faraone, Stephen V. Makris, Nikos Monuteaux, Michael C. Whitfield-Gabrieli, Susan Vitulano, Michael Schiller, Michael Seidman, Larry J. TI Sex Differences in the Functional Neuroanatomy of Working Memory in Adults With ADHD SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; CEREBRAL GLUCOSE-METABOLISM; PREFRONTAL CORTEX; BRAIN; CHILDREN; ACTIVATION; GENDER; GIRLS; METAANALYSIS AB Objective: Although attention deficit hyperactivity disorder (ADHD) in adults is associated with significant morbidity and dysfunction and afflicts both sexes, relatively few imaging studies have examined female subjects and none have had sufficient power to adequately examine sex differences. The authors examined sex differences in the neural functioning of adults with ADHD during performance of a verbal working memory task. Method: The participants were 44 adults with ADHD matched on age, sex, and estimated IQ to 49 comparison subjects. Accuracy and reaction time on an N-back task were measured to assess working memory. The blood-oxygen-level-dependent functional MRI response was used as a measure of neural activity. Results: A group-by-sex analysis of variance showed no between-group differences in either reaction time or percent correct for the working memory task. For both sexes combined, the adults with ADHD showed less activity than comparison subjects in prefrontal regions. However, sex-by-group analyses revealed an interaction, such that male ADHD subjects showed significantly less activity in right frontal, temporal, and subcortical regions and left occipital and cerebellar regions relative to male comparison subjects, whereas female ADHD subjects showed no differences from female comparison subjects. Exploratory correlation analyses revealed negative associations between working-memory-related activation and number of hyperactive symptoms for men and number of inattentive symptoms for women. Conclusions: Male but not female adults with ADHD showed significantly altered patterns of neural activity during a verbal working memory task. Men and women showed different associations between neural activity and ADHD symptoms. C1 [Valera, Eve M.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Clin & Res Program Adult ADHD, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Psychiat Neurosci Div, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. Massachusetts Gen Hosp, Psychiat Neurosci Div, Boston, MA 02114 USA. Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Clin & Res Program Adult ADHD, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Valera, EM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Rm 2660,149 13th St, Charlestown, MA 02129 USA. EM eve_valera@hms.harvard.edu OI Faraone, Stephen/0000-0002-9217-3982 FU NIH; Alza; AstraZeneca; Bristol-Myers Squibb; Eli Lilly; Janssen; McNeil; Merck; Organon; Otsuka; Shire; NIMH; National Institute of Child Health and Human Development; Abbott; Celltech; Cephalon; Esai; Forest; Glaxo; Gliatech; NARSAD; National Institute on Drug Abuse; New River; Novartis; Noven; Neurosearch; Pfizer; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma; Wyeth; NIMH [F32 MH065040, MH-16259, MH-57934, MH-62152, MH-071535, MH-084041]; National Center for Research Resources [P41 RR-14075]; National Center for Complementary and Alternative Medicine [1PO1 AT-002048-06]; Livingston Fellowship through Harvard Medical School; National Alliance for Research on Schizophrenia and Depression; Research Council for Pediatric Psychopharmacology at the Massachusetts General Hospital; Mental Illness and Neuroscience Discovery (MIND) Institute; March of Dimes Foundation; Commonwealth Research Center; Massachusetts Department of Mental Health FX In the past 12 months, Dr. Valera has received travel support and/or honoraria from divisions of Ortho-McNeil-Janssen Pharmaceuticals, honoraria from Massachusetts General Hospital, Reed Exhibitions, and Boston University, research support from NIH, and reimbursements from Veritas Institute; in the past, she has received travel support from Eli Lilly and Shire, honoraria from Shire, Remedica Medical Education and Publishing, Massachusetts General Hospital, Reed Exhibitions, Boston University, and Partners Healthcare, and research support from NIH. Dr. Biederman is currently receiving research support from Alza, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, McNeil, Merck, Organon, Otsuka, Shire, NIMH, and the National Institute of Child Health and Human Development; in 2009 he received speaking fees from the Fundacion Ramon Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association; in previous years he received research support, consultation fees, or speaking fees from Abbott, AstraZeneca, Celltech, Cephalon, Eli Lilly, Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, NARSAD, the National Institute on Drug Abuse, New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, the Prechter Foundation, Shire, the Stanley Foundation, UCB Pharma, and Wyeth. In the past year, Dr. Faraone has received consulting fees and been on advisory boards for Eli Lilly and Shire and has received research support from Eli Lilly, NIH, Pfizer, and Shire; in previous years, he received consulting fees, was on advisory boards, or was a speaker for Eli Lilly, Janssen, McNeil, Novartis, Pfizer, and Shire and received research support from Eli Lilly, NIH, Pfizer, and Shire. The other authors report no financial relationships with commercial interests.; Supported in part by National Research Service award F32 MH065040 from NIMH (Dr. Valera); by Clinical Research Training Program Fellowship in Biological and Social Psychiatry MH-16259 from NIMH (Dr. Valera); by NIMH grants MH-57934 (Dr. Faraone), MH-62152 (Dr. Seidman), MH-071535 (Dr. Valera), and MH-084041 (Dr. Makris); by National Center for Research Resources grant P41 RR-14075; by ARRA-NIH-NCCAM grant 1PO1 AT-002048-06 from the National Center for Complementary and Alternative Medicine (Dr. Makris); by a Livingston Fellowship through Harvard Medical School (Dr. Valera); by the National Alliance for Research on Schizophrenia and Depression (Dr. Biederman); by research grants from Janssen and McNeil (Dr. Biederman); by the Research Council for Pediatric Psychopharmacology at the Massachusetts General Hospital; and by the Mental Illness and Neuroscience Discovery (MIND) Institute, March of Dimes Foundation and the Commonwealth Research Center, Massachusetts Department of Mental Health (Dr. Seidman). These funders had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, and approval of the manuscript. NR 40 TC 58 Z9 58 U1 5 U2 13 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 JAN PY 2010 VL 167 IS 1 BP 86 EP 94 DI 10.1176/appi.ajp.2009.09020249 PG 9 WC Psychiatry SC Psychiatry GA 543KL UT WOS:000273575900014 PM 19884224 ER PT J AU Wells, TS LeardMann, CA Fortuna, SO Smith, B Smith, TC Ryan, MAK Boyko, EJ Blazer, D AF Wells, Timothy S. LeardMann, Cynthia A. Fortuna, Sarah O. Smith, Besa Smith, Tyler C. Ryan, Margaret A. K. Boyko, Edward J. Blazer, Dan CA Millennium Cohort Study Team TI A Prospective Study of Depression Following Combat Deployment in Support of the Wars in Iraq and Afghanistan SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MENTAL-HEALTH PROBLEMS; PERSIAN-GULF-WAR; MILLENNIUM COHORT; MILITARY SERVICE; PRIMARY-CARE; US MILITARY; MAJOR DEPRESSION; UNITED-STATES; PEACEKEEPING OPERATIONS AB Objective. We investigated relations between deployment and new-onset depression among US service members recently deployed to the wars in Iraq and Afghanistan. Methods. We included 40219 Millennium Cohort Study participants who completed baseline and follow-up questionnaires and met inclusion criteria. Participants were identified with depression if they met the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire criteria for depression at follow-up, but not at baseline. Results. Deployed men and women with combat exposures had the highest onset of depression, followed by those not deployed and those deployed without combat exposures. Combat-deployed men and women were at increased risk for new-onset depression compared with nondeployed men and women (men: adjusted odds ratio [AOR]=1.32; 95% confidence interval [CI]=1.13, 1.54; women: AOR=2.13; 95% CI=1.70, 2.65). Conversely, deployment without combat exposures led to decreased risk for new-onset depression compared with those who did not deploy (men: AOR=0.66; 95% CI=0.53, 0.83; women: AOR = 0.65; 95% CI = 0.47, 0.89). Conclusions. Deployment with combat exposures is a risk factor for new-onset depression among US service members. Post-deployment screening may be beneficial for US service members exposed to combat. (Am J Public Health. 2010;100:90-99. doi:10.2105/AJPH.2008.155432) C1 [Wells, Timothy S.; Fortuna, Sarah O.] USAF, Res Lab, Wright Patterson AFB, OH 45433 USA. [LeardMann, Cynthia A.; Smith, Besa; Smith, Tyler C.; Ryan, Margaret A. K.] USN, US Dept Def, Ctr Deployment Hlth Res, Hlth Res Ctr, San Diego, CA 92152 USA. [Boyko, Edward J.] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Blazer, Dan] Duke Univ, Med Ctr, Durham, NC USA. RP Wells, TS (reprint author), 711th HPW RHPA,Bldg 824,Room 206,2800 Q St, Wright Patterson AFB, OH 45433 USA. EM timothy.wells@wpafb.af.mil RI Blazer II, Dan/D-6675-2012 FU Department of Defense [60002] FX This work represents report 08-06, supported by the Department of Defense, under work unit no. 60002.The views expressed in this article are those of the authors and do not reflect the official policy or position ofthe Department of the Navy, Department of the Army, Department of the Air- Force, Department of Defense, Department of Veterans Affairs, or the US Govemment. NR 82 TC 106 Z9 106 U1 10 U2 17 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JAN PY 2010 VL 100 IS 1 BP 90 EP 99 DI 10.2105/AJPH.2008.155432 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 538EK UT WOS:000273166800020 PM 19910353 ER PT J AU Bajwa, E Christiani, DC Malhotra, CK Thompson, BT Gong, M AF Bajwa, E. Christiani, D. C. Malhotra, C. K. Thompson, B. T. Gong, M. TI Statin Therapy Prior To ICU Admission And Development Of ARDS SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Bajwa, E.; Malhotra, C. K.; Thompson, B. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Christiani, D. C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Gong, M.] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1700 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000700 ER PT J AU Bedigian, A Dunn, C Davies, Z Milla, CE Conrad, CK AF Bedigian, A. Dunn, C. Davies, Z. Milla, C. E. Conrad, C. K. TI DIAGNOSIS OF PULMONARY EXACERBATIONS IN PATIENTS WITH CYSTIC FIBROSIS. CORRELATION OF PATIENT REPORTED SYMPTOMS WITH PHYSICAN DIAGNOSIS SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Bedigian, A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Dunn, C.; Davies, Z.; Milla, C. E.] Stanford Univ, Palo Alto, CA 94304 USA. [Conrad, C. K.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. EM cconrad@stanford.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1822 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001030 ER PT J AU Britos-Bray, MF Smoot, E Liu, K Thompson, BT Brower, R AF Britos-Bray, M. F. Smoot, E. Liu, K. Thompson, B. T. Brower, R. CA ARDS Network Investigators TI Effects Of 24 Hours Of Higher PEEP On PaO2/FiO2 Ratios in Patients Enrolled In ARDS Network Trials SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Britos-Bray, M. F.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Smoot, E.; Thompson, B. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Liu, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Brower, R.; ARDS Network Investigators] Johns Hopkins Univ, Baltimore, MD USA. EM mbritos@medicine.umaryland.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2591 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001504 ER EF