FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kane, JM Strom, BL Eng, SM Faich, G Reynolds, RF D'Agostino, RB Ruskin, J Geier, J Karayal, ON Kremer, C AF Kane, John M. Strom, Brian L. Eng, Sybil M. Faich, Gerald Reynolds, Robert F. D'Agostino, Ralph B. Ruskin, Jeremy Geier, Jamie Karayal, Onur N. Kremer, Charlotte TI PRIMARY AND READJUDICATION MORTALITY RESULTS FROM ZODIAC, A LARGE SIMPLE TRIAL OF ZIPRASIDONE VS. OLANZAPINE IN PATIENTS WITH SCHIZOPHRENIA SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Kane, John M.] Zucker Hillside Hosp, Glen Oaks, NY USA. [Strom, Brian L.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Eng, Sybil M.; Reynolds, Robert F.; Geier, Jamie; Karayal, Onur N.; Kremer, Charlotte] Pfizer Inc, New York, NY USA. [Faich, Gerald] United BioSource Corp, Blue Bell, PA USA. [D'Agostino, Ralph B.] Boston Univ, Boston, MA 02215 USA. [Ruskin, Jeremy] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 183 EP 184 DI 10.1016/j.schres.2010.02.227 PG 2 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936800228 ER PT J AU Strom, BL Eng, SM Faich, G Reynolds, RF D'Agostino, RB Ruskin, J Kane, JM Geier, J Karaya, ON Kremer, C AF Strom, Brian L. Eng, Sybil M. Faich, Gerald Reynolds, Robert F. D'Agostino, Ralph B. Ruskin, Jeremy Kane, John M. Geier, Jamie Karaya, Onur N. Kremer, Charlotte TI THE ZIPRASIDONE OBSERVATIONAL STUDY OF CARDIAC OUTCOMES (ZODIAC): FINDINGS FROM A LARGE SIMPLE TRIAL OF ZIPRASIDONE VS. OLANZAPINE IN REAL-WORLD USE AMONG 18154 PATIENTS WITH SCHIZOPHRENIA SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Strom, Brian L.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Eng, Sybil M.; Reynolds, Robert F.; Geier, Jamie; Karaya, Onur N.; Kremer, Charlotte] Pfizer Inc, New York, NY USA. [Faich, Gerald] United BioSource Corp, Blue Bell, PA USA. [D'Agostino, Ralph B.] Boston Univ, Boston, MA 02215 USA. [Ruskin, Jeremy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kane, John M.] Zucker Hillside Hosp, Glen Oaks, NY USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 311 EP 311 DI 10.1016/j.schres.2010.02.523 PG 1 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936800525 ER PT J AU Nuechterlein, KH Green, MF Kern, RS AF Nuechterlein, Keith H. Green, Michael F. Kern, Robert S. TI RECENT ADVANCES IN TRANSLATING AND CULTURALLY ADAPTING THE MATRICS CONSENSUS COGNITIVE BATTERY FOR INTERNATIONAL USE SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Nuechterlein, Keith H.; Green, Michael F.; Kern, Robert S.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Nuechterlein, Keith H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Green, Michael F.; Kern, Robert S.] VA Greater Angeles Healthcare Syst, MIRECC, VISN 22, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 329 EP 330 DI 10.1016/j.schres.2010.02.564 PG 2 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936800566 ER PT J AU Ng, HP Kubicki, M Rathi, Y Malcolm, J Pelavin, P Kikinis, R Shenton, ME AF Ng, Hsiao Piau Kubicki, Marek Rathi, Yogesh Malcolm, James Pelavin, Paula Kikinis, Ron Shenton, Martha E. TI DECREASED FRACTIONAL ANISOTROPY IN INTER-HEMISPHERIC CONNECTION BETWEEN BILATERAL SUPERIOR TEMPORAL GYRUS GRAY MATTER IN CHRONIC SCHIZOPHRENIA SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Ng, Hsiao Piau; Kubicki, Marek; Rathi, Yogesh; Malcolm, James; Pelavin, Paula; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat,Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Ng, Hsiao Piau] Agcy Sci Technol & Res, Singapore Bioimaging Consortium, Singapore, Singapore. [Kubicki, Marek; Rathi, Yogesh; Shenton, Martha E.] Harvard Univ, VA Boston Healthcare Syst, Dept Psychiat, Clin Neurosci Div,Lab Neurosci,Sch Med, Brockton, MA 02401 USA. [Kikinis, Ron; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol,MRI Div,Surg Planning Lab, Boston, MA 02115 USA. NR 5 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 342 EP 343 PG 2 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936800598 ER PT J AU Milanovic, SM Thermenos, HW Brown, A Goldstein, JM Gabrieli, SW Makris, N Juelich, R Tsuang, MT Buka, SL Seidman, LJ AF Milanovic, Snezana M. Thermenos, Heidi W. Brown, Ariel Goldstein, Jill M. Gabrieli, Susan W. Makris, Nikos Juelich, Richard Tsuang, Ming T. Buka, Stephen L. Seidman, Larry J. TI MEDIAL PREFRONTAL CORTICAL ACTIVATION DURING WORKING MEMORY DIFFERENTIATES SCHIZOPHRENIA AND BIPOLAR PSYCHOTIC PATIENTS: A PILOT STUDY SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Milanovic, Snezana M.; Thermenos, Heidi W.; Goldstein, Jill M.; Juelich, Richard; Tsuang, Ming T.; Seidman, Larry J.] Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Div Publ Psychiat,Dept Psychiat,Beth Israel Deaco, Boston, MA 02115 USA. [Milanovic, Snezana M.; Thermenos, Heidi W.; Goldstein, Jill M.; Makris, Nikos; Seidman, Larry J.] MGH HST Athinoula Martinos, Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Milanovic, Snezana M.; Brown, Ariel; Goldstein, Jill M.; Makris, Nikos; Tsuang, Ming T.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brown, Ariel; Seidman, Larry J.] MGH, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Goldstein, Jill M.] Harvard Univ, Sch Med, Dept Med, Div Womens Hlth,Connors Ctr Womens Hlth Gender Bi, Boston, MA 02115 USA. [Goldstein, Jill M.] Dept Psychiat, Brigham & Womens Hosp, Boston, MA 02115 USA. [Gabrieli, Susan W.] MIT, Dept Brain & Cognit Sci, Harvard Mit Div Hlth Sci & Technol, Boston, MA 02139 USA. [Makris, Nikos] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr,Dept Neurol Services, Boston, MA 02129 USA. [Makris, Nikos] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr,Dept Radiol Services, Boston, MA 02129 USA. [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Gen, La Jolla, CA 92093 USA. [Buka, Stephen L.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. RI Buka, Stephen/H-7335-2014 OI Buka, Stephen/0000-0002-8578-9308 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 355 EP 355 DI 10.1016/j.schres.2010.02.623 PG 1 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936800625 ER PT J AU Genevsky, A Fisher, M Garrett, CT Cook, C Vinogradov, S AF Genevsky, Alexander Fisher, Melissa Garrett, Coleman T. Cook, Colleen Vinogradov, Sophia TI INCREASED SERUM BDNF INDUCED BY COGNITIVE TRAINING IN SCHIZOPHRENIA IS NEGATIVELY ASSOCIATED WITH BASELINE SAA SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Genevsky, Alexander; Fisher, Melissa; Garrett, Coleman T.; Cook, Colleen; Vinogradov, Sophia] San Francisco VA Med Ctr, San Francisco, CA USA. [Genevsky, Alexander; Fisher, Melissa; Garrett, Coleman T.; Cook, Colleen; Vinogradov, Sophia] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 368 EP 368 DI 10.1016/j.schres.2010.02.653 PG 1 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936801023 ER PT J AU Pietersen, CY Lim, MP Chen, J Stephens, R McCarley, RM Wool, TUW AF Pietersen, Charmaine Y. Lim, Maribel P. Chen, Jack Stephens, Robert McCarley, Robert M. Wool, Tsung-Ung W. TI MICROARRAY ANALYSIS OF PARVALBUMIN-CONTAINING INHIBITORY NEURONS IN THE SUPERIOR TEMPORAL GYRUS IN SCHIZOPHRENIA SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Pietersen, Charmaine Y.; Lim, Maribel P.; Wool, Tsung-Ung W.] McLean Hosp, Belmont, MA 02178 USA. [Chen, Jack; Stephens, Robert] SAIC Frederik, NCI, NIH, ABCC, Bethesda, MD USA. [Pietersen, Charmaine Y.; McCarley, Robert M.; Wool, Tsung-Ung W.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Pietersen, Charmaine Y.; McCarley, Robert M.; Wool, Tsung-Ung W.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [McCarley, Robert M.] VA Boston Healthcare Syst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 371 EP 372 PG 2 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936801032 ER PT J AU Keefe, R Vinogradov, S Medalia, A Buckley, P Caroff, S D'Souza, D Harvey, P Graham, K Marder, S Miller, D Olson, S Patel, J Velligan, D Walker, T Haim, A Stroup, S AF Keefe, Richard Vinogradov, Sophia Medalia, Alice Buckley, Peter Caroff, Stanley D'Souza, Deepak Harvey, Phillip Graham, Karen Marder, Steve Miller, Del Olson, Steve Patel, Jayendra Velligan, Dawn Walker, Trina Haim, Adam Stroup, Scott TI FEASIBILITY STUDY OF MULTI-SITE COGNITIVE REMEDIATION IN THE SCHIZOPHRENIA TRIALS NETWORK (CRSTN) SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Keefe, Richard; Walker, Trina] Duke Univ, Med Ctr, Durham, NC USA. [Vinogradov, Sophia] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Medalia, Alice; Stroup, Scott] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Buckley, Peter] Med Coll Georgia, Augusta, GA 30912 USA. [Caroff, Stanley] Univ Penn, Sch Med, Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [D'Souza, Deepak] Yale Univ, Sch Med, New Haven, CT USA. [Harvey, Phillip] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Graham, Karen] Univ N Carolina, Chapel Hill, NC USA. [Marder, Steve] Univ Calif Los Angeles, Semel Inst, Los Angeles, CA USA. [Marder, Steve] VA Desert Pacific Mental Illness Res Educ & Clin, Los Angeles, CA USA. [Miller, Del] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Olson, Steve] Univ Minnesota, Minneapolis, MN USA. [Patel, Jayendra] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Velligan, Dawn] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Haim, Adam] NIMH, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 394 EP 394 PG 1 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936801081 ER PT J AU Wesnes, K Brooker, H Evins, AE AF Wesnes, Keith Brooker, Helen Evins, A. Eden TI A STUDY COMPARING THE MATRICS BATTERY WITH THE CDR SYSTEM IN SHIZOPHRENIA SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Wesnes, Keith; Brooker, Helen] United BioSource Corp, Goring on Thames, Oxon, England. [Wesnes, Keith] Swinburne Univ, Melbourne, Vic, Australia. [Evins, A. Eden] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Evins, A. Eden] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 416 EP 416 DI 10.1016/j.schres.2010.02.1044 PG 1 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936801132 ER PT J AU Schneiderman, JS Whitford, TJ Pelavin, PE Terry, DP Swisher, T Mesholam-Gately, RI Seidman, LJ Goldstein, JM McCarley, RW Kubicki, M Shenton, ME AF Schneiderman, Jason S. Whitford, Thomas J. Pelavin, Paula E. Terry, Douglas P. Swisher, Tali Mesholam-Gately, Raquelle I. Seidman, Larry J. Goldstein, Jill M. McCarley, Robert W. Kubicki, Marek Shenton, Martha E. TI DIFFUSION TENSOR IMAGING OF THE CINGULUM BUNDLE IN FIRST EPISODE SCHIZOPHRENIA SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Schneiderman, Jason S.; Whitford, Thomas J.; Pelavin, Paula E.; Terry, Douglas P.; Swisher, Tali; Kubicki, Marek; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Mesholam-Gately, Raquelle I.; Seidman, Larry J.; Goldstein, Jill M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [McCarley, Robert W.] VA Boston Healthcare Syst, Brockton, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 461 EP 461 DI 10.1016/j.schres.2010.02.862 PG 1 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936801233 ER PT J AU Thermenos, HW Whitfield-Gabrieli, S Makris, N Brown, ALB Lee, E Giuliano, A Faraone, S Tsuang, MT Seidman, LJ AF Thermenos, Heidi W. Whitfield-Gabrieli, Susan Makris, Nikos Brown, Arid L. B. Lee, Erica Giuliano, Anthony Faraone, Stephen Tsuang, Ming T. Seidman, Larry J. TI ALTERED BRAIN FUNCTION DURING WORKING MEMORY IN ADOLESCENTS AND YOUNG ADULTS AT GENETIC RISK FOR BIPOLAR DISORDER: PRELIMINARY FINDINGS SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 2nd Conference of the Schizophrenia-International-Research-Society (SIRS) CY APR 10-14, 2010 CL Florence, ITALY SP Schizophrenia Int Res Soc C1 [Thermenos, Heidi W.; Lee, Erica; Giuliano, Anthony; Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Boston, MA 02215 USA. [Thermenos, Heidi W.; Makris, Nikos; Brown, Arid L. B.; Seidman, Larry J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Faraone, Stephen] Upstate Med Univ, Med Genet Res Program, Syracuse, NY USA. [Tsuang, Ming T.] Univ Calif La Jolla, Dept Psychiat Ctr Behav Genom, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2010 VL 117 IS 2-3 SI SI BP 473 EP 473 DI 10.1016/j.schres.2010.02.891 PG 1 WC Psychiatry SC Psychiatry GA 586TR UT WOS:000276936801262 ER PT J AU Lieberman, J AF Lieberman, Judy TI Master of the Cell SO SCIENTIST LA English DT Article ID FAS PROTECTS MICE; RNA; INTERFERENCE; INFECTION C1 [Lieberman, Judy] Childrens Hosp Boston, Immune Dis Inst, Boston, MA USA. [Lieberman, Judy] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Lieberman, Judy] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Lieberman, J (reprint author), Childrens Hosp Boston, Immune Dis Inst, Boston, MA USA. RI Lieberman, Judy/A-2717-2015 NR 7 TC 0 Z9 1 U1 0 U2 1 PU SCIENTIST INC PI PHILADELPHIA PA 400 MARKET ST, STE 1250, PHILADELPHIA, PA 19106 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD APR PY 2010 VL 24 IS 4 BP 42 EP 48 PG 7 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 574TX UT WOS:000276017700020 ER PT J AU Mayer, KH Mimiaga, MJ Safren, SA AF Mayer, Kenneth H. Mimiaga, Matthew J. Safren, Steven A. TI Out of the Closet and Into Public Health Focus: HIV and STDs in Men Who Have Sex With Men in Middle Income and Resource-Limited Countries SO SEXUALLY TRANSMITTED DISEASES LA English DT Editorial Material ID RISK-FACTORS; INFECTION; BEHAVIOR C1 [Mayer, Kenneth H.] Brown Univ, Miriam Hosp, Providence, RI 02906 USA. [Mayer, Kenneth H.] Brown Univ, Dept Med, Warren Alpert Sch Med, Providence, RI 02906 USA. [Mayer, Kenneth H.] Brown Univ, Dept Community Hlth, Warren Alpert Sch Med, Providence, RI 02906 USA. [Mimiaga, Matthew J.; Safren, Steven A.] Massachusetts Gen Hosp, Dept Psychiat, Fenway Inst, Boston, MA 02114 USA. [Mimiaga, Matthew J.; Safren, Steven A.] Harvard Univ, Sch Med, Boston, MA USA. RP Mayer, KH (reprint author), Brown Univ, Miriam Hosp, 164 Summit Ave, Providence, RI 02906 USA. EM kenneth_mayer@brown.edu NR 23 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD APR PY 2010 VL 37 IS 4 BP 205 EP 207 DI 10.1097/OLQ.0b013e3181d13d3e PG 3 WC Infectious Diseases SC Infectious Diseases GA 579MC UT WOS:000276373700001 PM 20145587 ER PT J AU Muessig, KE Tucker, JD Wang, BX Chen, XS AF Muessig, Kathryn E. Tucker, Joseph D. Wang, Bao-Xi Chen, Xiang-Sheng TI HIV and Syphilis Among Men Who Have Sex With Men in China: The Time to Act is Now SO SEXUALLY TRANSMITTED DISEASES LA English DT Editorial Material ID HEPATITIS-B; PREVALENCE; BEHAVIORS; SHANGHAI; INFECTIONS; HIV/AIDS; SPREAD; RISKS; WOMEN; CITY C1 [Chen, Xiang-Sheng] Chinese Acad Med Sci, Natl Ctr STD Control, China CDC, Nanjing 210042, Peoples R China. [Muessig, Kathryn E.; Wang, Bao-Xi; Chen, Xiang-Sheng] Peking Union Med Coll, Inst Dermatol, Nanjing, Peoples R China. [Muessig, Kathryn E.] Johns Hopkins Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Tucker, Joseph D.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Chen, XS (reprint author), Chinese Acad Med Sci, Natl Ctr STD Control, China CDC, 12 Jiangwangmiao St, Nanjing 210042, Peoples R China. EM chenxs@ncstdlc.org FU FIC NIH HHS [K01 TW008200]; NIMH NIH HHS [F31 MH086345-01, F31 MH086345] NR 32 TC 7 Z9 7 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD APR PY 2010 VL 37 IS 4 BP 214 EP 216 DI 10.1097/OLQ.0b013e3181d13d2b PG 3 WC Infectious Diseases SC Infectious Diseases GA 579MC UT WOS:000276373700003 PM 20220563 ER PT J AU Brim, NM Venkatan, SK Gordon, JA Alexander, EK AF Brim, Nancy M. Venkatan, Suresh K. Gordon, James A. Alexander, Erik K. TI Long-Term Educational Impact of a Simulator Curriculum on Medical Student Education in an Internal Medicine Clerkship SO SIMULATION IN HEALTHCARE LA English DT Article DE Simulation; Medical student; Clinical reasoning ID HUMAN PATIENT SIMULATOR; CARDIOLOGY; RESPONSES; SKILLS AB Background: Medical simulation is frequently used in postgraduate medical training, but its value and sustainability in medical student education are less clear. We report the first long-term experience of mannequin simulation in an internal medicine clerkship. Methods: During a 6-year period (2002-2009), 327 Harvard medical students participated in a simulator-based teaching experience designed to expose students to the principles of myocardial infarction (MI). This experience was additive to a 12-week clerkship curriculum. Through blinded survey instruments, we sought to determine how the simulator exercise modified student exposure to a core curricular objective in the traditional clerkship. We also sought student and faculty perception of this educational tool and factors important to sustainability. Results: Three hundred twenty-seven consecutive students were exposed to the simulation exercise and their experiences evaluated. Three hundred twenty-six students (99%) described the simulation experience as valuable, with >69% requesting multiple sessions be provided during each clerkship. Although a core objective, only 78% of students reported having a didactic teaching session on MI during the clerkship, and only 47% of students reported exposure to a live patient with MI. Furthermore, only 15% of students reported exposure to at least two different clinical presentations of MI, allowing comparison and reflection. Thus, the simulation exercise provided the only exposure to this topic for 22% of students and facilitated comparisons of different clinical presentations for 85% of students. When students participated in both the simulator and the didactic sessions, 74% favored the simulation exercise. Faculty cited small group size, once monthly delivery and focused curricula as key points for sustainability of this effort. Conclusion: Mannequin simulation is a valuable and sustainable addition to a third-year internal medicine clerkship. For some students, simulation provides otherwise unavailable exposure to core content material. For the majority of students, simulation also provides the only means of exposure to multiple presentations of a single illness. Together, these data strongly suggest that simulation promotes both experiential learning and comparative analysis in a clerkship setting. (Sim Healthcare 5:75-81, 2010) C1 [Brim, Nancy M.; Alexander, Erik K.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Venkatan, Suresh K.; Gordon, James A.] Harvard Univ, Sch Med, GS Beckwith Gilbert & Katharine S Gilbert Med Edu, Boston, MA USA. [Gordon, James A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Alexander, EK (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St,PBB-B4, Boston, MA 02115 USA. EM ekalexander@partners.org NR 21 TC 7 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-2332 J9 SIMUL HEALTHC JI Simul. Healthc. PD APR PY 2010 VL 5 IS 2 BP 75 EP 81 DI 10.1097/SIH.0b013e3181ca8edc PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 586UG UT WOS:000276938400002 PM 20389232 ER PT J AU Vazquez, J Rosenthal, DI AF Vazquez, Josue Rosenthal, Daniel I. TI Bilateral, symmetrical soft tissue calcifications in the face SO SKELETAL RADIOLOGY LA English DT Article DE Radiesse; Calcifications; Bisphosphonates; Soft tissue; CT; Face; Lipoatrophy; Cosmetic AB A 50-year-old woman with jaw pain and a history of bisphosphonate use was shown on radiography to have ill-defined soft tissue calcifications overlying the maxilla, mandible, and zygomatic bones bilaterally. The bones were normal. CT revealed similar findings. Although a broad imaging differential diagnosis was initially considered, further questioning of the patient revealed a history of facial injections with a calcium hydroxylapatite product for cosmetic purposes. The appearance of this increasingly popular treatment should be recognized to avoid errors in interpretation. C1 [Vazquez, Josue; Rosenthal, Daniel I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Vazquez, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Yawkey 6, Boston, MA 02114 USA. EM josuebmw3@gmail.com NR 5 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD APR PY 2010 VL 39 IS 4 BP 387 EP 389 DI 10.1007/s00256-009-0853-0 PG 3 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 559US UT WOS:000274854100011 PM 20049592 ER PT J AU Richards, K Sawyer, AM AF Richards, Kathy Sawyer, Amy M. TI What We Don't Know about Sleep-Related Breathing Disorders in the Elderly SO SLEEP LA English DT Editorial Material ID WORKING-MEMORY; INTERMITTENT HYPOXIA; APNEA; BRAIN; CONSEQUENCES; IMPAIRMENT; ACTIVATION; DISEASE C1 [Richards, Kathy] Univ Penn, Sch Nursing, John A Hartford Ctr Geriatr Nursing Excellence, Philadelphia, PA 19104 USA. [Richards, Kathy] Univ Penn, Sch Nursing, Ctr Integrat Sci Aging, Philadelphia, PA 19104 USA. [Richards, Kathy] Madlyn & Leonard Abramson Ctr Jewish Life, Polisher Res Inst, N Wales, PA USA. [Sawyer, Amy M.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Richards, K (reprint author), Univ Penn, Sch Nursing, John A Hartford Ctr Geriatr Nursing Excellence, Claire M Fagin Hall,418 Curie Blvd,Room 311, Philadelphia, PA 19104 USA. EM kathyr@nursing.upenn.edu FU NINR NIH HHS [K99 NR011173] NR 20 TC 1 Z9 1 U1 0 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 1 PY 2010 VL 33 IS 4 BP 423 EP 425 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 581IJ UT WOS:000276515500004 PM 20394310 ER PT J AU Brumberg, JS Nieto-Castanon, A Kennedy, PR Guenther, FH AF Brumberg, Jonathan S. Nieto-Castanon, Alfonso Kennedy, Philip R. Guenther, Frank H. TI Brain-computer interfaces for speech communication SO SPEECH COMMUNICATION LA English DT Article DE Brain-computer interface; Neural prosthesis; Speech restoration ID THOUGHT-TRANSLATION DEVICE; INTRACORTICAL ELECTRODE ARRAY; VISUAL-EVOKED POTENTIALS; NEURAL-NETWORK MODEL; CEREBRAL-CORTEX; CONE ELECTRODE; ELECTROCORTICOGRAPHIC SIGNALS; MICROELECTRODE ARRAYS; MACHINE INTERFACE; CORTICAL-NEURONS AB This paper briefly reviews current silent speech methodologies for normal and disabled individuals. Current techniques utilizing electromyographic (EMG) recordings of vocal tract movements are useful for physically healthy individuals but fail for tetraplegic individuals who do not have accurate voluntary control over the speech articulators. Alternative methods utilizing EMG from other body parts (e.g., hand, arm, or facial muscles) or electroencephalography (EEG) can provide capable silent communication to severely paralyzed users, though current interfaces are extremely slow relative to normal conversation rates and require constant attention to a computer screen that provides visual feedback and/or cueing. We present a novel approach to the problem of silent speech via an intracortical microelectrode brain-computer interface (BCI) to predict intended speech information directly from the activity of neurons involved in speech production. The predicted speech is synthesized and acoustically fed back to the user with a delay under 50 ms. We demonstrate that the Neurotrophic Electrode used in the BCI is capable of providing useful neural recordings for over 4 years, a necessary property for BCIs that need to remain viable over the lifespan of the user. Other design considerations include neural decoding techniques based on previous research involving BCIs for computer cursor or robotic arm control via prediction of intended movement kinematics from motor cortical signals in monkeys and humans. Initial results from a study of continuous speech production with instantaneous acoustic feedback show the BCI user was able to improve his control over an artificial speech synthesizer both within and across recording sessions. The success of this initial trial validates the potential of the intracortical microelectrode-based approach for providing a speech prosthesis that can allow much more rapid communication rates. (C) 2010 Elsevier By. All rights reserved. C1 [Brumberg, Jonathan S.; Guenther, Frank H.] Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02215 USA. [Guenther, Frank H.] Boston Univ, Sargent Coll Hlth & Rehabil Sci, Dept Speech Language & Hearing Sci, Boston, MA 02215 USA. [Guenther, Frank H.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Guenther, Frank H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Brumberg, Jonathan S.; Kennedy, Philip R.] Neural Signals Inc, Duluth, GA 30096 USA. [Nieto-Castanon, Alfonso] StatsANC LLC, Buenos Aires, DF, Argentina. RP Brumberg, JS (reprint author), Boston Univ, Dept Cognit & Neural Syst, 677 Beacon St, Boston, MA 02215 USA. EM brumberg@cns.bu.edu FU National Institute on Deafness and other Communication Disorders [R01 DC007683, R01 DC002852, R44 DC007050-02]; CELEST, an NSF Science of Learning Center [NSF SBE-0354378] FX This research was supported by the National Institute on Deafness and other Communication Disorders (R01 DC007683; R01 DC002852; R44 DC007050-02) and by CELEST, an NSF Science of Learning Center (NSF SBE-0354378). The authors thank the participant and his family for their dedication to this research project, Rob Law and Misha Panko for their assistance with the preparation of this manuscript and Tanja Schultz for her helpful comments. NR 76 TC 49 Z9 56 U1 1 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-6393 EI 1872-7182 J9 SPEECH COMMUN JI Speech Commun. PD APR PY 2010 VL 52 IS 4 SI SI BP 367 EP 379 DI 10.1016/j.specom.2010.01.001 PG 13 WC Acoustics; Computer Science, Interdisciplinary Applications SC Acoustics; Computer Science GA 574XB UT WOS:000276026400009 PM 20204164 ER PT J AU Genevay, S Atlas, SJ Katz, JN AF Genevay, Stephane Atlas, Steve J. Katz, Jeffrey N. TI Variation in Eligibility Criteria From Studies of Radiculopathy due to a Herniated Disc and of Neurogenic Claudication due to Lumbar Spinal Stenosis A Structured Literature Review SO SPINE LA English DT Review DE radiculopathy; herniated disc; neurogenic claudication; lumbar spine stenosis; eligibility criteria ID RANDOMIZED CONTROLLED-TRIAL; LOW-BACK-PAIN; PLACEBO-CONTROLLED TRIAL; FOLLOW-UP; MICROENDOSCOPIC DISKECTOMY; NONOPERATIVE TREATMENT; CLINICAL-TRIAL; SCIATICA; THERAPY; EFFICACY AB Study Design. A structured literature review. Summary of the Background Data. Widely recognized classification criteria for rheumatologic disorders have resulted in well-defined patient populations for clinical investigation. Objective. We sought to determine whether similar criteria were needed for back pain disorders by examining variability in eligibility criteria in published studies. Methods. Studies involving radiculopathy due to lumbar herniated disc (HD) and for neurogenic claudication due to lumbar spinal stenosis (LSS) were identified. Randomized controlled trials published between January 1, 2006 and October 1, 2008 in select peer reviewed journals were retrieved, their eligibility criteria were identified and categorized. Results. Twelve eligible HD studies were identified. Thirteen unique categories of eligibility criteria were identified with a mean of 3.9 (+/-2.0) and a range from 0 to 8 categories per study. More categories were present for studies that included nonsurgical (5.6 +/- 2.5) treatment for studies with only surgical treatment (2.6 +/- 1.7) P = 0.04). Seven LSS studies met eligibility criteria, and 9 unique categories were identified. A mean of 5.0 (+/-2.2) categories with a range from 2 to 7 was used per study. Conclusion. Wide variation in the number and type of eligibility criteria from randomized clinical trials of well defined back pain syndromes was identified. These results support the need for developing and disseminating international classification criteria for these clinical conditions. C1 [Genevay, Stephane] Univ Hosp Geneva, Div Rheumatol, CH-1211 Geneva 14, Switzerland. [Genevay, Stephane; Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Genevay, Stephane; Katz, Jeffrey N.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Atlas, Steve J.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Genevay, S (reprint author), Univ Hosp Geneva, Div Rheumatol, 26 Beau Sejour, CH-1211 Geneva 14, Switzerland. EM stephane.genevay@hcuge.ch OI Genevay, Stephane/0000-0003-4752-3186 FU NIH/NIAMS [P60 AR 47782, K24 02123, P60 AR048094] FX Supported by NIH/NIAMS P60 AR 47782 and NIH/NIAMS K24 02123 (to J.N.K.); and supported in part by a grant from (P60 AR048094) to the Multidisciplinary Clinical Research Center in Musculoskeletal Diseases from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (to S.J.A.). NR 40 TC 40 Z9 41 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD APR 1 PY 2010 VL 35 IS 7 BP 803 EP 811 DI 10.1097/BRS.0b013e3181bc9454 PG 9 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 585NV UT WOS:000276833500014 PM 20228710 ER PT J AU Hingtgen, SD Kasmieh, R van de Water, J Weissleder, R Shah, K AF Hingtgen, Shawn D. Kasmieh, Randa van de Water, Jeroen Weissleder, Ralph Shah, Khalid TI A Novel Molecule Integrating Therapeutic and Diagnostic Activities Reveals Multiple Aspects of Stem Cell-Based Therapy SO STEM CELLS LA English DT Article DE TRAIL; Stem cells Cancer Imaging; Pharmacokinetics ID APOPTOSIS-INDUCING LIGAND; DELIVERED S-TRAIL; IN-VIVO; TUMOR-REGRESSION; FUSION PROTEINS; GLIOMA THERAPY; PRECURSOR; CANCER; GENE; PHARMACOKINETICS AB Stem cells are promising therapeutic delivery vehicles; however pre-clinical and clinical applications of stem cell-based therapy would benefit significantly from the ability to simultaneously determine therapeutic efficacy and pharmacokinetics of therapies delivered by engineered stem cells. In this study, we engineered and screened numerous fusion variants that contained therapeutic (TRAIL) and diagnostic (luciferase) domains designed to allow simultaneous investigation of multiple events in stem cell-based therapy in vivo. When various stem cell lines were engineered with the optimized molecule, SRLOL2TR, diagnostic imaging showed marked differences in the levels and duration of secretion between stem cell lines, while the therapeutic activity of the molecule showed the different secretion levels translated to significant variability in tumor cell killing. In vivo, simultaneous diagnostic and therapeutic monitoring revealed that stem cell-based delivery significantly improved pharmacokinetics and anti-tumor effectiveness of the therapy compared to intravenous or intratumoral delivery. As treatment for highly malignant brain tumor xenografts, tracking SRLOL2TR showed stable stem cell-mediated delivery significantly regressed peripheral and intracranial tumors. Together, the integrated diagnostic and therapeutic properties of SRLOL2TR answer critical questions necessary for successful utilization of stem cells as novel therapeutic vehicles. STEM CELLS 2010;28:832-841 C1 [Hingtgen, Shawn D.; Kasmieh, Randa; van de Water, Jeroen; Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA 02114 USA. [Hingtgen, Shawn D.; Kasmieh, Randa; van de Water, Jeroen; Shah, Khalid] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Ctr Syst Biol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shah, Khalid] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shah, Khalid] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Shah, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 149 13th St, Charlestown, MA 02129 USA. EM kshah@helix.mgh.harvard.edu RI van de Water, Jeroen/F-1302-2011 OI van de Water, Jeroen/0000-0001-6974-2270 FU American Brain Tumor Association; American Cancer Gene Therapy; American Cancer Society; [R21 CA131980] FX This work was supported by the American Brain Tumor Association (K. S., S. H.), American Cancer Gene Therapy (K. S.), and American Cancer Society (K. S.), and R21 CA131980 (K. S.) NR 31 TC 21 Z9 21 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD APR PY 2010 VL 28 IS 4 BP 832 EP 841 DI 10.1002/stem.313 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 588SY UT WOS:000277095400021 PM 20127797 ER PT J AU Mandava, P Kalkonde, YV Rochat, RH Kent, TA AF Mandava, Pitchaiah Kalkonde, Yogeshwar V. Rochat, Ryan H. Kent, Thomas A. TI A Matching Algorithm to Address Imbalances in Study Populations Application to the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator Acute Stroke Trial SO STROKE LA English DT Article DE acute treatment; acute stroke; cerebrovascular accident; matching; nearest neighbor ID ACUTE ISCHEMIC-STROKE; NINDS; REANALYSIS; SCORE AB Background and Purpose-Outcome from stroke is highly dependent on baseline conditions. Patients with stroke have a wide range of severities, ages, and etiologies and it has proven difficult to achieve randomization of key variables in clinical trials. We present a new post hoc approach to achieve balance among selected variables. To illustrate the approach, we rebalanced the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator trial, in which the contribution of baseline imbalances continues to be debated. Methods-We selected baseline stroke severity (National Institutes of Health Stroke Scale), age, and glucose as matching criteria. The closest matched placebo and treated subjects were identified based on nearness to each other in 3-dimensional Euclidean space. Matching was performed within the quintiles of National Institutes of Health Stroke Scale that have been previously used to assess balance. Subjects who could not be matched were eliminated. Outcomes were assessed using the original specified National Institute of Neurological Diseases and Stroke trial measures. Results-We successfully matched the 2 arms resulting in nearly identical baseline characteristics and distribution among quintiles. Despite fewer subjects after outlier elimination, the primary outcome measures remained significantly improved. After rebalancing, the magnitude of benefit was reduced by 13% to 23%. Benefit was apparent mostly in the large vessel occlusion subtype. Conclusion-This study demonstrated the feasibility of rebalancing individual subjects within a randomized trial. After rebalancing and outlier elimination, recombinant tissue plasminogen activator continued to demonstrate improved outcome. That the apparent treatment effect was reduced suggests that imbalances contributed to the magnitude of the original National Institute of Neurological Diseases and Stroke outcomes. This method could in theory be applied to any data set to find matched subjects for outcome or other analyses. (Stroke. 2010; 41: 765-770.) C1 [Mandava, Pitchaiah] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. Baylor Coll Med, VA Med Ctr, Stroke Program, Houston, TX 77030 USA. RP Mandava, P (reprint author), Baylor Coll Med, Dept Neurol, 2002 Holcombe Blvd 127, Houston, TX 77030 USA. EM pmandava@bcm.tmc.edu RI Mandava, Pitchaiah/B-6046-2013; OI Mandava, Pitchaiah/0000-0003-4957-4518; Kent, Thomas/0000-0002-9877-7584 NR 28 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP 765 EP 770 DI 10.1161/STROKEAHA.109.574103 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100038 PM 20167911 ER PT J AU Almandoz, JED Su, HS Schaefer, PW Pomerantz, SR Lev, MH Gonzalez, RG Romero, JM AF Almandoz, Josser E. Delgado Su, Henry S. Schaefer, Pamela W. Pomerantz, Stuart R. Lev, Michael H. Gonzalez, R. Gilberto Romero, Javier M. TI Frequency of Adequate Contrast Opacification of the Dural Venous Sinuses With CT Angiography in the Setting of Intracerebral Hemorrhage: Comparison of 16 and 64-Slice CT Angiography Techniques SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Almandoz, Josser E. Delgado] Massachusetts Gen Hosp, Edward Mallinckrodt Inst Radiol, Boston, MA 02114 USA. [Almandoz, Josser E. Delgado] Massachusetts Gen Hosp, Edward Mallinckrodt Inst Radiol, St Louis, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E312 EP E313 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100477 ER PT J AU Almandoz, JED Kelly, HR Brouwers, HB Yoo, AJ Stone, MJ Schaefer, PW Goldstein, JN Rosand, J Lev, MH Gonzalez, RG Romero, JM AF Almandoz, Josser E. Delgado Kelly, Hillary R. Brouwers, H. Bart Yoo, Albert J. Stone, Michael J. Schaefer, Pamela W. Goldstein, Joshua N. Rosand, Jonathan Lev, Michael H. Gonzalez, R. Gilberto Romero, Javier M. TI Frequency and Predictive Value of the CT Angiography Spot Sign in Secondary ICH SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Almandoz, Josser E. Delgado] Massachusetts Gen Hosp, Mallinckrodt Inst Radiol, Boston, MA 02114 USA. RI Goldstein, Joshua/H-8953-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E310 EP E311 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100471 ER PT J AU Almandoz, JED Schaefer, PW Goldstein, JN Rosand, J Lev, MH Gonzalez, RG Romero, JM AF Almandoz, Josser E. Delgado Schaefer, Pamela W. Goldstein, Joshua N. Rosand, Jonathan Lev, Michael H. Gonzalez, R. Gilberto Romero, Javier M. TI Practical Risk Stratification for the Presence of Underlying Vascular Lesions in Patients With Intracerebral Hemorrhage: The Secondary ICH Score SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Almandoz, Josser E. Delgado] Massachusetts Gen Hosp, Mallinckrodt Inst Radiol, Boston, MA 02114 USA. [Almandoz, Josser E. Delgado] Massachusetts Gen Hosp, Mallinckrodt Inst Radiol, St Louis, MA USA. RI Goldstein, Joshua/H-8953-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E211 EP E211 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100104 ER PT J AU Arsava, EM Gokcay, F Baykaner, T Garg, P Wu, O Singhal, AB Furie, KL Sorensen, AG Ay, H AF Arsava, Ethem Murat Gokcay, Figen Baykaner, Tuna Garg, Priya Wu, Ona Singhal, Aneesh B. Furie, Karen L. Sorensen, A. Gregory Ay, Hakan TI Conversion of Ischemic but Viable Tissue Into Infarction is Different Between Men and Women SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Arsava, Ethem Murat; Gokcay, Figen; Baykaner, Tuna; Garg, Priya; Wu, Ona; Sorensen, A. Gregory; Ay, Hakan] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Cntr Biomed Imaging, Boston, MA 02114 USA. [Singhal, Aneesh B.; Furie, Karen L.; Ay, Hakan] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E274 EP E274 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100333 ER PT J AU Ay, H Arsava, EM Furie, KL Schwamm, LH Sorensen, AG AF Ay, Hakan Arsava, Ethem Murat Furie, Karen L. Schwamm, Lee H. Sorensen, A. Gregory TI Prediction of Subsequent Stroke Risk in TIA Patients With Brain Infarction SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Ay, Hakan; Furie, Karen L.; Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. [Ay, Hakan; Arsava, Ethem Murat; Sorensen, A. Gregory] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Cntr Biomed Imaging, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E241 EP E241 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100212 ER PT J AU Batista, LM Lima, FO Januzzi, JL Donahue, V Snydeman, C Greer, DM AF Batista, Leonardo M. Lima, Fabricio O. Januzzi, James L., Jr. Donahue, Vivian Snydeman, Colleen Greer, David M. TI Combined Cardiac Catheterization and Therapeutic Hypothermia Following Cardiac Arrest is Feasible and Safe SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Batista, Leonardo M.; Lima, Fabricio O.; Januzzi, James L., Jr.; Donahue, Vivian; Snydeman, Colleen; Greer, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Lima, Fabricio/E-6507-2015 OI Lima, Fabricio/0000-0002-0383-4145 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E260 EP E260 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100276 ER PT J AU Biffi, A Halpin, A Towfighi, A Gilson, A Busl, K Rost, NS Smith, EE Greenberg, SM Rosand, J Viswanathan, A AF Biffi, Alessandro Halpin, Amy Towfighi, Amytis Gilson, Aaron Busl, Katharina Rost, Natalia S. Smith, Eric E. Greenberg, Steven M. Rosand, Jonathan Viswanathan, Anand TI Antiplatelet Agents, Cerebral Amyloid Angiopathy and Recurrent Intracerebral Hemorrhage SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Biffi, Alessandro; Halpin, Amy; Gilson, Aaron; Busl, Katharina; Rost, Natalia S.; Greenberg, Steven M.; Rosand, Jonathan; Viswanathan, Anand] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Towfighi, Amytis] Univ So Calif, Los Angeles, CA USA. [Smith, Eric E.] Univ Calgary, Calgary, AB, Canada. RI Smith, Eric/C-5443-2012 OI Smith, Eric/0000-0003-3956-1668 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E378 EP E378 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100730 ER PT J AU Cheng-Ching, E Levy, EI Zaidat, O Natarajan, SK Kalia, JS Jovin, TG Yoo, AJ Nogueira, RG Rymer, M Tayal, AH Hsu, DP Liebeskind, DS Abou-Chebl, A Nanda, A Tian, M Hao, Q Nguyen, TN Chen, M Gupta, R AF Cheng-Ching, Esteban Levy, Elad I. Zaidat, Osama Natarajan, Sabareesh K. Kalia, Junaid S. Jovin, Tudor G. Yoo, Albert J. Nogueira, Raul G. Rymer, Marilyn Tayal, Ashis H. Hsu, Daniel P. Liebeskind, David S. Abou-Chebl, Alex Nanda, Ashish Tian, Melissa Hao, Qing Nguyen, Thanh N. Chen, Michael Gupta, Rishi CA UCLA Revascularization Investigato TI Intracranial Stenting is Associated With Higher Rates of Vessel Recanalization During Endovascular Therapy for Acute Ischemic Stroke SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Gupta, Rishi] Cleveland Clin Fdn, Cerebrovasc Ctr, Cleveland, OH 44195 USA. [Levy, Elad I.; Natarajan, Sabareesh K.] SUNY Buffalo, Buffalo, NY 14260 USA. [Zaidat, Osama; Kalia, Junaid S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Jovin, Tudor G.] Univ Pittsburgh, Med Ctr, Stroke Inst, Pittsburgh, PA USA. [Nogueira, Raul G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rymer, Marilyn] St Lukes Brain & Stroke Inst, Kansas City, MO USA. [Tayal, Ashis H.; Tian, Melissa] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Hsu, Daniel P.; Nanda, Ashish] Univ Hosp, Cleveland, OH USA. [Liebeskind, David S.; Hao, Qing; UCLA Revascularization Investigato] Univ Calif Los Angeles, Los Angeles, CA USA. [Abou-Chebl, Alex] Univ Louisville, Med Ctr, Louisville, KY 40292 USA. [Nguyen, Thanh N.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Chen, Michael] Rush Univ, Med Ctr, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E228 EP E228 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100161 ER PT J AU Choi, JH Neimark, MA Konstas, AA Lee, LK Chiang, YT Marshall, RS Pile-Spellman, J AF Choi, Jae H. Neimark, Matthew A. Konstas, Angelos A. Lee, Leslie K. Chiang, Yi T. Marshall, Randolph S. Pile-Spellman, John TI Brain and Systemic Temperature Changes During Selective Endovascular Brain Cooling With Cold Saline: A Translational Research Project SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Choi, Jae H.; Neimark, Matthew A.; Lee, Leslie K.; Chiang, Yi T.; Marshall, Randolph S.; Pile-Spellman, John] Columbia Univ, Med Ctr, New York, NY USA. [Konstas, Angelos A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E373 EP E373 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100714 ER PT J AU Corbin, ZA Rost, NS Parides, MK Blumberg, JB Milbury, PE Arai, K Hartdegen, SN Lo, EH Feske, SK Furie, KL AF Corbin, Zachary A. Rost, Natalia S. Parides, Michael K. Blumberg, Jeffrey B. Milbury, Paul E. Arai, Ken Hartdegen, Sophia N. Lo, Eng H. Feske, Steven K. Furie, Karen L. TI White Matter Hyperintensity Volume Correlates With Levels of Matrix Metalloproteinase-2 SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Corbin, Zachary A.; Rost, Natalia S.; Furie, Karen L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Parides, Michael K.] Mt Sinai Sch Med, New York, NY USA. [Blumberg, Jeffrey B.; Milbury, Paul E.] Tufts Univ, Boston, MA 02111 USA. [Arai, Ken; Hartdegen, Sophia N.; Lo, Eng H.] Massachusetts Gen Hosp, Charlestown, MA USA. [Feske, Steven K.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E370 EP E370 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100700 ER PT J AU Dierksen, GA Skehan, ME Khan, MA Becker, JA Betensky, RA Frosch, MP Rosand, J Viswanathan, A Johnson, K Salat, DH Greenberg, SM AF Dierksen, Gregory A. Skehan, Maureen E. Khan, Muhammad A. Becker, John A. Betensky, Rebecca A. Frosch, Matthew P. Rosand, Jonathan Viswanathan, Anand Johnson, Keith Salat, David H. Greenberg, Steven M. TI Spatial Association Between Cerebral Microbleeds and beta-Amyloid Deposition in Cerebral Amyloid Angiopathy SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Dierksen, Gregory A.; Skehan, Maureen E.; Khan, Muhammad A.; Rosand, Jonathan; Viswanathan, Anand; Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Becker, John A.; Johnson, Keith; Salat, David H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Neuropathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E342 EP E342 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100589 ER PT J AU Fan, X Yu, ZY Dai, HB Lok, JM Singhal, AB Van Cott, EM Lo, EH Wang, XY AF Fan, Xiang Yu, Zhanyang Dai, Haibin Lok, Josephine M. Singhal, Aneesh B. Van Cott, Elizabeth M. Lo, Eng H. Wang, Xiaoying TI Impaired Reperfusion and Worse Neurological Outcomes in a Focal Embolic Stroke Model of Diabetic Rats After tPA Thrombolytic Therapy SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Fan, Xiang; Yu, Zhanyang; Dai, Haibin; Lok, Josephine M.; Singhal, Aneesh B.; Van Cott, Elizabeth M.; Lo, Eng H.; Wang, Xiaoying] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E349 EP E349 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100617 ER PT J AU Greenberg, CH Frosch, MP Greenberg, SM AF Greenberg, Charles H. Frosch, Matthew P. Greenberg, Steven M. TI Modeling the Growth of Microbleeds Into Macrobleeds SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Greenberg, Charles H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Frosch, Matthew P.; Greenberg, Steven M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Frosch, Matthew P.; Greenberg, Steven M.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 1 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 APR PY 2010 VL 41 IS 4 BP E376 EP E377 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100725 ER PT J AU Gupta, R Jovin, TG Levy, EI Yoo, AJ Rymer, MM Tayal, AH Hsu, DP Liebeskind, DS Natarajan, SK Nogueira, RG Nanda, A Tian, M Zaidat, O Hao, Q Kalia, JS Nguyen, TN Chen, M Abou-Chebl, A AF Gupta, Rishi Jovin, Tudor G. Levy, Elad I. Yoo, Albert J. Rymer, Marilyn M. Tayal, Ashis H. Hsu, Daniel P. Liebeskind, David S. Natarajan, Sabareesh K. Nogueira, Raul G. Nanda, Ashish Tian, Melissa Zaidat, Osama Hao, Qing Kalia, Junaid S. Nguyen, Thanh N. Chen, Michael Abou-Chebl, Alex CA UCLA Revascularization Investigato TI General Anesthesia During Endovascular Therapy for Acute Stroke Intervention is Associated With Increased Mortality and Worse Clinical Outcomes SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Gupta, Rishi] Cleveland Clin Fdn, Cerebrovasc Ctr, Cleveland, OH 44195 USA. [Jovin, Tudor G.] Univ Pittsburgh, Med Ctr, Stroke Inst, Pittsburgh, PA USA. [Levy, Elad I.; Natarajan, Sabareesh K.] SUNY Buffalo, Buffalo, NY 14260 USA. [Yoo, Albert J.; Nogueira, Raul G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rymer, Marilyn M.] St Lukes Brain & Stroke Inst, Kansas City, MO USA. [Tayal, Ashis H.; Tian, Melissa] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Hsu, Daniel P.; Nanda, Ashish] Univ Hosp, Cleveland, OH USA. [Liebeskind, David S.; Hao, Qing; UCLA Revascularization Investigato] Univ Calif Los Angeles, Los Angeles, CA USA. [Zaidat, Osama; Kalia, Junaid S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Nguyen, Thanh N.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Chen, Michael] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Abou-Chebl, Alex] Univ Louisville, Med Ctr, Louisville, KY 40292 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E228 EP E228 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100162 ER PT J AU Gurol, ME Davis, PH Leira, EC Strader, S Adams, HP AF Gurol, Mahmut E. Davis, Patricia H. Leira, Enrique C. Strader, Scott Adams, Harold P., Jr. TI The Extent of White Matter Disease on Acute Magnetic Resonance Imaging is an Independent Predictor of Outcome in Ischemic Stroke SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Gurol, Mahmut E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davis, Patricia H.; Leira, Enrique C.; Strader, Scott; Adams, Harold P., Jr.] Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E297 EP E298 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100418 ER PT J AU Hu, RL Yoo, A Hakimelahi, R Lev, M Nogueira, R Hirsch, J Gonzalez, RG Schaefer, P AF Hu, Ranliang Yoo, Albert Hakimelahi, Reza Lev, Michael Nogueira, Raul Hirsch, Joshua Gonzalez, Ramon G. Schaefer, Pamela TI CTA Source Images in the Era of Fast, Volume CT Scanning: Are They Still "DWI" Weighted? SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Hu, Ranliang; Yoo, Albert; Hakimelahi, Reza; Lev, Michael; Nogueira, Raul; Hirsch, Joshua; Gonzalez, Ramon G.; Schaefer, Pamela] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E238 EP E238 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100201 ER PT J AU Kalia, JS Batista, LM Rayes, M Etezadi, V Sweeney, J Pryor, JC Nogueira, RG Xavier, AR Gupta, R Linfante, I Norbash, A Nguyen, T Edgell, R Lynch, JR Fitzsimmons, BF Zaidat, OO AF Kalia, Junaid S. Batista, Leonardo M. Rayes, Mahmoud Etezadi, Vahid Sweeney, Justin Pryor, Johnny C. Nogueira, Raul G. Xavier, Andrew R. Gupta, Rishi Linfante, Italo Norbash, Alexander Nguyen, Thanh Edgell, Randy Lynch, John R. Fitzsimmons, Brian-Fred Zaidat, Osama O. CA Endovasc Coiling Small Aneurysm Mu TI Safety and Feasibility of Elective Endovascular Coiling of Very Small (2-7 mm) Unruptured Cerebral Aneurysms (ECOSA Study): A Multicenter Experience Analysis SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Kalia, Junaid S.; Lynch, John R.; Fitzsimmons, Brian-Fred; Zaidat, Osama O.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Batista, Leonardo M.; Pryor, Johnny C.; Nogueira, Raul G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rayes, Mahmoud; Xavier, Andrew R.] Wayne State Univ, Detroit, MI USA. [Etezadi, Vahid; Linfante, Italo] Baptist Cardiac & Vasc Inst, Miami, FL USA. [Sweeney, Justin; Edgell, Randy] St Louis Univ, St Louis, MO 63103 USA. [Gupta, Rishi] Cleveland Clin, Cleveland, OH 44106 USA. [Norbash, Alexander; Nguyen, Thanh] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E242 EP E242 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100216 ER PT J AU Kelly, HR Almandoz, JED Passanese, JC Lev, MH Schaefer, PW Gonzalez, RG Romero, JM AF Kelly, Hillary R. Almandoz, Josser E. Delgado Passanese, John C. Lev, Michael H. Schaefer, Pamela W. Gonzalez, R. G. Romero, Javier M. TI The CT Angiography Spot Sign Predicts Hematoma Expansion and In-hospital Mortality in Traumatic Subdural Hemorrhage SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Almandoz, Josser E. Delgado] Massachusetts Gen Hosp, Mallinckrodt Inst Radiol, Boston, MA 02114 USA. [Passanese, John C.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E311 EP E312 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100474 ER PT J AU Kemmling, A Pervez, MA Lev, MH Masrur, S Payabvash, S Schwamm, LH AF Kemmling, Andre Pervez, Muhammad A. Lev, Michael H. Masrur, Shibab Payabvash, Seyedmehdi Schwamm, Lee H. TI Hospital Acquired Pneumonia is Linked to Peri-insular Right Hemispheric and Infratentorial Acute Stroke SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Kemmling, Andre] Univ Munster, Munster, Germany. [Pervez, Muhammad A.; Lev, Michael H.; Masrur, Shibab; Payabvash, Seyedmehdi; Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E380 EP E380 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100741 ER PT J AU Lima, FO Silva, GS Batista, LM Camargo, EC Singhal, AB Ay, H Greer, DM Yoo, AJ Lev, MH Harris, GJ Koroshetz, WJ Smith, WS Furie, KL Nogueira, RG AF Lima, Fabricio O. Silva, Gisele S. Batista, Leonardo M. Camargo, Erica C. Singhal, Aneesh B. Ay, Hakan Greer, David M. Yoo, Albert J. Lev, Michael H. Harris, Gordon J. Koroshetz, Walter J. Smith, Wade S. Furie, Karen L. Nogueira, Raul G. TI Natural History of Untreated Strokes Due to Proximal Anterior Circulation Occlusions Detected on CT Angiography SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Lima, Fabricio O.; Silva, Gisele S.; Batista, Leonardo M.; Camargo, Erica C.; Singhal, Aneesh B.; Ay, Hakan; Greer, David M.; Yoo, Albert J.; Lev, Michael H.; Harris, Gordon J.; Furie, Karen L.; Nogueira, Raul G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Koroshetz, Walter J.] NINDS, NIH, Bethesda, MD 20892 USA. [Smith, Wade S.] UCSF Med Ctr, San Francisco, CA USA. RI Lima, Fabricio/E-6507-2015 OI Lima, Fabricio/0000-0002-0383-4145 NR 0 TC 1 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 APR PY 2010 VL 41 IS 4 BP E333 EP E333 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100559 ER PT J AU Lima, FO Silva, GS Levy, MH Harris, G Smith, WS Halpern, EF Koroshetz, W Furie, KL AF Lima, Fabricio O. Silva, Gisele S. Levy, Michael H. Harris, Gordon Smith, Wade S. Halpern, Elkan F. Koroshetz, Walter Furie, Karen L. TI Differences in Risk Factors Between Intracranial and Extracranial Atherosclerosis in a Predominantly White American Population SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Lima, Fabricio O.; Silva, Gisele S.; Levy, Michael H.; Harris, Gordon; Halpern, Elkan F.; Furie, Karen L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Wade S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Koroshetz, Walter] NINDS, Bethesda, MD 20892 USA. RI Lima, Fabricio/E-6507-2015 OI Lima, Fabricio/0000-0002-0383-4145 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E271 EP E271 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100320 ER PT J AU Liu, J Gao, BB Clermont, A Chilcote, T Sinha, S Feener, E AF Liu, Jia Gao, Ben-Bo Clermont, Allen Chilcote, Tamie Sinha, Sukanto Feener, Edward TI Activated Plasma Kallikrein Impairs Hemostasis and Contributes to Cerebral Hemorrhage in Hyperglycemia SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Liu, Jia; Gao, Ben-Bo; Clermont, Allen; Feener, Edward] Joslin Diabet Ctr, Boston, MA 02215 USA. [Chilcote, Tamie; Sinha, Sukanto] ActiveSite Pharmaceut Inc, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E377 EP E377 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100726 ER PT J AU Natarajan, SK Ogilvy, CS Hopkins, LN Siddiqui, AH Levy, EI AF Natarajan, Sabareesh K. Ogilvy, Christopher S. Hopkins, Leo N. Siddiqui, Adnan H. Levy, Elad I. TI Initial Experience With a Second-generation Everolimus-eluting Stent for Treatment of Intracranial Atherosclerosis SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Natarajan, Sabareesh K.; Hopkins, Leo N.; Siddiqui, Adnan H.; Levy, Elad I.] SUNY Buffalo, Buffalo, NY 14260 USA. [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E314 EP E314 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100482 ER PT J AU Nguyen, TN Zaidat, OO Gupta, R Nogueira, RG Tariq, N Kalia, JS Norbash, AM Qureshi, AI AF Nguyen, Thanh N. Zaidat, Osama O. Gupta, Rishi Nogueira, Raul G. Tariq, Nauman Kalia, Junaid S. Norbash, Alexander M. Qureshi, Adnan I. TI Balloon Angioplasty for Intracranial Atherosclerotic Disease Using New Generation Angioplasty Balloon Catheters: Periprocedural Risks and Short Term Outcomes in a Multicenter Study SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Nguyen, Thanh N.; Norbash, Alexander M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Zaidat, Osama O.; Kalia, Junaid S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Gupta, Rishi] Cleveland Clin, Cerebrovasc Cntr, Cleveland, OH 44106 USA. [Nogueira, Raul G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tariq, Nauman; Qureshi, Adnan I.] Univ Minnesota, Zeenat Qureshi Stroke Rsch Cntr, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E355 EP E355 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100639 ER PT J AU Nogueira, RG Gupta, R Liebeskind, DS Rymer, MM Barreto, AD Levy, EI Zaidat, OO Rai, A Baxter, B Jovin, T AF Nogueira, Raul G. Gupta, Rishi Liebeskind, David S. Rymer, Marilyn M. Barreto, Andrew D. Levy, Elad I. Zaidat, Osama O. Rai, Ansaar Baxter, Blaise Jovin, Tudor TI Neither Time to Treatment Nor the Use of Adjunctive Intra-arterial Thrombolytics Increase the Risk for Symptomatic Intracranial Hemorrhage After Endovascular Treatment of CT Perfusion or MRI-selected Stroke Patients Treated at Late Time Windows: Analysis of the Pre-DAWN Dataset SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Nogueira, Raul G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gupta, Rishi] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Liebeskind, David S.] UCLA Revascularizat Investigators, Los Angeles, CA USA. [Rymer, Marilyn M.] St Lukes Brain & Stroke Inst, Kansas City, MO USA. [Barreto, Andrew D.] Univ Texas Houston Med Sch, Houston, TX USA. [Levy, Elad I.] SUNY Buffalo, Buffalo, NY 14260 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Rai, Ansaar] W Virginia Univ, Morgantown, VA USA. [Baxter, Blaise] Erlanger Reg Stroke Ctr, Chattanooga, TN USA. [Jovin, Tudor] UPMC, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E227 EP E227 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100159 ER PT J AU Nogueira, RG Smith, WS Jovin, T Liebeskind, DS Budzik, RF Baxter, B Rymer, MM AF Nogueira, Raul G. Smith, Wade S. Jovin, Tudor Liebeskind, David S. Budzik, Ronald F. Baxter, Blaise Rymer, Marilyn M. TI Thrombectomy for Acute Ischemic Stroke Patients Aged 80 Years or Older: Long-term Outcomes in 178 Patients SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Nogueira, Raul G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Wade S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Jovin, Tudor] UPMC, Pittsburgh, PA USA. [Liebeskind, David S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Budzik, Ronald F.] Riverside Methodist Hosp, Columbus, OH 43214 USA. [Baxter, Blaise] Erlanger Med Ctr, Chattanooga, TN USA. [Rymer, Marilyn M.] St Lukes Hosp, Kansas City, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E227 EP E228 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100160 ER PT J AU Oleinik, A Romero, J Almandoz, JED Schwab, K Hillary, RK Greenberg, SM Rosand, J Goldstein, JN AF Oleinik, Alexandra Romero, Javier Almandoz, Josser E. Delgado Schwab, Kristin Hillary, R. K. Greenberg, Steven M. Rosand, Jonathan Goldstein, Joshua N. TI Patients With Hematoma Expansion Following Acute Intracerebral Hemorrhage Often Present Late or With an Unknown Onset Time SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Oleinik, Alexandra; Romero, Javier; Schwab, Kristin; Hillary, R. K.; Greenberg, Steven M.; Rosand, Jonathan; Goldstein, Joshua N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Almandoz, Josser E. Delgado] Washington Univ, St Louis Sch Med, St Louis, MO USA. RI Goldstein, Joshua/H-8953-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E313 EP E313 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100479 ER PT J AU Pervez, MA Rymer, M Lainhart, K Masrur, S Jauch, EC Schwamm, LH AF Pervez, Muhammad A. Rymer, Marilyn Lainhart, Kathy Masrur, Shihab Jauch, Edward C. Schwamm, Lee H. TI EMS Treatment and Transport of Stroke Patients Post IV tPA: Baseline Adherence to Recommended Processes of Care for "Drip and Ship" Patients SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Pervez, Muhammad A.; Masrur, Shihab; Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rymer, Marilyn; Lainhart, Kathy] St Lukes Hosp, Kansas City, MO USA. [Jauch, Edward C.] Med Univ S Carolina, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E287 EP E288 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100380 ER PT J AU Pikula, A Beiser, AS Himali, JJ Debette, S DeCarli, C Au, R Selhub, J Tofler, GH Wang, TJ Kelly-Hayes, M Kase, CS Benjamin, EJ Vasan, RS Wolf, PA Seshadri, S AF Pikula, Aleksandra Beiser, Alexa S. Himali, Jayandra J. Debette, Stephanie DeCarli, Charles Au, Rhoda Selhub, Jacob Tofler, Geoffrey H. Wang, Thomas J. Kelly-Hayes, Margaret Kase, Carlos S. Benjamin, Emelia J. Vasan, Ramachandran S. Wolf, Philip A. Seshadri, Sudha TI Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury: The Framingham Offspring Study SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Pikula, Aleksandra; Beiser, Alexa S.; Himali, Jayandra J.; Debette, Stephanie; Au, Rhoda; Kelly-Hayes, Margaret; Kase, Carlos S.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med & Publ Hlth, Boston, MA 02215 USA. [Pikula, Aleksandra; Beiser, Alexa S.; Himali, Jayandra J.; Debette, Stephanie; Au, Rhoda; Kelly-Hayes, Margaret; Kase, Carlos S.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Wolf, Philip A.; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Pikula, Aleksandra; Beiser, Alexa S.; Himali, Jayandra J.; Debette, Stephanie; Au, Rhoda; Kelly-Hayes, Margaret; Kase, Carlos S.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Wolf, Philip A.; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Boston, MA USA. [DeCarli, Charles] Univ Calif Davis, Sacramento, CA 95817 USA. [Selhub, Jacob] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer US Dept Agr, Boston, MA 02111 USA. [Tofler, Geoffrey H.] Royal N Shore Hosp, Sydney, NSW, Australia. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RI DeCarli, Charles/B-5541-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E240 EP E240 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100209 ER PT J AU Poisson, SN Nguyen-Huynh, MN Johnston, SC Furie, KL Lev, MH Smith, WS AF Poisson, Sharon N. Nguyen-Huynh, Mai N. Johnston, S. Claiborne Furie, Karen L. Lev, Michael H. Smith, Wade S. TI Large Vessel Occlusion Does Not Predict Outcome in TIA SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Poisson, Sharon N.; Nguyen-Huynh, Mai N.; Johnston, S. Claiborne; Smith, Wade S.] UCSF, San Francisco, CA USA. [Furie, Karen L.; Lev, Michael H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E314 EP E314 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100483 ER PT J AU Romero, JR Schwamm, LH Frey, JL Demaerschalk, BM Chaliki, HP Parikh, G Babikian, V AF Romero, Jose Rafael Schwamm, Lee H. Frey, James L. Demaerschalk, Bart M. Chaliki, Hari P. Parikh, Gunjan Babikian, Viken TI Safety of TCD "Bubble Study" Response SO STROKE LA English DT Letter C1 [Romero, Jose Rafael; Babikian, Viken] Boston Univ, Med Ctr, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Romero, Jose Rafael] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Schwamm, Lee H.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Frey, James L.; Parikh, Gunjan] Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA. [Demaerschalk, Bart M.; Chaliki, Hari P.] Mayo Clin Hosp, Dept Neurol, Phoenix, AZ USA. RP Romero, JR (reprint author), Boston Univ, Med Ctr, Sch Med, Dept Neurol, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E196 EP E196 DI 10.1161/STROKEAHA.109.563668 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100063 ER PT J AU Sale, MM Hsu, FC Mychaleckyj, JC Rich, SS Furie, KL Worrall, BB AF Sale, Michele M. Hsu, Fang-Chi Mychaleckyj, Josyf C. Rich, Stephen S. Furie, Karen L. Worrall, Bradford B. TI A Variant in the Adenosine 2B Receptor Gene is Associated With Homocysteine Levels and Stroke Severity in African American Subjects From the Vitamin Intervention for Stroke Prevention (VISP) Trial SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Sale, Michele M.; Mychaleckyj, Josyf C.; Rich, Stephen S.; Worrall, Bradford B.] Univ Virginia, Charlottesville, VA USA. [Hsu, Fang-Chi] Wake Forest Univ, Winston Salem, NC 27109 USA. [Furie, Karen L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Furie, Karen L.] Harvard Univ, Boston, MA 02115 USA. NR 0 TC 2 Z9 2 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 APR PY 2010 VL 41 IS 4 BP E334 EP E334 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100562 ER PT J AU Schaefer, P Kamalian, S Kamalian, MS Wang, B Yoo, A Gonzalez, RG Lev, MH AF Schaefer, Pamela Kamalian, Shahmir Kamalian, Mohammed S. Wang, Bing Yoo, ALbert Gonzalez, Ramon G. Lev, Michael H. TI Infarct Core Size Greater Than 58 cc on Thresholded CT Cerebral Blood Flow Maps is Highly Correlated With Poor Outcome SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Schaefer, Pamela; Kamalian, Shahmir; Kamalian, Mohammed S.; Wang, Bing; Yoo, ALbert; Gonzalez, Ramon G.; Lev, Michael H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Kamalian, Shervin/D-7667-2013 OI Kamalian, Shervin/0000-0001-8962-4773 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E344 EP E344 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100595 ER PT J AU Silva, G Smith, EE Topcuoglu, MA Singhal, AB AF Silva, Gisele Smith, Eric E. Topcuoglu, Mehmet A. Singhal, Aneesh B. TI Paradoxical Responses on Breath-holding TCD in Reversible Cerebral Vasoconstriction Syndromes (RCVS) SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Silva, Gisele; Singhal, Aneesh B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Eric E.] Univ Calgary, Calgary, AB, Canada. [Topcuoglu, Mehmet A.] Hacettepe Univ, Ankara, Turkey. RI Smith, Eric/C-5443-2012 OI Smith, Eric/0000-0003-3956-1668 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E316 EP E316 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100491 ER PT J AU Singhal, AB Hajj-Ali, RA Topcuoglu, MA Fok, JW Bena, J Yang, DS Calabrese, LH AF Singhal, Aneesh B. Hajj-Ali, Rula A. Topcuoglu, Mehmet A. Fok, Joshua W. Bena, James Yang, Dongsheng Calabrese, Leonard H. TI Empiric Immunosuppressive Therapy in Reversible Cerebral Vasoconstriction Syndromes (RCVS) is Associated With Worse Clinical Outcome SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Singhal, Aneesh B.; Fok, Joshua W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hajj-Ali, Rula A.; Bena, James; Yang, Dongsheng; Calabrese, Leonard H.] Cleveland Clin, Cleveland, OH 44106 USA. [Topcuoglu, Mehmet A.] Hacettepe Univ Hosp, Ankara, Turkey. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E233 EP E233 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100182 ER PT J AU Smith, EE Shobha, N Dai, D Olson, D Reeves, MJ Saver, J Peterson, ED Hernandez, A Fonarow, GC Schwamm, LH AF Smith, Eric E. Shobha, Nandavar Dai, David Olson, DaWai Reeves, Mathew J. Saver, Jeffrey Peterson, Eric D. Hernandez, Adrian Fonarow, Gregg C. Schwamm, Lee H. TI Prediction of In-hospital Stroke Mortality Using Data From the Get With the Guidelines-Stroke Registry SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Smith, Eric E.; Shobha, Nandavar] Univ Calgary, Calgary, AB, Canada. [Dai, David; Olson, DaWai; Peterson, Eric D.; Hernandez, Adrian] Duke Clin Rsch Inst, Durham, NC USA. [Reeves, Mathew J.] Michigan State Univ, E Lansing, MI 48824 USA. [Saver, Jeffrey; Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Smith, Eric/C-5443-2012 OI Smith, Eric/0000-0003-3956-1668 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E220 EP E220 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100137 ER PT J AU Souza, LC Payabvash, S Wang, YF Kamalian, S Gonzalez, RG Furie, KL Lev, MH AF Souza, Leticia C. Payabvash, Seyedmehdi Wang, Yifei Kamalian, Shahmir Gonzalez, R. Gilberto Furie, Karen L. Lev, Michael H. TI CT Perfusion Imaging (CTP) Mean Transit Time Prolongation, NIH Stroke Scale Score, and Thrombolytic Therapy Are Independent Predictors of Hemorrhagic Transformation (HT) in Acute Ischemic Stroke SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Souza, Leticia C.; Payabvash, Seyedmehdi; Kamalian, Shahmir; Gonzalez, R. Gilberto; Furie, Karen L.; Lev, Michael H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wang, Yifei] Univ Western Ontario, Schulich Sch Med & Dent, London, ON, Canada. RI Kamalian, Shervin/D-7667-2013 OI Kamalian, Shervin/0000-0001-8962-4773 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E311 EP E311 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100473 ER PT J AU Wu, GX Chilcote, TJ Sinha, S Feener, EP AF Wu, Gongxiong Chilcote, Tamie J. Sinha, Sukanto Feener, Edward P. TI Role of Plasma Kallikrein on Ischemic Stroke in Diabetic Rats SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Wu, Gongxiong; Feener, Edward P.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Wu, Gongxiong; Feener, Edward P.] Harvard Univ, Sch Med, Boston, MA USA. [Chilcote, Tamie J.; Sinha, Sukanto] ActiveSite Pharmaceut Inc, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E354 EP E354 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100636 ER PT J AU Wu, O Schwamm, LH Garg, P Pervez, MA Yoo, AJ Chutinet, A Irie, RE Yook, B Copen, WA Schaefer, PW Singhal, AB Furie, KL Sorensen, AG AF Wu, Ona Schwamm, Lee H. Garg, Priya Pervez, Muhammad A. Yoo, Albert J. Chutinet, Aurauma Irie, Robert E. Yook, Byeongseo Copen, William A. Schaefer, Pamela W. Singhal, Aneesh B. Furie, Karen L. Sorensen, A. G. TI Using MRI as the Witness: Multimodal MRI-based Determination of Acute Stroke Onset SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Wu, Ona; Schwamm, Lee H.; Garg, Priya; Pervez, Muhammad A.; Yoo, Albert J.; Chutinet, Aurauma; Irie, Robert E.; Yook, Byeongseo; Copen, William A.; Schaefer, Pamela W.; Singhal, Aneesh B.; Furie, Karen L.; Sorensen, A. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E273 EP E273 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100330 ER PT J AU Wu, O Batista, LM Lima, FO Furie, KL Greer, DM AF Wu, Ona Batista, Leonardo M. Lima, Fabricio O. Furie, Karen L. Greer, David M. TI Predicting Clinical Outcome in Comatose Cardiac Arrest Patients Using Early CT SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Wu, Ona; Batista, Leonardo M.; Lima, Fabricio O.; Furie, Karen L.; Greer, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Lima, Fabricio/E-6507-2015 OI Lima, Fabricio/0000-0002-0383-4145 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E238 EP E239 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100203 ER PT J AU Yavagal, D Drazin, D Gifford, E Edgell, R Rayes, M Xavier, A Hussain, MS Gupta, R Kalia, J Zaidat, OO Linfante, I Nogueira, R Nguyen, T Boulos, A AF Yavagal, Dileep Drazin, Doniel Gifford, Edward Edgell, Randall Rayes, Mahmood Xavier, Andrew Hussain, Muhammad S. Gupta, Rishi Kalia, Junaid Zaidat, Osama O. Linfante, Italo Nogueira, Raul Nguyen, Thanh Boulos, Alan TI US Multicenter Study of Endovascular Therapy in Ruptured Cerebral Aneurysms With Partent Artery Vasospasm SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Yavagal, Dileep] Univ Miami, Miller Sch, Miami, FL USA. [Drazin, Doniel] Cedars Sinai Med Cntr, Los Angeles, CA USA. [Gifford, Edward; Boulos, Alan] Albany Med Cntr, Albany, NY USA. [Edgell, Randall] St Louis Univ, St Louis, MO 63103 USA. [Rayes, Mahmood; Xavier, Andrew] Wayne State Univ, Detroit, MI USA. [Hussain, Muhammad S.; Gupta, Rishi] Cleveland Clin, Cleveland, OH 44106 USA. [Kalia, Junaid; Zaidat, Osama O.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Linfante, Italo] Baptist Med Cntr, Miami, FL USA. [Nogueira, Raul] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nguyen, Thanh] Boston Univ, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E237 EP E237 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100199 ER PT J AU Zaganas, I Halpin, AP Oleink, A Kotzamani, D Chlapoutaki, C Tsimoulis, D Zafiris, S Giannakoudakis, E Alegakis, A Papadaki, E Furie, KL Greenberg, SM Plaitakis, A AF Zaganas, Ioannis Halpin, Amy P. Oleink, Alexandra Kotzamani, Dimitra Chlapoutaki, Chryssanthi Tsimoulis, Dimitris Zafiris, Spiros Giannakoudakis, Emmanouil Alegakis, Athanasios Papadaki, Efrosini Furie, Karen L. Greenberg, Steven M. Plaitakis, Andreas TI A Comparison of Acute Hemorrhagic Stroke Outcomes in Two Populations: The Crete-Boston Study SO STROKE LA English DT Meeting Abstract CT International Stroke Conference CY FEB 23-26, 2010 CL San Antonio, TX SP Amer Heart Assoc, Amer Stroke Assoc C1 [Zaganas, Ioannis; Kotzamani, Dimitra; Chlapoutaki, Chryssanthi; Tsimoulis, Dimitris; Zafiris, Spiros; Giannakoudakis, Emmanouil; Plaitakis, Andreas] Univ Hosp Crete, Dept Neurol, Iraklion, Crete, Greece. [Papadaki, Efrosini] Univ Hosp Crete, Dept Radiol, Iraklion, Crete, Greece. [Alegakis, Athanasios] Univ Hosp Crete, Dept Toxicol, Iraklion, Crete, Greece. [Halpin, Amy P.; Oleink, Alexandra; Furie, Karen L.; Greenberg, Steven M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2010 VL 41 IS 4 BP E212 EP E212 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 575XU UT WOS:000276106100105 ER PT J AU Meeker, JD Hauser, R AF Meeker, John D. Hauser, Russ TI Exposure to Polychlorinated Biphenyls (PCBs) and Male Reproduction SO SYSTEMS BIOLOGY IN REPRODUCTIVE MEDICINE LA English DT Review DE endocrine; environment; epidemiology; hormone; semen; sperm ID SPERM CHROMATIN INTEGRITY; TESTICULAR CANCER; FISH CONSUMPTION; SEMEN QUALITY; HUMAN HEALTH; PERSISTENT ORGANOCHLORINES; ENVIRONMENTAL EXPOSURE; CONSTRUCTION WORKERS; ENDOGENOUS HORMONES; EUROPEAN COUNTRIES AB Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants that were widely used in the mid-20th century. Though their production and use was banned by most countries several decades ago, the general population continues to be exposed due to the persistence and bioaccumulation of PCBs. A number of human epidemiological studies have assessed the relationship between environmental PCB exposure and markers of male reproductive health, namely semen quality parameters (sperm concentration, motility, and morphology), sperm DNA integrity (DNA damage or chromatin fragmentation), and circulating reproductive hormone levels. Despite a wide range of study designs and locations, measurement methods, and PCB exposure levels, reports of inverse associations between PCBs and sperm motility have been consistent which may suggest a lack of exposure threshold for a PCB-related effect on sperm motility. Several studies have also reported inverse associations between PCBs and circulating testosterone levels in men, though the specific form of testosterone (i.e. total, bound, or free testosterone) associated with exposure has not been fully consistent between studies. In conclusion, although PCBs are no longer used and can be considered a legacy chemical, concerns regarding altered male fertility in relation to PCBs remain due to the existing human data demonstrating inverse associations with markers of male reproductive function coupled with recent evidence for continued population exposure.= 3 compared with 2 drinks/drinking day. Conclusions In 9 nationally representative samples of U. S. adults, light and moderate alcohol consumption were inversely associated with CVD mortality, even when compared with lifetime abstainers, but consumption above recommended limits was not. (J Am Coll Cardiol 2010; 55: 1328-35) (C) 2010 by the American College of Cardiology Foundation C1 [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Chen, Chiung M.] CSR Inc, Arlington, VA USA. [Rao, Sowmya R.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Rao, Sowmya R.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Breslow, Rosalind A.] NIAAA, Div Epidemiol & Prevent Res, Rockville, MD 20852 USA. RP Mukamal, KJ (reprint author), BIDMC, Div Gen Med & Primary Care, Res Program, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. EM kmukamal@bidmc.harvard.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [N0AA32007, HHSN267200800023C]; GE Corporate Healthcare FX From the *Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts; dagger CSR Incorporated, Arlington, Virginia; Biostatistics Center and Institute for Health Policy, Massachusetts General Hospital, Boston, Massachusetts; and the Division of Epidemiology and Prevention Research, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland. Computer programming and statistical support were provided through the Alcohol Epidemiologic Data System funded by contracts N0AA32007 and HHSN267200800023C from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The NIAAA reviewed and approved this report before submission. The findings and conclusions in this report are those of the authors and not necessarily those of the agency. Dr. Rao has received funding from GE Corporate Healthcare. NR 53 TC 80 Z9 81 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 30 PY 2010 VL 55 IS 13 BP 1328 EP 1335 DI 10.1016/j.jacc.2009.10.056 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 573CL UT WOS:000275885900006 PM 20338493 ER PT J AU Maron, DJ Boden, WE O'Rourke, RA Hartigan, PM Calfas, KJ Mancini, GBJ Spertus, JA Dada, M Kostuk, WJ Knudtson, M Harris, CL Sedlis, SP Zoble, RG Title, LM Gosselin, G Nawaz, S Gau, GT Blaustein, AS Bates, ER Shaw, LJ Berman, DS Chaitman, BR Weintraub, WS Teo, KK AF Maron, David J. Boden, William E. O'Rourke, Robert A. Hartigan, Pamela M. Calfas, Karen J. Mancini, G. B. John Spertus, John A. Dada, Marcin Kostuk, William J. Knudtson, Merril Harris, Crystal L. Sedlis, Steven P. Zoble, Robert G. Title, Lawrence M. Gosselin, Gilbert Nawaz, Shah Gau, Gerald T. Blaustein, Alvin S. Bates, Eric R. Shaw, Leslee J. Berman, Daniel S. Chaitman, Bernard R. Weintraub, William S. Teo, Koon K. CA COURAGE Trial Res Grp TI Intensive Multifactorial Intervention for Stable Coronary Artery Disease Optimal Medical Therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary disease; medical therapy; risk factors; secondary prevention ID CONVERTING ENZYME-INHIBITORS; ACUTE MYOCARDIAL-INFARCTION; QUALITY-OF-LIFE; RANDOMIZED-TRIALS; SECONDARY PREVENTION; GLUCOSE CONTROL; HEART-DISEASE; DIET-HEART; TASK-FORCE; METAANALYSIS AB Objectives This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. Background Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. Methods All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. Results The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked >= 150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 +/- 0.13 kg/m(2) to 29.3 +/- 0.23 kg/m(2) (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 +/- 0.49 mm Hg to 123 +/- 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 +/- 0.83 mg/dl to 72 +/- 0.88 mg/dl. Conclusions Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657) (J Am Coll Cardiol 2010; 55: 1348-58) (C) 2010 by the American College of Cardiology Foundation C1 [Maron, David J.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Maron, David J.] Vanderbilt Univ, Sch Med, Dept Emergency Med, Nashville, TN 37212 USA. [Boden, William E.] SUNY Buffalo, Buffalo, NY 14260 USA. [Boden, William E.] Buffalo Gen Hosp, Buffalo, NY 14203 USA. [O'Rourke, Robert A.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Hartigan, Pamela M.] VA Cooperat Studies Program, Coordinating Ctr, West Haven, CT USA. [Calfas, Karen J.] Univ Calif San Diego, San Diego, CA 92103 USA. [Mancini, G. B. John] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Spertus, John A.] Univ Missouri, Mid Amer Heart Inst, Kansas City, MO 64110 USA. [Kostuk, William J.] London Hlth Sci Ctr, London, ON, Canada. [Dada, Marcin] Hartford Hosp, Hartford, CT 06115 USA. [Knudtson, Merril] Libin Cardiovasc Inst Alberta, Edmonton, AB, Canada. [Harris, Crystal L.] VA Cooperat Studies Program, Albuquerque, NM USA. [Sedlis, Steven P.] NYU, Sch Med, New York, NY USA. [Sedlis, Steven P.] Vet Affairs New York Harbor Hlth Care Syst, New York, NY USA. [Zoble, Robert G.] James A Haley Vet Adm Med Ctr, Tampa, FL 33612 USA. [Title, Lawrence M.] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Gosselin, Gilbert] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Nawaz, Shah] Sudbury Reg Hosp, Sudbury, ON, Canada. [Gau, Gerald T.] Mayo Clin, Rochester, MN USA. [Blaustein, Alvin S.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Bates, Eric R.] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Shaw, Leslee J.] Emory Univ, Atlanta, GA 30322 USA. [Berman, Daniel S.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Chaitman, Bernard R.] St Louis Univ, St Louis, MO 63103 USA. [Weintraub, William S.] Christiana Care Hlth Syst, Newark, DE USA. [Teo, Koon K.] McMaster Univ, Med Ctr, Hamilton, ON, Canada. RP Maron, DJ (reprint author), Vanderbilt Heart & Vasc Inst, 1215 21st Ave S,MCE 5th Floor S Tower, Nashville, TN 37232 USA. EM david.maron@vanderbilt.edu OI Sedlis, Steven/0000-0002-8194-8017 FU Merck; Abbott Laboratories; Amgen; Roche Diagnostics; Lilly; CV Therapeutics; Bristol-Myers Squibb; Astellas Healthcare; Sanofi-Aventis; Boehringer Ingelheim FX Dr. Boden has received consulting fees and lecture fees from Kos Pharmaceuticals, PDL BioPharma, Pfizer, CV Therapeutics, and Sanofi-Aventis and grant support from Merck and Abbott Laboratories. Dr. O'Rourke has received consulting fees from King Pharmaceuticals, Lilly, and CV Therapeutics. Dr. Calfas has been a stockholder of SanTech, Inc. a company founded in cooperation with San Diego State University and exclusively licensed to disseminate the PACE materials. Dr. Mancini has received honoraria from Merck, GlaxoSmithKline, Sanofi-Aventis, AstraZeneca and Abbott. Dr. Spertus has received consulting fees from Amgen and United Healthcare and grant support from Amgen, Roche Diagnostics, and Lilly (and in the past, consulting fees and grant support from CV Therapeutics and has been owner of the copyright for the Seattle Angina Questionnaire, the Peripheral Artery Questionnaire, and the Kansas City Cardiomyopathy Questionnaire). Dr. Bates has received consulting fees from Sanofi-Aventis and AstraZeneca and lecture fees from Sanofi-Aventis. Dr. Shaw has received grant support from Bristol-Myers Squibb and Astellas Healthcare. Dr. Berman has received consulting fees, lecture fees, and grant support from Bristol-Myers Squibb and software royalties from Cedars Sinai Medical Center. Dr. Chaitman has received consulting fees from CV Therapeutics, Roche, Merck, Lilly, Sanofi-Aventis, Forest; lecture fees from CV Therapeutics; and research grants from Roche and CV Therapeutics. Dr. Weintraub has received consulting fees from Sanofi-Aventis and Bristol-Myers Squibb and grant support from Sanofi-Aventis. Dr. Teo has received grant support from Boehringer Ingelheim. NR 50 TC 50 Z9 52 U1 1 U2 14 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 MAR 30 PY 2010 VL 55 IS 13 BP 1348 EP 1358 DI 10.1016/j.jacc.2009.10.062 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 573CL UT WOS:000275885900009 PM 20338496 ER PT J AU Cornier, MA Salzberg, AK Endly, DC Bessesen, DH Tregellas, JR AF Cornier, Marc-Andre Salzberg, Andrea K. Endly, Dawnielle C. Bessesen, Daniel H. Tregellas, Jason R. TI Sex-based differences in the behavioral and neuronal responses to food SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE fMRI; Neuroimaging; Obesity; Food intake; Gender; Appetite ID REDUCED-OBESE INDIVIDUALS; BODY-WEIGHT; GENDER-DIFFERENCES; BRAIN ACTIVATION; OVARIECTOMIZED RATS; ESTRADIOL DECREASES; DIETARY RESTRAINT; PREFRONTAL CORTEX; ENERGY-BALANCE; FEMALE RATS AB Sex-based differences in food intake related behaviors have been observed previously. The objective of this study was to examine sex-based differences in the behavioral and neuronal responses to food. 22 women and 21 men were studied. After 6 days of controlled eucaloric feeding, ad libitum energy intake (El) was measured for 3 days. Appetite ratings using visual analog scales were obtained before and after each meal. Functional magnetic resonance imaging was performed in the overnight fasted state on the last day of eucaloric feeding while subjects were presented visual stimuli of food and neutral non-food objects. While hunger and prospective consumption were not different between sexes, women had higher post-meal satiety ratings and dietary restraint than men. Images of hedonic foods resulted in significantly greater activation of lateral and dorsolateral prefrontal cortex (DLPFC) and parietal cortex in women as compared to men. No brain regions were more activated in men as compared to women. Men increased their El during the ad libitum diet phase. While measures of appetite or feeding behaviors did not correlate with either neuronal activation or subsequent El. DLPFC activation in response to hedonic foods was negatively correlated with El. In summary, greater prefrontal neuronal responses to food cues in women may suggest increased cognitive processing related to executive function, such as planning, guidance or evaluation of behavior. Finally, increased DLPFC activation, perhaps relating to inhibitory cognitive control in response to food cues may be a better predictor of food intake than behavioral measures. (C) 2010 Elsevier Inc. All rights reserved. C1 [Cornier, Marc-Andre; Salzberg, Andrea K.; Endly, Dawnielle C.; Bessesen, Daniel H.] Univ Colorado Denver, Div Endocrinol Diabet & Metab, Dept Med, Aurora, CO 80045 USA. [Tregellas, Jason R.] Univ Colorado Denver, Dept Psychiat, Aurora, CO 80045 USA. [Cornier, Marc-Andre; Bessesen, Daniel H.] Denver Hlth Med Ctr, Dept Med, Denver, CO 80204 USA. [Tregellas, Jason R.] Denver VA Med Ctr, Res Serv, Denver, CO 80220 USA. RP Cornier, MA (reprint author), Univ Colorado Denver, Div Endocrinol Diabet & Metab, Dept Med, Mail Stop 8106,12801 E 17th Ave,Room 7103, Aurora, CO 80045 USA. EM marc.cornier@ucdenver.edu RI Tregellas, Jason/J-3637-2015 FU NIH/NCRR Colorado CTSI [UL1 RR025780]; NIH/NIDDK Clinical Nutrition Research Unit [DK48520]; NIH/NCRR [RR016185] FX We acknowledge and thank Debra Singel and Yiping Du for their assistance with the fMRI studies. We also thank the dietary services and metabolic kitchen of the University of Colorado Denver CTRC. This publication was supported by NIH/NCRR Colorado CTSI grant number UL1 RR025780, NIH/NIDDK Clinical Nutrition Research Unit grant number DK48520, and NIH/NCRR grant number RR016185. Its contents are the authors' sole responsibility and do not necessarily represent official NIH views. NR 53 TC 76 Z9 76 U1 7 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD MAR 30 PY 2010 VL 99 IS 4 BP 538 EP 543 DI 10.1016/j.physbeh.2010.01.008 PG 6 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 576KQ UT WOS:000276143700018 PM 20096712 ER PT J AU Feuerer, M Hill, JA Kretschmer, K von Boehmer, H Mathis, D Benoist, C AF Feuerer, Markus Hill, Jonathan A. Kretschmer, Karsten von Boehmer, Harald Mathis, Diane Benoist, Christophe TI Genomic definition of multiple ex vivo regulatory T cell subphenotypes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Foxp3; microarray ID TRANSCRIPTION FACTOR FOXP3; TGF-BETA; RETINOIC-ACID; IN-VIVO; INDUCTION; ANTIGEN; TOLERANCE; RESPONSES; LINEAGE; MICE AB Regulatory T (Treg) cells that express the Foxp3 transcription factor are essential for lymphoid homeostasis and immune tolerance to self. Other nonimmunological functions of Treg cells, such as controlling metabolic function in adipose tissue, are also emerging. Treg cells originate primarily in the thymus, but can also be elicited from conventional T cells by in vivo exposure to low-dose antigen or homeostatic expansion or by activation in the presence of TGF beta in vitro. Treg cells are characterized by a distinct transcriptional signature controlled in part, but not solely, by Foxp3. For a better perspective on transcriptional control in Treg cells, we compared gene expression profiles of a broadpanel of Treg cells from various origins or anatomical locations. Treg cells generated by different means form different subphenotypes and were identifiable by particular combinations of transcripts, none of which fully encompassed the entire Treg signature. Molecules involved in Treg cell effector function, chemokine receptors, and the transcription factors that control them were differentially represented in these subphenotypes. Treg cells from the gut proved dissimilar to cells elicited by exposure to TGF beta in vitro, but instead they resembled a CD103(+)Klrg1(+) subphenotype preferentially generated in response to lymphopenia. C1 [Feuerer, Markus; Hill, Jonathan A.; Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Feuerer, Markus; Hill, Jonathan A.; Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02115 USA. [Kretschmer, Karsten; von Boehmer, Harald] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Benoist, C (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu RI Kretschmer, Karsten/E-8174-2010 FU Juvenile Diabetes Research Foundation [4-2007-1057]; National Institutes of Health [7R01AI51530, R37 AI053102]; Joslin Diabetes Center's National Institute of Diabetes and Digestive; Digestive and Kidney Diseases; German Research Foundation [FE 801/1-1]; Charles A. King Trust Postdoctoral Fellowship; Canadian Institutes of Health Research; Canadian Diabetes Association FX We thank J. Pagan and K. Hattori for assistance with mice, J. LaVecchio and G. Buruzala for help with cytometry, J. Perez and K. Leatherbee for microarrays, and S. Davis for computational analysis. This work was supported by grants from the Juvenile Diabetes Research Foundation (4-2007-1057) and the National Institutes of Health (7R01AI51530), by Joslin Diabetes Center's National Institute of Diabetes and Digestive and Kidney Diseases-funded Diabetes Endocrinology Research Care core facilities (D. M. and C. B.), and by National Institutes of Health Grant R37 AI053102 (to H. v. B.). M. F. was supported by postdoctoral fellowships from the German Research Foundation (Emmy-Noether Fellowship, FE 801/1-1) and the Charles A. King Trust Postdoctoral Fellowship. J. A. H. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and the Canadian Diabetes Association. NR 47 TC 121 Z9 121 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 30 PY 2010 VL 107 IS 13 BP 5919 EP 5924 DI 10.1073/pnas.1002006107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 576QA UT WOS:000276159500042 PM 20231436 ER PT J AU Burgdorf, S Schuette, V Semmling, V Hochheiser, K Lukacs-Kornek, V Knolle, PA Kurts, C AF Burgdorf, Sven Schuette, Verena Semmling, Verena Hochheiser, Katharina Lukacs-Kornek, Veronika Knolle, Percy A. Kurts, Christian TI Steady-state cross-presentation of OVA is mannose receptor-dependent but inhibitable by collagen fragments SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID ANTIGEN; PATHWAYS C1 [Burgdorf, Sven; Schuette, Verena; Semmling, Verena; Hochheiser, Katharina; Knolle, Percy A.; Kurts, Christian] Univ Hosp Bonn, Inst Mol Med, D-53105 Bonn, Germany. [Burgdorf, Sven; Schuette, Verena; Semmling, Verena; Hochheiser, Katharina; Knolle, Percy A.; Kurts, Christian] Univ Hosp Bonn, Inst Expt Immunol, D-53105 Bonn, Germany. [Lukacs-Kornek, Veronika] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Burgdorf, S (reprint author), Univ Hosp Bonn, Inst Mol Med, D-53105 Bonn, Germany. EM sven.burgdorf@ukb.uni-bonn.de; ckurts@web.de OI Knolle, Percy A./0000-0003-2983-0414 NR 5 TC 20 Z9 20 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 30 PY 2010 VL 107 IS 13 BP E48 EP E49 DI 10.1073/pnas.1000598107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 576QA UT WOS:000276159500082 PM 20308535 ER PT J AU Egede, LE Strom, JL Durkalski, VL Mauldin, PD Moran, WP AF Egede, Leonard E. Strom, Joni L. Durkalski, Valerie L. Mauldin, Patrick D. Moran, William P. TI Rationale and design: telephone-delivered behavioral skills interventions for Blacks with type 2 diabetes SO TRIALS LA English DT Article ID FUNCTIONAL HEALTH LITERACY; URBAN AFRICAN-AMERICANS; PRIMARY-CARE PROVIDERS; PHYSICAL-ACTIVITY; SELF-MANAGEMENT; UNITED-STATES; PSYCHOMETRIC PROPERTIES; CLINICAL INERTIA; GLYCEMIC CONTROL; QUESTIONNAIRE AB Background: African Americans with Type 2 diabetes (T2DM) have higher prevalence of diabetes, poorer metabolic control, and greater risk for complications and death compared to American Whites. Poor outcomes in African Americans with T2DM can be attributed to patient, provider, and health systems level factors. Provider and health system factors account for <10% of variance in major diabetes outcomes including hemoglobin A1c (HbA1c), lipid control, and resource use. Key differences appear to be at the patient level. Of the patient level factors, consistent differences between African Americans and American Whites with T2DM have been found in diabetes knowledge, self-management skills, empowerment, and perceived control. A variety of interventions to improve diabetes self-management have been tested including: 1) knowledge interventions; 2) lifestyle interventions; 3) skills training interventions; and 4) patient activation and empowerment interventions. Most of these interventions have been tested individually, but rarely have they been tested in combination, especially among African Americans who have the greatest burden of diabetes related complications. This study provides a unique opportunity to address this gap in the literature. Methods/Design: We describe an ongoing four-year randomized clinical trial, using a 2 x 2 factorial design, which will test the efficacy of separate and combined telephone-delivered, diabetes knowledge/information and motivation/behavioral skills training interventions in high risk African Americans with poorly controlled T2DM (HbA1c = 9%). Two-hundred thirty-two (232) male and female African-American participants, 18 years of age or older and with an HbA1c = 9%, will be randomized into one of four groups for 12-weeks of phone interventions: (1) an education group, (2) a motivation/skills group, (3) a combined group or (4) a usual care/general health education group. Participants will be followed for 12-months to ascertain the effect of the interventions on glycemic control. Our primary hypothesis is that among African Americans with poorly controlled T2DM, patients randomized to the combined diabetes knowledge/information and motivation/behavioral skills training intervention will have significantly greater reduction in HbA1c at 12 months of follow-up compared to the usual care/general health education group. Discussion: Results from this study will provide important insight into how best to deliver diabetes education and skills training in ethnic minorities and whether combined knowledge/information and motivation/behavioral skills training is superior to the usual method of delivering diabetes education for African Americans with poorly controlled T2DM. C1 [Egede, Leonard E.; Mauldin, Patrick D.] Ctr Dis Prevent & Hlth Intervent Diverse Populat, Ralph H Johnson VAMC, Charleston, SC USA. [Egede, Leonard E.; Strom, Joni L.; Moran, William P.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Egede, Leonard E.; Strom, Joni L.; Mauldin, Patrick D.; Moran, William P.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Durkalski, Valerie L.] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Mauldin, Patrick D.] Med Univ S Carolina, Dept Clin Pharm & Outcome Sci, Charleston, SC 29425 USA. RP Egede, LE (reprint author), Ctr Dis Prevent & Hlth Intervent Diverse Populat, Ralph H Johnson VAMC, Charleston, SC USA. EM egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK081121-01A1] FX The study is funded by grant # R01DK081121-01A1 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 48 TC 4 Z9 4 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD MAR 29 PY 2010 VL 11 AR 35 DI 10.1186/1745-6215-11-35 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 584MF UT WOS:000276755400001 PM 20350322 ER PT J AU Hu, YD Lu, XC Luo, GB AF Hu, Yiduo Lu, Xincheng Luo, Guangbin TI Effect of Recql5 deficiency on the intestinal tumor susceptibility of Apc(min) mice SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Recql5; Apc; Tumor suppressor; Genome instability; Colon cancer; Apc(min/+) mice ID RNA-POLYMERASE-II; CANCER; TRANSCRIPTION; EPITHELIUM; ANEUPLOIDY; SUPPRESSOR; GENES AB AIM: To investigate whether Recql5, a DNA helicase that plays an important role in the maintenance of genome integrity, is a tumor suppressor in the gastrointestinal tract in mice. METHODS: We generated cohorts of both Recql5-proficient and Recql5-deficient Apc(min/+) mice and compared the tumor susceptibility in their gastrointestinal tracts. RESULTS: Recql5 deficiency in Apc(min/+) mice resulted in a significant increase in the tumor incidence in both the colon (P = 0.0162) and the small intestine (P < 0.01). These findings have provided the first genetic evidence for a tumor suppression role of Recql5 in the gastrointestinal tract of mice. Importantly, since mouse Recql5 and human RECQL5 are highly conserved, these findings also suggest that RECQL5 may be a tumor suppressor for human colon cancer. CONCLUSION: Recql5 has a tumor suppression role in the mouse gastrointestinal tract. (C) 2010 Baishideng. All rights reserved. C1 [Hu, Yiduo; Lu, Xincheng; Luo, Guangbin] Case Western Reserve Univ, Case Comprehens Canc Ctr, Dept Genet, Cleveland, OH 44106 USA. [Hu, Yiduo; Lu, Xincheng; Luo, Guangbin] Case Western Reserve Univ, Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Hu, Yiduo] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Luo, GB (reprint author), Case Western Reserve Univ, Case Comprehens Canc Ctr, Dept Genet, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM guangbin.luo@case.edu FU US National Institutes of Health [RO1 CA88939, P20 CA 103736]; Searle Scholar Program [01-E-109] FX Supported by Grants RO1 CA88939, P20 CA 103736 from the US National Institutes of Health and Searle Scholar Award 01-E-109 from the Searle Scholar Program NR 19 TC 7 Z9 10 U1 0 U2 0 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAR 28 PY 2010 VL 16 IS 12 BP 1482 EP 1486 DI 10.3748/wjg.v16.i12.1482 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 574TS UT WOS:000276017200009 PM 20333788 ER PT J AU Zhou, WJ Hur, W McDermott, U Dutt, A Xian, W Ficarro, SB Zhang, JM Sharma, SV Brugge, J Meyerson, M Settleman, J Gray, NS AF Zhou, Wenjun Hur, Wooyoung McDermott, Ultan Dutt, Amit Xian, Wa Ficarro, Scott B. Zhang, Jianming Sharma, Sreenath V. Brugge, Joan Meyerson, Matthew Settleman, Jeffrey Gray, Nathanael S. TI A Structure-Guided Approach to Creating Covalent FGFR Inhibitors SO CHEMISTRY & BIOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; IMATINIB MESYLATE; CANCER; MUTATIONS; PROLIFERATION; SENSITIVITY; ACTIVATION; RESISTANCE; LEUKEMIA AB The fibroblast growth factor receptor tyrosine kinases (FGFR1, 2, 3, and 4) represent promising therapeutic targets in a number of cancers. We have developed the first potent and selective irreversible inhibitor of FGFR1, 2, 3, and 4, which we named FIIN-1 that forms a covalent bond with cysteine 486 located in the P loop of the FGFR1 ATP binding site. We demonstrated that the inhibitor potently inhibits Tel-FGFR1-transformed Ba/F3 cells (EC50 = 14 nM) as well as numerous FGFR-dependent cancer cell lines. A biotin-derivatized version of the inhibitor, FIIN-1-biotin, was shown to covalently label FGFR1 at Cys486. FIIN-1 is a useful probe of FGFR-dependent cellular phenomena and may provide a starting point of the development of therapeutically relevant irreversible inhibitors of wild-type and drug-resistant forms of FGFR kinases. C1 [Zhou, Wenjun; Ficarro, Scott B.; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. [Dutt, Amit; Meyerson, Matthew] Harvard Univ, Dana Farber Canc Inst, Sch Med, Broad Inst,Dept Med Oncol, Boston, MA 02115 USA. [Hur, Wooyoung] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [McDermott, Ultan; Sharma, Sreenath V.; Settleman, Jeffrey] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Xian, Wa; Brugge, Joan] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Gray, NS (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Dutt, Amit/I-1911-2013; OI Dutt, Amit/0000-0002-1119-4774; McDermott, Ultan/0000-0001-9032-4700 FU Damon Runyon Cancer Foundation; Mary Kay Ash Foundation; National Science Foundation FX This work was supported by grants from the Damon Runyon Cancer Foundation, the Mary Kay Ash Foundation, and the National Science Foundation. We acknowledge generous assistance from Ambit Biosciences for performing KinomeScan profiling and Invitrogen for performing the Z'-Iyte kinase assays. The authors declare no competing financial interests. NR 47 TC 61 Z9 64 U1 2 U2 38 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD MAR 26 PY 2010 VL 17 IS 3 BP 285 EP 295 DI 10.1016/j.chembiol.2010.02.007 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 583MI UT WOS:000276680200011 PM 20338520 ER PT J AU Seker, E Berdichevsky, Y Begley, MR Reed, ML Staley, KJ Yarmush, ML AF Seker, Erkin Berdichevsky, Yevgeny Begley, Matthew R. Reed, Michael L. Staley, Kevin J. Yarmush, Martin L. TI The fabrication of low-impedance nanoporous gold multiple-electrode arrays for neural electrophysiology studies SO NANOTECHNOLOGY LA English DT Article ID MICROELECTRODE ARRAYS; CONDUCTING POLYMERS; NEURONAL NETWORKS; INTERFACES; CULTURE; SYSTEM AB Neural electrodes are essential tools for the study of the nervous system and related diseases. Low electrode impedance is a figure of merit for sensitive detection of neural electrical activity and numerous studies have aimed to reduce impedance. Unfortunately, most of these efforts have been tethered by a combination of poor functional coating adhesion, complicated fabrication techniques, and poor fabrication repeatability. We address these issues with a facile method for reliably producing multiple-electrode arrays with low impedance by patterning highly adherent nanoporous gold films using conventional microfabrication techniques. The high surface area-to-volume ratio of self-assembled nanoporous gold results in a more than 25-fold improvement in the electrode-electrolyte impedance, where at 1 kHz, 850 k Omega impedance for conventional Au electrodes is reduced to 30 k Omega for nanoporous gold electrodes. Low impedance provides a superior signal-to-noise ratio for detection of neural activity in noisy environments. We systematically studied the effect of film morphology on electrode impedance and successfully recorded field potentials from rat hippocampal slices. Here, we present our fabrication approach, the relationship between film morphology and impedance, and field potential recordings. C1 [Seker, Erkin; Berdichevsky, Yevgeny; Yarmush, Martin L.] Harvard Univ, Sch Med, Dept Surg,Shriners Hosp Children, Massachusetts Gen Hosp,Ctr Engn Med, Boston, MA 02115 USA. [Begley, Matthew R.] Univ Calif Santa Barbara, Dept Mech Engn, Santa Barbara, CA 93106 USA. [Reed, Michael L.] Univ Virginia, Dept Elect & Comp Engn, Charlottesville, VA USA. [Staley, Kevin J.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Yarmush, ML (reprint author), Harvard Univ, Sch Med, Dept Surg,Shriners Hosp Children, Massachusetts Gen Hosp,Ctr Engn Med, Boston, MA 02115 USA. EM ireis@sbi.org OI Seker, Erkin/0000-0003-2401-3562 FU NIH [P41-EB002503, F32-MH079662]; New Jersey Commission on Brain Injury Research [08-3210-BIR-E-1]; NSF [DMI-0507023] FX This work was sponsored in part by NIH Grant P41-EB002503, New Jersey Commission on Brain Injury Research Grant 08-3210-BIR-E-1, and NSF Grant DMI-0507023. YB was supported by NIH F32-MH079662. NR 26 TC 40 Z9 40 U1 4 U2 31 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 J9 NANOTECHNOLOGY JI Nanotechnology PD MAR 26 PY 2010 VL 21 IS 12 AR 125504 DI 10.1088/0957-4484/21/12/125504 PG 7 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 564OH UT WOS:000275224100015 PM 20203356 ER PT J AU Wang, YZ Krivtsov, AV Sinha, AU North, TE Goessling, W Feng, ZH Zon, LI Armstrong, SA AF Wang, Yingzi Krivtsov, Andrei V. Sinha, Amit U. North, Trista E. Goessling, Wolfram Feng, Zhaohui Zon, Leonard I. Armstrong, Scott A. TI The Wnt/beta-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML SO SCIENCE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BETA-CATENIN; COLON-CANCER; HEMATOPOIETIC-CELLS; SIGNALING PATHWAY; IN-VIVO; PROGENITORS; EXPRESSION; EXPANSION; RENEWAL AB Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/beta-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/beta-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. beta-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in AML. C1 [Wang, Yingzi; Krivtsov, Andrei V.; Sinha, Amit U.; Feng, Zhaohui; Zon, Leonard I.; Armstrong, Scott A.] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. [Sinha, Amit U.; Feng, Zhaohui; Armstrong, Scott A.] Harvard Univ, Sch Med, Dept Pediat Oncol, Boston, MA 02115 USA. [North, Trista E.] Harvard Univ, Sch Med, Beth Israel Deaconess Hosp, Dept Pathol, Boston, MA 02115 USA. [North, Trista E.; Goessling, Wolfram; Zon, Leonard I.; Armstrong, Scott A.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Goessling, Wolfram] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Zon, Leonard I.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Armstrong, SA (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. EM scott.armstrong@childrens.harvard.edu OI Goessling, Wolfram/0000-0001-9972-1569 FU NIH [5P01CA66996, 5R01HL048801]; American Cancer Society [RSG-09-068-01]; Harvard Stem Cell Institute FX We thank D. Fisher, X. He, and H. Widlund for plasmid pcDNA3.1-beta cat-*-Flag; D. Williams for helpful discussion and advice; and M. Smith for administrative assistance. This work was supported by the NIH grants 5P01CA66996 ( to S. A. A.) and 5R01HL048801 ( to L.I.Z.), the American Cancer Society (RSG-09-068-01), and the Harvard Stem Cell Institute. S. A. A. is a Leukemia and Lymphoma Society Scholar. Microarray data was submitted to the National Center for Biotechnology Information Gene Expression Omnibus (GEO) GSE20377. L.I.Z. is a founding member of and stockholder in Fate Therapeutics, a biotechnology company that is developing stem cell therapeutics and that has acquired a patent covering the use of prostaglandin E2 in hematopoietic stem cell modulation and tissue regeneration. W. G. and T.E.N. are paid consultants for Fate Therapeutics. NR 25 TC 303 Z9 321 U1 2 U2 42 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 MAR 26 PY 2010 VL 327 IS 5973 BP 1650 EP 1653 DI 10.1126/science.1186624 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 574ED UT WOS:000275970600046 PM 20339075 ER PT J AU Rieckmann, T Fuller, BE Saedi, GA McCarty, D AF Rieckmann, Traci Fuller, Bret E. Saedi, Goal Auzeen McCarty, Dennis TI Adoption of practice guidelines and assessment tools in substance abuse treatment SO SUBSTANCE ABUSE TREATMENT PREVENTION AND POLICY LA English DT Article ID DIFFUSION; BELIEFS; STAFF AB Background: The gap between research and practice limits utilization of relevant, progressive and empirically validated strategies in substance abuse treatment. Methods: Participants included substance abuse treatment programs from the Northeastern United States. Structural equation models were constructed with agency level data to explore two outcome variables: adoption of practice guidelines and assessment tools at two points in time; models also included organizational, staffing and service variables. Results: In 1997, managed care involvement and provision of primary care services had the strongest association with increased use of assessment tools, which, along with provision of counseling services, were associated with a greater use of practice guidelines. In 2001, managed care involvement, counseling services and being a stand-alone drug treatment agency were associated with a greater use of assessment tools, which was in turn related to an increase in the use of practice guidelines. Conclusions: This study provides managers, clinicians and policy-makers with a framework for understanding factors related to the adoption of new technologies in substance abuse treatment. C1 [Rieckmann, Traci; McCarty, Dennis] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Fuller, Bret E.] Portland VA Med Ctr, Portland, OR 97239 USA. [Saedi, Goal Auzeen] Univ Notre Dame, Dept Psychol, Notre Dame, IN 46556 USA. RP Rieckmann, T (reprint author), Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, 3181 SW Sam Jackson Pk Rd,Mailcode CB669, Portland, OR 97239 USA. EM rieckman@ohsu.edu FU NIAAA NIH HHS [R01 AA011363, R01-AA11363, R01 AA011363-05]; NIDA NIH HHS [U10 DA013036, K23 DA021225] NR 38 TC 2 Z9 2 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1747-597X J9 SUBST ABUSE TREAT PR JI Subst/ Abus. Treatment Prev. Pol. PD MAR 26 PY 2010 VL 5 AR 4 DI 10.1186/1747-597X-5-4 PG 9 WC Substance Abuse SC Substance Abuse GA 593BL UT WOS:000277426500001 PM 20346158 ER PT J AU Pollard, JA Alonzo, TA Gerbing, RB Ho, PA Zeng, R Ravindranath, Y Dahl, G Lacayo, NJ Becton, D Chang, M Weinstein, HJ Hirsch, B Raimondi, SC Heerema, NA Woods, WG Lange, BJ Hurwitz, C Arceci, RJ Radich, JP Bernstein, ID Heinrich, MC Meshinchi, S AF Pollard, Jessica A. Alonzo, Todd A. Gerbing, Robert B. Ho, Phoenix A. Zeng, Rong Ravindranath, Yaddanapudi Dahl, Gary Lacayo, Norman J. Becton, David Chang, Myron Weinstein, Howard J. Hirsch, Betsy Raimondi, Susana C. Heerema, Nyla A. Woods, William G. Lange, Beverly J. Hurwitz, Craig Arceci, Robert J. Radich, Jerald P. Bernstein, Irwin D. Heinrich, Michael C. Meshinchi, Soheil TI Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; BONE-MARROW-TRANSPLANTATION; CHILDRENS ONCOLOGY GROUP; RAS GENE-MUTATIONS; C-KIT; CHILDHOOD-AML; IMATINIB MESYLATE; KINASE INHIBITOR; FLT3 MUTATIONS AB KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML). However, their prevalence and prognostic significance in pediatric CBF AML is not well established. We performed KIT mutational analysis (exon 8 and exon 17) on diagnostic specimens from 203 pediatric patients with CBF AML enrolled on 4 pediatric AML protocols. KIT mutations were detected in 38 (19%) of 203 (95% CI, 14%-25%) patient samples of which 20 (52.5%) of 38 (95% CI, 36%-69%) involved exon 8, 17 (45%) of 38 (95% CI, 29%-62%) involved exon 17, and 1 (2.5%; 95% CI, 0%-14%) involved both locations. Patients with KIT mutations had a 5-year event-free survival of 55% (+/- 17%) compared with 59% (+/- 9%) for patients with wild-type KIT (P = .86). Rates of complete remission, overall survival, disease-free survival, or relapse were not significantly different for patients with or without KIT mutations. Location of the KIT mutation and analysis by cytogenetic subtype [t(8; 21) vs inv(16)] also lacked prognostic significance. Our study shows that KIT mutations lack prognostic significance in a large series of pediatric patients with CBF AML. This finding, which differs from adult series and a previously published pediatric study, may reflect variations in therapeutic approaches and/or biologic heterogeneity within CBF AML. Two of 4 studies included in this analysis are registered at http://clinicaltrials.gov as NCT00002798(CCG-2961) and NCT00070174 (COG AAML03P1). (Blood. 2010; 115: 2372-2379) C1 [Pollard, Jessica A.; Ho, Phoenix A.; Zeng, Rong; Radich, Jerald P.; Bernstein, Irwin D.; Meshinchi, Soheil] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Pollard, Jessica A.; Ho, Phoenix A.; Bernstein, Irwin D.; Meshinchi, Soheil] Univ Washington, Seattle, WA 98195 USA. [Alonzo, Todd A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Alonzo, Todd A.; Gerbing, Robert B.] Childrens Oncol Grp, Arcadia, CA USA. [Ravindranath, Yaddanapudi] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Dahl, Gary; Lacayo, Norman J.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. [Becton, David] Univ Arkansas, Little Rock, AR 72204 USA. [Chang, Myron] Childrens Oncol Grp, Gainesville, FL USA. [Weinstein, Howard J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Betsy] Univ Minnesota, Ctr Canc, Minneapolis, MN USA. [Raimondi, Susana C.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Heerema, Nyla A.] Ohio State Univ, Columbus, OH 43210 USA. [Woods, William G.] Emory Univ, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Lange, Beverly J.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Hurwitz, Craig] Maine Med Ctr, Portland, ME 04102 USA. [Arceci, Robert J.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Heinrich, Michael C.] Portland VA Med Ctr, Portland, OR USA. RP Pollard, JA (reprint author), Seattle Childrens Hosp, Div Heme Onc, 4800 Sandpoint Way NE,MS-B-6553, Seattle, WA 98105 USA. EM jessica.pollard@seattlechildrens.org OI Ho, Phoenix/0000-0003-3786-7583 FU National Cancer Institute [5K12CA076930-08]; St Baldrick's Foundation Career Development Award; CureSearch Research Fellowship Award; For Julie Foundation; VA Merit Review Grant; Leukemia & Lymphoma Society; National Institutes of Health [R21 CA10262-01, R01 CA114563-01]; Children's Oncology Group Chair [NIH U10 CA98543] FX This work was supported by the National Cancer Institute (5K12CA076930-08) (J.A.P.), St Baldrick's Foundation Career Development Award (J.A.P.), CureSearch Research Fellowship Award (J.A.P.), For Julie Foundation Research Grant (J.A.P.), VA Merit Review Grant (M.C.H.), Leukemia & Lymphoma Society (M.C.H.), and the National Institutes of Health (grants R21 CA10262- 01 and R01 CA114563- 01, Children's Oncology Group Chair's grant NIH U10 CA98543). NR 40 TC 78 Z9 82 U1 0 U2 6 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 MAR 25 PY 2010 VL 115 IS 12 BP 2372 EP 2379 DI 10.1182/blood-2009-09-241075 PG 8 WC Hematology SC Hematology GA 574IF UT WOS:000275981900010 PM 20056794 ER PT J AU Sahin, E DePinho, RA AF Sahin, Erguen DePinho, Ronald A. TI Linking functional decline of telomeres, mitochondria and stem cells during ageing SO NATURE LA English DT Review ID MAMMALIAN LIFE-SPAN; AGE-RELATED-CHANGES; DNA-DAMAGE; DYSFUNCTIONAL TELOMERES; CHROMOSOMAL INSTABILITY; REVERSE-TRANSCRIPTASE; TERMINAL TRANSFERASE; TUMOR SUPPRESSION; OXIDATIVE STRESS; ARF/P53 PATHWAY AB The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signalling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders. C1 [Sahin, Erguen; DePinho, Ronald A.] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Sahin, Erguen; DePinho, Ronald A.] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med & Genet,Dana Farber Canc Inst, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu FU National Institutes of Health [RO1CA84628, U01 CA84313]; US Department of Defense [W81XWH-08-1-0133]; Ellison Medical Foundation; Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science; Deutsche Forschungsgemeinschaft FX We thank L. Chin, N. Sharpless, S. Artandi, F. Muller, V. Walsh, S. Colla, M. Ugolotti, M. Jaskelioff, D. Liu and A.-J. Chen for discussions and critical reading of the manuscript. A. Protopopov and E. Ivanova kindly provided the chromosomal and telomere analysis in Fig. 2. We apologize to the members of the scientific community whose work could not be cited owing to space limitations. Grant support for our work was provided by National Institutes of Health grants RO1CA84628 and U01 CA84313, US Department of Defense grant W81XWH-08-1-0133, and the Ellison Medical Foundation. R. A. D. is an American Cancer Society Research Professor and is supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science. E. S. was supported by the Deutsche Forschungsgemeinschaft. NR 99 TC 312 Z9 325 U1 15 U2 104 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 25 PY 2010 VL 464 IS 7288 BP 520 EP 528 DI 10.1038/nature08982 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 574FL UT WOS:000275974200035 PM 20336134 ER PT J AU Gupta, RK Arany, Z Seale, P Mepani, RJ Ye, L Conroe, HM Roby, YA Kulaga, H Reed, RR Spiegelman, BM AF Gupta, Rana K. Arany, Zoltan Seale, Patrick Mepani, Rina J. Ye, Li Conroe, Heather M. Roby, Yang A. Kulaga, Heather Reed, Randall R. Spiegelman, Bruce M. TI Transcriptional control of preadipocyte determination by Zfp423 SO NATURE LA English DT Article ID PPAR-GAMMA; OLIGONUCLEOTIDE ARRAYS; CEREBELLAR DEVELOPMENT; ADIPOSE CONVERSION; ADIPOCYTE LINEAGE; GENE-EXPRESSION; IN-VIVO; CELLS; DIFFERENTIATION; ADIPOGENESIS AB The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPAR gamma and several other transcription factors(1), but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non-preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. Furthermore, both brown and white adipocyte differentiation is markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signalling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. This study identifies Zfp423 as a transcriptional regulator of preadipocyte determination. C1 [Gupta, Rana K.; Arany, Zoltan; Seale, Patrick; Mepani, Rina J.; Ye, Li; Conroe, Heather M.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gupta, Rana K.; Arany, Zoltan; Seale, Patrick; Mepani, Rina J.; Ye, Li; Conroe, Heather M.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Metab & Chron Dis, Boston, MA 02115 USA. [Gupta, Rana K.; Arany, Zoltan; Seale, Patrick; Mepani, Rina J.; Ye, Li; Conroe, Heather M.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Roby, Yang A.; Kulaga, Heather; Reed, Randall R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Ctr Sensory Biol,Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu FU Ruth Kirstein NRSA [F32 DK079507-01]; NHLBI [K08 HL79172-01]; Smith Family Foundation; NIH [DK081605, DK31405]; NIDCD [R01DC008295] FX We are grateful to S. Kleiner and S. Kajimura for critical reading of the manuscript and to all members of the Spiegelman laboratory for useful discussions. We thank B. Wagner for technical assistance in using robotic liquid handlers, B. Seed's laboratory for help with high-through query of Primer bank, and J. Brestelli for performing high-throughput queries of the Primer 3 program. We are also grateful to D. Bernlohr for the FABP4 antiserum. R. K. G. is supported by the Ruth Kirstein NRSA (F32 DK079507-01), Z. A. is supported by K08 HL79172-01 (NHLBI) and the Smith Family Foundation Grant, P. S. is supported by NIH DK081605, and the research described in this study was supported by NIH DK31405 to B. M. S. and by NIDCD R01DC008295 to R. R. R. NR 27 TC 174 Z9 179 U1 2 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 25 PY 2010 VL 464 IS 7288 BP 619 EP U187 DI 10.1038/nature08816 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 574FL UT WOS:000275974200054 PM 20200519 ER PT J AU Ross, SE Mardinly, AR McCord, AE Zurawski, J Cohen, S Jung, C Hu, LD Mok, SI Shah, A Savner, EM Tolias, C Corfas, R Chen, SZ Inquimbert, P Xu, Y McInnes, RR Rice, FL Corfas, G Ma, QF Woolf, CJ Greenberg, ME AF Ross, Sarah E. Mardinly, Alan R. McCord, Alejandra E. Zurawski, Jonathan Cohen, Sonia Jung, Cynthia Hu, Linda Mok, Stephanie I. Shah, Anar Savner, Erin M. Tolias, Christos Corfas, Roman Chen, Suzhen Inquimbert, Perrine Xu, Yi McInnes, Roderick R. Rice, Frank L. Corfas, Gabriel Ma, Qiufu Woolf, Clifford J. Greenberg, Michael E. TI Loss of Inhibitory Interneurons in the Dorsal Spinal Cord and Elevated Itch in Bhlhb5 Mutant Mice SO NEURON LA English DT Article ID SPINOTHALAMIC TRACT NEURONS; PERIPHERAL-NERVE INJURY; PAIN HYPERSENSITIVITY; CENTRAL SENSITIZATION; GABAERGIC INHIBITION; SCRATCHING BEHAVIOR; FORMALIN TEST; HORN; RECEPTORS; RESPONSES AB Itch is the least well understood of all the somatic senses, and the neural circuits that underlie this sensation are poorly defined. Here we show that the atonal-related transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord and appears to play a role in the formation and regulation of pruritic (itch) circuits. Mice lacking Bhlhb5 develop self-inflicted skin lesions and show significantly enhanced scratching responses to pruritic agents. Through genetic fate-mapping and conditional ablation, we provide evidence that the pruritic phenotype in Bhlhb5 mutants is due to selective loss of a subset of inhibitory interneurons in the dorsal horn. Our findings suggest that Bhlhb5 is required for the survival of a specific population of inhibitory interneurons that regulate pruritis, and provide evidence that the loss of inhibitory synaptic input results in abnormal itch. C1 [Ross, Sarah E.; Mardinly, Alan R.; McCord, Alejandra E.; Zurawski, Jonathan; Cohen, Sonia; Hu, Linda; Mok, Stephanie I.; Shah, Anar; Savner, Erin M.; Tolias, Christos; Corfas, Roman; Ma, Qiufu; Woolf, Clifford J.; Greenberg, Michael E.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Jung, Cynthia; McInnes, Roderick R.] Hosp Sick Children, Res Inst, Program Dev Biol, Toronto, ON M5G 1L7, Canada. [Jung, Cynthia; McInnes, Roderick R.] Hosp Sick Children, Res Inst, Genet Program, Toronto, ON M5G 1L7, Canada. [Cohen, Sonia; Inquimbert, Perrine; Corfas, Gabriel; Woolf, Clifford J.] Childrens Hosp, Dept Neurol, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Xu, Yi; Ma, Qiufu] Dana Farber Canc Inst, Boston, MA 02115 USA. [McInnes, Roderick R.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [McInnes, Roderick R.] Univ Toronto, Dept Pediat, Toronto, ON M5S 1A1, Canada. [McInnes, Roderick R.] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada. [Rice, Frank L.] Albany Med Coll, Ctr Neuropharmacol Neurosci, Albany, NY 12208 USA. [Rice, Frank L.] Integrated Tissue Dynam LL, Rensselaer, NY 12144 USA. RP Greenberg, ME (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM michael_greenberg@hms.harvard.edu OI Corfas, Roman/0000-0002-3096-6813 FU Jane Coffin Childs Fellowship; Dystonia Medical Research Foundation Fellowship; NIH [R01-NS-028829]; Developmental Disabilities Mental Retardation Research Center [NIH-P30-HD-18655] FX We thank E.C. Griffith for critical readings of the manuscript; D. Harmin for help with statistical analysis; M. Gee and P. Zhang for assistance with mouse colony management; the MRDDRC Gene Manipulation Core (M. Thompson, Y. Zhou, and H. Ye); the MRDDRC Imaging Core (L. Bu); and the MRDDRC Histology Core (M. Liana). This work was supported by a Jane Coffin Childs Fellowship and a Dystonia Medical Research Foundation Fellowship to S.E.R., NIH grant R01-NS-028829 to M.E.G., and the Developmental Disabilities Mental Retardation Research Center grant NIH-P30-HD-18655 for core support. NR 48 TC 141 Z9 144 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 25 PY 2010 VL 65 IS 6 BP 886 EP 898 DI 10.1016/j.neuron.2010.02.025 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 576MP UT WOS:000276148900016 PM 20346763 ER PT J AU Ross, JS Normand, SLT Wang, Y Ko, DT Chen, J Drye, EE Keenan, PS Lichtman, JH Bueno, H Schreiner, GC Krumholz, HM AF Ross, Joseph S. Normand, Sharon-Lise T. Wang, Yun Ko, Dennis T. Chen, Jersey Drye, Elizabeth E. Keenan, Patricia S. Lichtman, Judith H. Bueno, Hector Schreiner, Geoffrey C. Krumholz, Harlan M. TI Hospital Volume and 30-Day Mortality for Three Common Medical Conditions SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; HEALTH-CARE; QUALITY; MODEL; RATES; TIME AB BACKGROUND The association between hospital volume and the death rate for patients who are hospitalized for acute myocardial infarction, heart failure, or pneumonia remains unclear. It is also not known whether a volume threshold for such an association exists. METHODS We conducted cross-sectional analyses of data from Medicare administrative claims for all fee-for-service beneficiaries who were hospitalized between 2004 and 2006 in acute care hospitals in the United States for acute myocardial infarction, heart failure, or pneumonia. Using hierarchical logistic-regression models for each condition, we estimated the change in the odds of death within 30 days associated with an increase of 100 patients in the annual hospital volume. Analyses were adjusted for patients' risk factors and hospital characteristics. Bootstrapping procedures were used to estimate 95% confidence intervals to identify the condition-specific volume thresholds above which an increased volume was not associated with reduced mortality. RESULTS There were 734,972 hospitalizations for acute myocardial infarction in 4128 hospitals, 1,324,287 for heart failure in 4679 hospitals, and 1,418,252 for pneumonia in 4673 hospitals. An increased hospital volume was associated with reduced 30-day mortality for all conditions (P<0.001 for all comparisons). For each condition, the association between volume and outcome was attenuated as the hospital's volume increased. For acute myocardial infarction, once the annual volume reached 610 patients ( 95% confidence interval [CI], 539 to 679), an increase in the hospital volume by 100 patients was no longer significantly associated with reduced odds of death. The volume threshold was 500 patients ( 95% CI, 433 to 566) for heart failure and 210 patients ( 95% CI, 142 to 284) for pneumonia. CONCLUSIONS Admission to higher-volume hospitals was associated with a reduction in mortality for acute myocardial infarction, heart failure, and pneumonia, although there was a volume threshold above which an increased condition-specific hospital volume was no longer significantly associated with reduced mortality. C1 [Ross, Joseph S.] Mt Sinai Sch Med, New York, NY 10029 USA. [Ross, Joseph S.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Boston, MA USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Wang, Yun; Chen, Jersey; Drye, Elizabeth E.; Schreiner, Geoffrey C.; Krumholz, Harlan M.] Yale New Haven Med Ctr, New Haven, CT 06504 USA. [Wang, Yun; Chen, Jersey; Lichtman, Judith H.; Krumholz, Harlan M.] Yale Univ, Sch Med, New Haven, CT USA. [Ko, Dennis T.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Ko, Dennis T.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Bueno, Hector] Hosp Gen Univ Gregorio Maranon, Madrid, Spain. RP Ross, JS (reprint author), Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1070, New York, NY 10029 USA. EM joseph.ross@mssm.edu RI Max, Mad/E-5238-2010; BUENO, HECTOR/I-3910-2015; OI Max, Mad/0000-0001-6966-6829; BUENO, HECTOR/0000-0003-0277-7596; Ko, Dennis/0000-0001-6840-8051 FU CMS [HHSM-500-2005-CO001C]; National Institute on Aging [K08 AG032886]; American Federation for Aging Research; Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Madrid [BA08/90010] FX Supported by a contract (HHSM-500-2005-CO001C) with the CMS, by a grant (K08 AG032886, to Dr. Ross) from the National Institute on Aging, by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program, and by a grant (BA08/90010, to Dr. Bueno) from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Madrid. NR 22 TC 125 Z9 128 U1 1 U2 15 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 MAR 25 PY 2010 VL 362 IS 12 BP 1110 EP 1118 DI 10.1056/NEJMsa0907130 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 573FU UT WOS:000275894600008 PM 20335587 ER PT J AU Pless, ML Chen, YB Copen, WA Frosch, MP AF Pless, Misha L. Chen, Yi-Bin Copen, William A. Frosch, Matthew P. TI A Woman with Paresthesias and Ataxia Intravascular large-B-cell lymphoma. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; ANTHRACYCLINE-BASED CHEMOTHERAPY; HIGH-DOSE CHEMOTHERAPY; PRIMARY CNS LYMPHOMA; MATRIX METALLOPROTEINASES; ADHESION MOLECULES; MULTIPLE-SCLEROSIS; 1ST-LINE TREATMENT; TRANSPLANTATION; RADIOTHERAPY C1 [Pless, Misha L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. [Copen, William A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Pless, Misha L.] Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02138 USA. [Chen, Yi-Bin] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Copen, William A.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Pless, ML (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. FU Bayer; EMD Serono; Pfizer; Teva Neuroscience; Novartis; Elsevier FX Dr. Pless reports receiving consulting fees from Bayer, EMD Serono, Pfizer, and Teva Neuroscience; honoraria from Bayer, EMD Serono, Novartis, Pfizer, and Teva Neuroscience; and grant support from EMD Serono; and Dr. Frosch, receiving honoraria from Elsevier. No other potential conflict of interest relevant to this article was reported. NR 30 TC 2 Z9 2 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 25 PY 2010 VL 362 IS 12 BP 1129 EP 1138 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 573FU UT WOS:000275894600012 PM 20335590 ER PT J AU Kathiresan, S AF Kathiresan, Sekar TI Genetic Variants in Lp(a) Lipoprotein and Coronary Disease REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 2 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 MAR 25 PY 2010 VL 362 IS 12 BP 1147 EP 1148 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 573FU UT WOS:000275894600019 ER PT J AU Wilber, ST Sullivan, AF Camargo, CA AF Wilber, Scott T. Sullivan, Ashley F. Camargo, Carlos A., Jr. TI Chronic Pain and Risk of Falls in Older Adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID VITAMIN-D C1 [Wilber, Scott T.] Summa Akron City Hosp, Akron, OH USA. [Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wilber, ST (reprint author), Summa Akron City Hosp, Akron, OH USA. EM wilbers@summa-health.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 24 PY 2010 VL 303 IS 12 BP 1148 EP 1148 DI 10.1001/jama.2010.324 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 573AC UT WOS:000275879600015 PM 20332398 ER PT J AU Hung, AY Sung, CC Brito, IL Sheng, M AF Hung, Albert Y. Sung, Clifford C. Brito, Ilana L. Sheng, Morgan TI Degradation of Postsynaptic Scaffold GKAP and Regulation of Dendritic Spine Morphology by the TRIM3 Ubiquitin Ligase in Rat Hippocampal Neurons SO PLOS ONE LA English DT Article ID RING FINGER PROTEIN; EXCITATORY SYNAPSES; SYNAPTIC PROTEIN; DIFFERENTIAL EXPRESSION; PROTEASOME SYSTEM; DENSITY PROTEINS; SHANK FAMILY; MYOSIN-V; COMPLEX; PSD-95 AB Changes in neuronal activity modify the structure of dendritic spines and alter the function and protein composition of synapses. Regulated degradation of postsynaptic density (PSD) proteins by the ubiquitin-proteasome system is believed to play an important role in activity-dependent synaptic remodeling. Stimulating neuronal activity in vitro and in vivo induces the ubiquitination and degradation of GKAP/SAPAP and Shank, major scaffold proteins of the PSD. However, the specific ubiquitin ligases that regulate postsynaptic protein composition have not been identified. Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites. Suppression of endogenous TRIM3 by RNA interference (RNAi) results in increased accumulation of GKAP and Shank1 at synapses, as well as enlargement of dendritic spine heads. RNAi of TRIM3 also prevented the loss of GKAP induced by synaptic activity. Thus, TRIM3 is a novel E3 ligase that mediates activity-dependent turnover of PSD scaffold proteins and is a negative regulator of dendritic spine morphology. C1 [Hung, Albert Y.; Sung, Clifford C.; Brito, Ilana L.; Sheng, Morgan] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Hung, Albert Y.; Sung, Clifford C.; Brito, Ilana L.; Sheng, Morgan] MIT, Dept Biol, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Hung, Albert Y.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Hung, AY (reprint author), MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, E25-618, Cambridge, MA 02139 USA. EM msheng@mit.edu FU National Institutes of Health [K08 Award NS41411] FX The work was funded by National Institutes of Health K08 Award NS41411 (A. Y. H.). M. S. was an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 57 Z9 57 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 24 PY 2010 VL 5 IS 3 AR e9842 DI 10.1371/journal.pone.0009842 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 573FT UT WOS:000275894500011 PM 20352094 ER PT J AU Ix, JH de Boer, IH Wassel, CL Criqui, MH Shlipak, MG Whooley, MA AF Ix, Joachim H. de Boer, Ian H. Wassel, Christina L. Criqui, Michael H. Shlipak, Michael G. Whooley, Mary A. TI Urinary Creatinine Excretion Rate and Mortality in Persons With Coronary Artery Disease The Heart and Soul Study SO CIRCULATION LA English DT Article DE cardiovascular diseases; creatinine; muscles; mortality ID CARDIOVASCULAR-DISEASE; MUSCLE MASS; CYSTATIN-C; RESISTANCE EXERCISE; CLINICAL-CARDIOLOGY; SEDENTARY MEN; ASSOCIATION; INDIVIDUALS; METABOLISM; VARIABILITY AB Background-In persons with coronary artery disease, low body mass index is associated with greater mortality; however, it is uncertain whether low muscle mass is a risk factor for mortality in this setting. Methods and Results-In this study, 903 individuals with coronary artery disease provided 24-hour urine collections. We measured urine creatinine and volume and calculated creatinine excretion rate, a marker of muscle mass. Cox proportional-hazards models evaluated the association of creatinine excretion rate with mortality risk. Over a median follow-up of 6.0 years, 232 participants (26%) died. Compared with the highest sex-specific creatinine excretion rate tertile, the lowest tertile (<1068 mg/d in men, <766 mg/d in women) was associated with >2-fold risk of mortality (hazard ratio, 2.30; 95% confidence interval, 1.51 to 3.51) in models adjusted for age, sex, race, cystatin C-based estimated glomerular filtration rate, body mass index, traditional cardiovascular disease risk factors, and C-reactive protein levels. The association was essentially unaltered with further adjustment for physical fitness, left ventricular mass, left ventricular ejection fraction, or fasting insulin and glucose levels. Conclusions-Lower creatinine excretion rate is strongly associated with mortality in outpatients with coronary artery disease, independently of conventional measures of body composition, kidney function, and traditional coronary artery disease risk factors. Future studies should determine whether low creatinine excretion rate may be a modifiable risk factor for mortality among persons with coronary artery disease, potentially through resistive exercise training or nutrition interventions. (Circulation. 2010; 121: 1295-1303.) C1 [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol, San Diego, CA 92161 USA. [Ix, Joachim H.; Wassel, Christina L.; Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, San Diego, CA 92161 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Med, Div Cardiol, San Diego, CA 92161 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA 92161 USA. [de Boer, Ian H.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [de Boer, Ian H.] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [Shlipak, Michael G.; Whooley, Mary A.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Ix, JH (reprint author), Univ Calif San Diego, Dept Med, Div Nephrol & Hypertens, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu FU American Heart Association; National Heart Lung and Blood Institute (NHLBI) [R01HL096851, R01 HL079235]; Department of Veterans Epidemiology; Department of Veterans Affairs Health Services Research and Development service; American Federation for Aging Research; Robert Wood Johnson Foundation; Ischemia Research and Education Foundation; American Diabetes Association; National Institutes on Aging; National Institutes on Diabetes Digestive and Kidney Diseases; Department of Defense FX This study was supported by grants from the American Heart Association (Fellow-to-Faculty Transition) and the National Heart Lung and Blood Institute (NHLBI: R01HL096851) to Dr Ix. The Heart and Soul Study was supported by the Department of Veterans Epidemiology Merit Review Program, the Department of Veterans Affairs Health Services Research and Development service, the NHLBI (R01 HL079235), the American Federation for Aging Research (Paul Beeson Scholars Program), the Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program), and the Ischemia Research and Education Foundation. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.; Dr Ix reports receiving grant support from the NHLBI, the American Heart Association, and the American Diabetes Association. Drs Wassel and Criqui report receiving grants from the NHLBI. Dr Shlipak reports receiving grant support from the American Heart Association, NHLBI, National Institutes on Aging, and National Institutes on Diabetes Digestive and Kidney Diseases. Dr Whooley reports receiving grants from the NHLBI, Veterans Affairs, and Department of Defense. Dr de Boer reports no conflicts. NR 33 TC 52 Z9 53 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 23 PY 2010 VL 121 IS 11 BP 1295 EP 1303 DI 10.1161/CIRCULATIONAHA.109.924266 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 572VW UT WOS:000275863200005 PM 20212276 ER PT J AU Shah, RV Januzzi, JL AF Shah, Ravi V. Januzzi, James L., Jr. TI ST-Elevation Alternans and Nonsustained Polymorphic Ventricular Tachycardia in a Patient With Prinzmetal (Variant) Angina SO CIRCULATION LA English DT Editorial Material ID SEGMENT C1 [Januzzi, James L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org NR 5 TC 1 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 23 PY 2010 VL 121 IS 11 BP 1371 EP 1373 DI 10.1161/CIR.0b013e3181d8d759 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 572VW UT WOS:000275863200014 PM 20308628 ER PT J AU Drachman, DE AF Drachman, Douglas E. TI Response to Letter Regarding Article, "Drug-Eluting Stents in Animals and Patients: Where Do We Stand Today?" SO CIRCULATION LA English DT Letter C1 Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Drachman, DE (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 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 MAR 23 PY 2010 VL 121 IS 11 BP E247 EP E247 DI 10.1161/CIR.0b013e3181d8723a PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 572VW UT WOS:000275863200017 ER PT J AU Morrow, DA Scirica, BM Sabatine, MS de Lemos, JA Murphy, SA Jarolim, P Theroux, P Bode, C Braunwald, E AF Morrow, David A. Scirica, Benjamin M. Sabatine, Marc S. de Lemos, James A. Murphy, Sabina A. Jarolim, Petr Theroux, Pierre Bode, Christophe Braunwald, Eugene TI B-Type Natriuretic Peptide and the Effect of Ranolazine in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Observations From the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE angina; myocardial infarction; natriuretic peptides; ranolazine; unstable angina ID LEFT-VENTRICULAR FUNCTION; CHRONIC HEART-FAILURE; ARTERY-DISEASE; PROGNOSTIC VALUE; TROPONIN-T; RISK; MORTALITY; OXIDATION; ANGINA; MYOCYTES AB Objectives We designed a prospective evaluation of the interaction between B-type natriuretic peptide (BNP) and the effect of ranolazine in patients with acute coronary syndromes (ACS) as part of a randomized, blinded, placebo-controlled trial. Background Ranolazine is believed to exert anti-ischemic effects by reducing myocardial sodium and calcium overload and consequently ventricular wall stress. BNP increases in response to increased wall stress and is a strong risk indicator in ACS. Methods We measured plasma BNP in all available baseline samples (n = 4,543) among patients with non-ST-segment elevation ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial and followed them for a mean of 343 days. The primary end point was a composite of cardiovascular death, myocardial infarction, and recurrent ischemia. BNP elevation was defined as >80 pg/ml. Results Patients with elevated BNP (n = 1,935) were at significantly higher risk of the primary trial end point (26.4% vs. 20.4%, p < 0.0001), cardiovascular death (8.0% vs. 2.1%, p < 0.001), and myocardial infarction (10.6% vs. 5.8%, p < 0.001) at 1 year. In patients with BNP > 80 pg/ml, ranolazine reduced the primary end point (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.66 to 0.94, p = 0.009). The effect of ranolazine in patients with BNP > 80 pg/ml was directionally similar for recurrent ischemia (HR: 0.78; 95% CI: 0.62 to 0.98; p = 0.04) and cardiovascular death or myocardial infarction (HR: 0.83; 95% CI: 0.66 to 1.05, p = 0.12). There was no detectable effect in those with low BNP (p interaction value = 0.05). Conclusions Our findings indicate that ranolazine may have enhanced efficacy in high-risk patients with ACS identified by increased BNP. The interaction of biomarkers of hemodynamic stress and the effects of ranolazine warrants additional investigation. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788) (J Am Coll Cardiol 2010; 55: 1189-96) (C) 2010 by the American College of Cardiology Foundation C1 [Morrow, David A.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Morrow, David A.; Scirica, Benjamin M.; Sabatine, Marc S.; Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Jarolim, Petr] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Jarolim, Petr] Harvard Univ, Sch Med, Boston, MA USA. [de Lemos, James A.] Univ Texas Southwestern Med Sch, Dallas, TX USA. [Theroux, Pierre] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Bode, Christophe] Univ Freiburg, Med Univ Klin, Freiburg, Germany. RP Morrow, DA (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org FU CV Therapeutics (Palo Alto, California); Accumetrics; Amgen; AstraZeneca; Bayer Healthcare; Beckman-Coulter; Biosite; Bristol-Myers Squibb; CV Therapeutics; Daiichi Sankyo; Eisai Medical Research; Eli Lilly and Co.; Genentech; GlaxoSmithKline; Integrated Therapeutics; Johnson Johnson; Merck and Company; Millennium Pharmaceuticals; Nanosphere; Novartis Pharmaceuticals; Nuvelo; Ortho-Clinical Diagnostics,; Pfizer; Roche Diagnostics; Sanofi-Aventis; Sanofi-Synthelabo; Schering-Plough; Siemens; Singulex; CVT/Gilead; OrthoClinical Diagnostics FX The MERLIN-TIMI 36 trial was supported by CV Therapeutics (Palo Alto, California).; The TIMI Study Group has received significant research grant support from Accumetrics, Amgen, AstraZeneca, Bayer Healthcare, Beckman-Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Daiichi Sankyo, Eisai Medical Research, Eli Lilly and Co., Genentech, GlaxoSmithKline, Integrated Therapeutics, Johnson & Johnson, Merck and Company, Millennium Pharmaceuticals, Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Sanofi-Synthelabo, Schering-Plough, Siemens, and Singulex. Dr. Morrow has received honoraria for educational presentations from CV Therapeutics, Eli Lilly, and Sanofi-Aventis; served as a consultant for Beckman Coulter, Critical Diagnostics, CV Therapeutics, Sanofi-Aventis, Schering Plough, and Siemens; and is a paid member of a Clinical Events Committed for AstraZeneca. Dr. Scirica is a consultant for, educational presenter for, and has received research support from CVT/Gilead, and has received research support from Roche Diagnostics. Dr. Sabatine has received research support from CV Therapeutics and OrthoClinical Diagnostics. Dr. de Lemos has received grant support and consulting income from Biosite and Roche Diagnostics. Dr. Jarolim has received research support from Amgen, Beckman-Coulter, OrthoClinical Diagnostics, Roche Diagnostics, and Siemens Healthcare Diagnostics; and honoraria for educational presentations from OrthoClinical Diagnostics. Dr. Braunwald is the Chairman of the TIMI Study Group at the Brigham and Women's Hospital. Dr. Braunwald has received honorarium from Bayer AG, CV Therapeutics, Daiichi Sankyo, Eli Lilly, Merck & Co., Momenta, Schering-Plough, Sanofi-Aventis, Cytokinetics, Genzyme, GlaxoSmithKline, and Broadview Ventures. NR 34 TC 31 Z9 32 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 23 PY 2010 VL 55 IS 12 BP 1189 EP 1196 DI 10.1016/j.jacc.2009.09.068 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 570HK UT WOS:000275663200003 PM 20298924 ER PT J AU Cho, JM Raffel, OC Stone, JR Kim, CJ Jang, IK AF Cho, Jin-Man Raffel, Owen C. Stone, James R. Kim, Chong-Jin Jang, Ik-Kyung TI Spontaneous Recanalization of a Coronary Artery After Thrombotic Occlusion In Vivo Demonstration With Optical Coherence Tomography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material C1 [Cho, Jin-Man; Kim, Chong-Jin] Kyung Hee Univ, E W Neo Med Ctr, Seoul, South Korea. [Raffel, Owen C.; Stone, James R.; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Cho, JM (reprint author), Kyung Hee Univ, E W Neo Med Ctr, Seoul, South Korea. NR 0 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 23 PY 2010 VL 55 IS 12 BP 1274 EP 1274 DI 10.1016/j.jacc.2008.11.071 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 570HK UT WOS:000275663200015 PM 20298935 ER PT J AU Cudkowicz, ME Swash, M AF Cudkowicz, Merit E. Swash, Michael TI CSF markers in amyotrophic lateral sclerosis Has the time come? SO NEUROLOGY LA English DT Editorial Material ID BIOMARKERS C1 [Swash, Michael] Queen Mary Univ London, Royal London Hosp, Dept Neurol, London E1 1BB, England. [Cudkowicz, Merit E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Swash, M (reprint author), Queen Mary Univ London, Royal London Hosp, Dept Neurol, London E1 1BB, England. EM mswash@btinternet.com OI Swash, Michael/0000-0002-8717-8914 NR 4 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 23 PY 2010 VL 74 IS 12 BP 949 EP 950 DI 10.1212/WNL.0b013e3181d72c31 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 577WD UT WOS:000276253800004 PM 20308678 ER PT J AU Fernandes, F Ansari, IUH Striker, R AF Fernandes, Fiona Ansari, Israr-ul H. Striker, Rob TI Cyclosporine Inhibits a Direct Interaction between Cyclophilins and Hepatitis C NS5A SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VITRO; RNA-POLYMERASE; CELL-CULTURE; REPLICATION; PROTEIN; GENOME; BINDING; STRAIN; DOMAIN AB Background: Hepatitis C Virus (HCV) infection is a leading indication for liver transplantation. HCV infection reoccurs almost universally post transplant, decreasing both graft longevity and patient survival. The immunosuppressant, cyclosporine A (CsA) has potent anti-HCV activity towards both HCV replicons and the genotype 2a cell culture infectious virus. Previously, we isolated mutations in the 1bN replicon with less sensitivity to CsA that mapped to both NS5A and NS5B regions of the virus. Mutations in NS5A alone conferred decreased CsA susceptibility regardless of NS5B mutations. Methodology/Principal Findings: We examined the mechanisms by which NS5A mutations contribute to CsA resistance and if they are strain dependent. Using in vitro mutagenesis, the amino acid position 321 mutation of NS5A was restored to the wild-type tyrosine residue conferring partial CsA susceptibility on the mutant replicon. The 321 mutation also alters CsA susceptibility of the JFH cell culture virus. Additionally, we demonstrated a novel CsA-sensitive interaction between NS5A and both cyclophilin A and B. Both the mutant NS5A and wild type NS5A bind cyclophilin in vitro. The NS5A: cyclophilin interaction requires both the NS5A region identified by the resistance mutants and cyclophilin catalytic residues. In cell culture, NS5A from CsA resistant mutant has an enhanced interaction with cyclophilin B. Additionally; NS5B facilitates a stronger binding of mutant NS5A to endogenous cyclophilin B than wild-type in cell culture. Conclusions/Significance: Collectively, this data suggests direct interactions between cyclophilins and NS5A are critical to understand for optimal use of cyclophilin inhibitors in anti-HCV therapy. C1 [Fernandes, Fiona; Ansari, Israr-ul H.; Striker, Rob] Univ Wisconsin, Dept Med, Madison, WI USA. [Striker, Rob] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. RP Fernandes, F (reprint author), SUNY Stony Brook, Dept Microbiol & Mol Genet, Stony Brook, NY 11794 USA. EM tstriker@wisc.edu FU American Cancer Society Research Scholar [07-077-01]; Office of Research and Development; Biomedical Laboratory R&D Service, Department of Veterans Affairs; University of Wisconsin Institute for Clinical and Translational Research; NIH Clinical and Translational Science [1UL1RR025011] FX This research was supported by the American Cancer Society Research Scholar Grant (07-077-01) to R. S., by the Office of Research and Development, Biomedical Laboratory R&D Service, Department of Veterans Affairs, and by the University of Wisconsin Institute for Clinical and Translational Research, funded through an NIH Clinical and Translational Science Award, grant number 1UL1RR025011. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 57 Z9 57 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 23 PY 2010 VL 5 IS 3 AR e9815 DI 10.1371/journal.pone.0009815 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 573FS UT WOS:000275894400017 PM 20352119 ER PT J AU Beerman, I Bhattacharya, D Zandi, S Sigvardsson, M Weissman, IL Bryder, D Rossi, DJ AF Beerman, Isabel Bhattacharya, Deepta Zandi, Sasan Sigvardsson, Mikael Weissman, Irving L. Bryder, David Rossi, Derrick J. TI Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HSCs; leukemia; lineage specification ID COMPARTMENT AB Aging of the hematopoietic stem cell compartment is believed to contribute to the onset of a variety of age-dependent blood cell pathophysiologies. Mechanistic drivers of hematopoietic stem cell (HSC) aging include DNA damage accumulation and induction of tumor suppressor pathways that combine to reduce the regenerative capacity of aged HSCs. Such mechanisms do not however account for the change in lymphoid and myeloid lineage potential characteristic of HSC aging, which is believed to be central to the decline of immune competence and predisposition to myelogenous diseases in the elderly. Here we have prospectively isolated functionally distinct HSC clonal subtypes, based on cell surface phenotype, bearing intrinsically different capacities to differentiate toward lymphoid and myeloid effector cells mediated by quantitative differences in lineage priming. Finally, we present data supporting a model in which clonal expansion of a class of intrinsically myeloid-biased HSCs with robust self-renewal potential is a central component of hematopoietic aging. C1 [Weissman, Irving L.] Stanford Univ, Ctr Canc, Stanford Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Beerman, Isabel; Rossi, Derrick J.] Childrens Hosp Boston, Harvard Stem Cell Inst, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA 02115 USA. [Beerman, Isabel; Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Bhattacharya, Deepta] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Zandi, Sasan; Sigvardsson, Mikael] Linkoping Univ, Dept Biomed & Surg, Linkoping, Sweden. [Weissman, Irving L.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Bryder, David] Lund Univ, Immunol Unit, Inst Expt Med Sci, Lund, Sweden. RP Weissman, IL (reprint author), Stanford Univ, Ctr Canc, Stanford Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. EM irv@stanford.edu; david.bryder@med.lu.se; rossi@idi.harvard.edu OI Sigvardsson, Mikael/0000-0001-8527-7276 FU Swedish Medical Research Council; Swedish Strategic Research Foundation; Swedish Cancer Society; Crafoord foundation; Medical Faculty at Lund University; National Institutes of Aging; Harvard Stem Cell Institute FX D. B. is supported by the Swedish Medical Research Council, the Swedish Strategic Research Foundation, the Swedish Cancer Society, the Crafoord foundation, and the Medical Faculty at Lund University. D. J. R. is supported by grants from the National Institutes of Aging and the Harvard Stem Cell Institute. NR 18 TC 214 Z9 217 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 23 PY 2010 VL 107 IS 12 BP 5465 EP 5470 DI 10.1073/pnas.1000834107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 573GY UT WOS:000275898300037 PM 20304793 ER PT J AU Fishman, J Ten Have, T Casarett, D AF Fishman, Jessica Ten Have, Thomas Casarett, David TI Cancer and the Media How Does the News Report on Treatment and Outcomes? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID BREAST-CANCER; NURSING-HOMES; CARE; COVERAGE; LIFE; DEATH; PAIN; END; CREDIBILITY; MANAGEMENT AB Background: Cancer receives a great deal of news media attention. Although approximately half of all US patients with cancer die of their illness or of related complications, it is unknown whether reports in the news media reflect this reality. Methods: To determine how cancer news coverage repot-is about cancer care and outcornes, we conducted a content analysis of US cancer news reporting in 8 large-readership newspapers and 5 national magazines. Trained coders determined the proportion of articles reporting about cancer survival, cancer death and dying, aggressive cancer treatment, cancer treatment failure, adverse events of cancer treatment, and end-of-life palliative or hospice care. Results: Of 436 articles about cancer, 140 (32.1%; 95% confidence interval [CI], 28%-37%) focused Oil survival and only 33 (7.6 %; 5%-.1.0%) focused on death and dying (p<.001, chi(2) test). Only 57 articles (13.1%; 10%-17%) reported that aggressive cancer treatments can fail, and 131. (30.0%; 26%-35%) reported that aggressive treatments can result in adverse events. Although most articles (249 of 436 [57.1%]; 95% CI, 52%-62%) discussed aggressive treatments exclusively, almost none (2 of 436; [0.5%]; 0%-2%) discussed end-of-life palliative or hospice care exclusively (P <.001, chi(2) test), and only a few (11 of 436 [2.5%]; 1%-6%) discussed aggressive treatment, and end-of-life care. Conclusions: News reports about cancer frequently discuss aggressive treatment and survival but rarely discuss treatment failure, adverse events, end-of-life care, or death. These portrayals of cancer care in the news media may give patients an inappropriately optimistic view of cancer treatment, outcomes, and prognosis. C1 [Fishman, Jessica; Ten Have, Thomas] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Fishman, Jessica] Univ Penn, Annenberg Sch Commun, Philadelphia, PA 19104 USA. [Casarett, David] Univ Penn, VA Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Casarett, David] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Fishman, Jessica; Ten Have, Thomas; Casarett, David] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Fishman, J (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, 711 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM fishman1@mail.med.upenn.edu FU NCI NIH HHS [5P50CA095856-05, P20 CA095856] NR 49 TC 16 Z9 16 U1 1 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 22 PY 2010 VL 170 IS 6 BP 515 EP 518 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 571QB UT WOS:000275768400002 PM 20233800 ER PT J AU Lobb, R Allen, JD Emmons, KM Ayanian, JZ AF Lobb, Rebecca Allen, Jennifer D. Emmons, Karen M. Ayanian, John Z. TI Timely Care After an Abnormal Mammogram Among Low-Income Women in a Public Breast Cancer Screening Program SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PATIENT NAVIGATION; FOLLOW-UP; NATIONAL BREAST; RETROSPECTIVE ANALYSIS; SOCIOECONOMIC-STATUS; SOCIAL DETERMINANTS; UNDERSERVED WOMEN; HEALTH-INSURANCE; URBAN-POPULATION; UNITED-STATES AB Background: Since 1990, the National Breast and Cervical Cancer Early Detection Program (BCCEDP) has funded breast cancer screening and diagnostic services for low-income, underinsured women. Case management was implemented in 2001 to address barriers to follow-up after an abnormal mammogram, and free treatment was introduced in 2004. However, the effect of these policies on timeliness of care has not been empirically evaluated. Methods: Among 2252 BCCEDP participants in Massachusetts during 1998 through 2007, we conducted a time-to-event analysis with prepolicy-postpolicy comparisons to examine associations of case management and free treatment with diagnostic and treatment delays (>60 days and >90 days, respectively) after an abnormal mammogram. Results: The proportion of women experiencing a diagnostic delay decreased from 33% to 23% after the introduction of case management (P<.001), with a significant reduction in the adjusted risk of diagnostic delay (relative risk [RR], 0.65; 95% confidence interval [CI], 0.53-0.79) that did not differ by race and ethnicity. However, case management was not associated with changes in treatment delay (RR, 0.93; 95% CI, 0.80-1.10). Free treatment was not associated with changes in the adjusted risk of diagnostic delay (RR, 0.61; 95% CI, 0.331.14) or treatment delay (RR, 0.77; 95% CI, 0.43-1.38) beyond improvements associated with case management. Conclusions: Case management to assist women in overcoming logistic and psychosocial barriers to care may improve time to diagnosis among low-income women who receive free breast cancer screening and diagnostic services. Programs that provide services to coordinate care, in addition to free screening and diagnostic tests, may improve population health. C1 [Lobb, Rebecca] St Michaels Hosp, Ctr Res Inner City Hlth, Toronto, ON M5B 1W8, Canada. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Allen, Jennifer D.; Emmons, Karen M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lobb, Rebecca; Allen, Jennifer D.; Emmons, Karen M.; Ayanian, John Z.] Harvard Univ, Sch Med, Sch Publ Hlth, Boston, MA 02115 USA. RP Lobb, R (reprint author), St Michaels Hosp, Ctr Res Inner City Hlth, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM lobbr@smh.toronto.on.ca RI Allen, Jennifer/M-2113-2015; OI Lobb, Rebecca/0000-0003-3503-0675 FU NCI NIH HHS [R25 CA057711-15, U01 CA114644-04, R25 CA057711, U01 CA114644, 5 R25 CA057711-15, K05 CA124415-02, 5 U01 CA114644, K05CA124415, K05 CA124415]; NCRR NIH HHS [1 UL1 RR 025758-01, UL1 RR025758-01, UL1 RR025758] NR 38 TC 20 Z9 21 U1 3 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 22 PY 2010 VL 170 IS 6 BP 521 EP 528 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 571QB UT WOS:000275768400004 PM 20233801 ER PT J AU Dockendorff, C Buhrlage, S Weiwer, M Kim, HJ Ting, A Nag, P Germain, A Johnston, S Doud, K Koehler, A Mandinova, A Scherer, C MacPherson, L AF Dockendorff, Chris Buhrlage, Sara Weiwer, Michel Kim, Han-Je Ting, Amal Nag, Partha Germain, Andrew Johnston, Stephen Doud, Katie Koehler, Angela Mandinova, Anna Scherer, Christina MacPherson, Lawrence TI Identification of novel macrocycles as potent inhibitors of the hedgehog signaling pathway SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Broad Inst, Dept Med Chem & Probe Dev, Cambridge, MA USA. Broad Inst, Dept Analyt Chem, Cambridge, MA USA. Broad Inst, Dept Ligand Discovery, Cambridge, MA USA. Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 21 PY 2010 VL 239 MA 367-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V21DW UT WOS:000208189303493 ER PT J AU Gray, NS AF Gray, Nathanael S. TI Screening and rational design approaches for developing selective protein kinase inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 21 PY 2010 VL 239 MA 21-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V21DW UT WOS:000208189300404 ER PT J AU Greytak, AB McLaurin, EJ Curtin, PN Liu, WH Martin, JD Lanning, RM Jain, RK Bawendi, MG Nocera, DG AF Greytak, Andrew B. McLaurin, Emily J. Curtin, Peter N. Liu, Wenhao Martin, John D. Lanning, Ryan M. Jain, Rakesh K. Bawendi, Moungi G. Nocera, Daniel G. TI Smart quantum dot sensing SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 MIT, Dept Chem, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 21 PY 2010 VL 239 MA 177-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V21DW UT WOS:000208189303075 ER PT J AU Huang, HC Yang, YS Koria, P Rege, K AF Huang, Huang-Chiao Yang, Yoonsun Koria, Piyush Rege, Kaushal TI Degradable polypeptide-nanoparticle matrices for combined photothermal ablation and drug delivery SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Arizona State Univ, Biol Design Program, Tempe, AZ USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 21 PY 2010 VL 239 MA 561-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V21DW UT WOS:000208189300669 ER PT J AU Holmes, MD Chen, WY Li, L Hertzmark, E Spiegelman, D Hankinson, SE AF Holmes, Michelle D. Chen, Wendy Y. Li, Lisa Hertzmark, Ellen Spiegelman, Donna Hankinson, Susan E. TI Aspirin Intake and Survival After Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MARGINAL STRUCTURAL MODELS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; LOW-DOSE ASPIRIN; NSAID USE; POSTMENOPAUSAL WOMEN; PRIMARY PREVENTION; RISK; COHORT; METAANALYSIS; RECURRENCE AB Purpose Animal and in vitro studies suggest that aspirin may inhibit breast cancer metastasis. We studied whether aspirin use among women with breast cancer decreased their risk of death from breast cancer. Methods This was a prospective observational study based on responses from 4,164 female registered nurses in the Nurses' Health Study who were diagnosed with stages I, II, or III breast cancer between 1976 and 2002 and were observed until death or June 2006, whichever came first. The main outcome was breast cancer mortality risk according to number of days per week of aspirin use (0, 1, 2 to 5, or 6 to 7 days) first assessed at least 12 months after diagnosis and updated. Results There were 341 breast cancer deaths. Aspirin use was associated with a decreased risk of breast cancer death. The adjusted relative risks (RRs) for 1, 2 to 5, and 6 to 7 days of aspirin use per week compared with no use were 1.07 (95% CI, 0.70 to 1.63), 0.29 (95% CI, 0.16 to 0.52), and 0.36 (95% CI, 0.24 to 0.54), respectively (test for linear trend, P < .001). This association did not differ appreciably by stage, menopausal status, body mass index, or estrogen receptor status. Results were similar for distant recurrence. The adjusted RRs were 0.91 (95% CI, 0.62 to 1.33), 0.40 (95% CI, 0.24 to 0.65), and 0.57 (95% CI, 0.39 to 0.82; test for trend, P = .03) for 1, 2 to 5, and 6 to 7 days of aspirin use, respectively. Conclusion Among women living at least 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk of distant recurrence and breast cancer death. C1 [Holmes, Michelle D.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Holmes, MD (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM michelle.holmes@channing.harvard.edu FU National Institutes of Health [CA87969] FX Supported by National Institutes of Health Grant No. CA87969. NR 40 TC 164 Z9 167 U1 2 U2 14 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2010 VL 28 IS 9 BP 1467 EP 1472 DI 10.1200/JCO.2009.22.7918 PG 6 WC Oncology SC Oncology GA 572IR UT WOS:000275824600006 PM 20159825 ER PT J AU Ryan, CJ Smith, MR Fong, L Rosenberg, JE Kantoff, P Raynaud, F Martins, V Lee, G Kheoh, T Kim, J Molina, A Small, EJ AF Ryan, Charles J. Smith, Matthew R. Fong, Lawrence Rosenberg, Jonathan E. Kantoff, Philip Raynaud, Florence Martins, Vanessa Lee, Gloria Kheoh, Thian Kim, Jennifer Molina, Arturo Small, Eric J. TI Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior Ketoconazole Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MITOXANTRONE PLUS PREDNISONE; ANTIANDROGEN WITHDRAWAL; MECHANISMS; DOCETAXEL; GUIDELINES; EXPRESSION; CARCINOMA; GENES AB Purpose Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy. Patients and Methods Thirty-three men with chemotherapy-naive progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing. Results Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed >= 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses. Conclusion Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted. C1 [Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94115 USA. Univ Calif San Francisco, Urol Oncol Program, San Francisco, CA 94143 USA. Cougar Biotechnol, Los Angeles, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Drug Metab & Pharmacokinet Team, Inst Canc Res, Sutton, Surrey, England. RP Ryan, CJ (reprint author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 1600 Divisadero St, San Francisco, CA 94115 USA. EM ryanc@medicine.ucsf.edu FU Cougar Biotechnology; Department of Defense Prostate Cancer Clinical Trials Consortium; National Institutes of Health [K23CA115775] FX Supported by Cougar Biotechnology, the Department of Defense Prostate Cancer Clinical Trials Consortium, and Grant No. K23CA115775 (C.J.R.) from the National Institutes of Health. V. M. and F. R. are employees of The Institute of Cancer Research, which has a commercial interest in the development of abiraterone and operates a rewards to inventors scheme. The Institute of Cancer Research has been involved in a commercial collaboration with Cougar Biotechnology. NR 19 TC 235 Z9 240 U1 2 U2 11 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2010 VL 28 IS 9 BP 1481 EP 1488 DI 10.1200/JCO.2009.24.1281 PG 8 WC Oncology SC Oncology GA 572IR UT WOS:000275824600008 PM 20159824 ER PT J AU Danila, DC Morris, MJ de Bono, JS Ryan, CJ Denmeade, SR Smith, MR Taplin, ME Bubley, GJ Kheoh, T Haqq, C Molina, A Anand, A Koscuiszka, M Larson, SM Schwartz, LH Fleisher, M Scher, HI AF Danila, Daniel C. Morris, Michael J. de Bono, Johann S. Ryan, Charles J. Denmeade, Samuel R. Smith, Matthew R. Taplin, Mary-Ellen Bubley, Glenn J. Kheoh, Thian Haqq, Christopher Molina, Arturo Anand, Aseem Koscuiszka, Michael Larson, Steve M. Schwartz, Lawrence H. Fleisher, Martin Scher, Howard I. TI Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CIRCULATING TUMOR-CELLS; ADRENAL ANDROGENS; DOSE KETOCONAZOLE; END-POINTS; TESTOSTERONE; PROGRESSION; EXPRESSION; SURVIVAL; TRIAL; CYP17 AB Purpose Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy. Patients and Methods Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was >= 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated. Results A >= 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naive and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from >= 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen. Conclusion AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations. C1 Cornell Univ, Dept Med, Joan & Sanford E Weill Coll Med, Ithaca, NY USA. [Scher, Howard I.] Mem Sloan Kettering Canc Ctr, Genitourinary Oncol Serv, Sidney Kimmel Ctr Prostate & Urol Canc, Dept Med, New York, NY 10065 USA. Mem Sloan Kettering Canc Ctr, Dept Radiol, Clin Labs, New York, NY 10065 USA. Royal Marsden Hosp, Canc Res United Kingdom Ctr Canc Therapeut, Inst Canc Res, London SW3 6JJ, England. Univ Calif San Francisco, San Francisco Comprehens Canc Ctr, San Francisco, CA USA. Cougar Biotechnol, Dept Clin Res & Dev, Los Angeles, CA USA. Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Chem Therapeut Program, Baltimore, MD USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Scher, HI (reprint author), Mem Sloan Kettering Canc Ctr, Genitourinary Oncol Serv, Sidney Kimmel Ctr Prostate & Urol Canc, Dept Med, 1275 York Ave, New York, NY 10065 USA. EM Scherh@mskcc.org RI Anand, Aseem/P-1214-2014; OI Anand, Aseem/0000-0002-3606-540X; Morris, Michael J./0000-0002-9454-0096 FU Cougar Biotechnology; Memorial Sloan-Kettering Cancer Center Specialized Program of Research Excellence (SPORE) [P50 CA92629]; Department of Defense Prostate Cancer Research Program [PC051382]; Prostate Cancer Foundation FX Supported by Cougar Biotechnology, the Memorial Sloan-Kettering Cancer Center Specialized Program of Research Excellence (SPORE) Grant in Prostate Cancer (P50 CA92629), the Department of Defense Prostate Cancer Research Program (PC051382) and the Prostate Cancer Foundation. NR 32 TC 264 Z9 273 U1 0 U2 11 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2010 VL 28 IS 9 BP 1496 EP 1501 DI 10.1200/JCO.2009.25.9259 PG 6 WC Oncology SC Oncology GA 572IR UT WOS:000275824600010 PM 20159814 ER PT J AU Slatore, CG Chien, JW Au, DH Satia, JA White, E AF Slatore, Christopher G. Chien, Jason W. Au, David H. Satia, Jessie A. White, Emily TI Lung Cancer and Hormone Replacement Therapy: Association in the Vitamins and Lifestyle Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; GROWTH-FACTOR RECEPTOR; ESTROGEN-RECEPTOR; REPRODUCTIVE FACTORS; BETA-CAROTENE; WOMEN; RISK; SMOKING; COHORT; EPIDEMIOLOGY AB Purpose Lung cancer is the leading cause of cancer-related mortality among women. The role of hormone replacement therapy (HRT) in lung cancer development is unclear. Patients and Methods We evaluated a prospective cohort of 36,588 peri-and postmenopausal women aged 50 to 76 years from Washington State recruited in 2000 to 2002 (Vitamins and Lifestyle [VITAL] Study). Lung cancer cases (n = 344) were identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry during 6 years of follow-up. Hazard ratios (HRs) associated with use and duration of specific HRT formulations were calculated for total incident lung cancer, specific morphologies, and cancer by stage at diagnosis. Results After adjusting for smoking, age, and other potential confounders, there was an increased risk of incident lung cancer associated with increasing duration of estrogen plus progestin (E + P) use (HR = 1.27 for E + P use 1 to 9 years, 95% CI, 0.91 to 1.78; and HR = 1.48 for E + P use >= 10 years, 95% CI, 1.03 to 2.12; P for trend = . 03). There was no association with duration of unopposed estrogen use. Duration of E + P use was associated with an advanced stage at diagnosis (P for trend = .03). Conclusion Use of E + P increased the risk of incident lung cancer in a duration-dependent manner, with an approximate 50% increased risk for use of 10 years or longer. These findings may be helpful for informing women of their risk of developing lung cancer and delineating important pathways involved in hormone metabolism and lung cancer. C1 [Slatore, Christopher G.] Portland VA Med Ctr, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97201 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. Univ Washington, Div Pulm & Crit Care, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Slatore, CG (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd,R&D 66, Portland, OR 97239 USA. EM slatore@ohsu.edu OI Slatore, Christopher/0000-0003-0958-8122 FU CHEST Foundation of the American College of Chest Physicians; LUNGevity Foundation; National Institutes of Health [CA130328, CA74846, CA96556, CA119683]; Department of Veterans Affairs; Portland Veterans Affairs Medical Center, Portland, OR; Veterans Affairs Puget Sound Health Care System, Seattle, WA FX Supported by the CHEST Foundation of the American College of Chest Physicians and the LUNGevity Foundation to C. G. S. This work was also supported by the National Institutes of Health (Grant No. CA130328 to C.G.S., CA74846 to E.W., and CA96556 and CA119683 to J.S.). C.G.S. and D.H.A. were supported by the Department of Veterans Affairs. This study is the result of work supported by resources from the Portland Veterans Affairs Medical Center, Portland, OR, and Veterans Affairs Puget Sound Health Care System, Seattle, WA. NR 49 TC 52 Z9 56 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 MAR 20 PY 2010 VL 28 IS 9 BP 1540 EP 1546 DI 10.1200/JCO.2009.25.9739 PG 7 WC Oncology SC Oncology GA 572IR UT WOS:000275824600017 PM 20159813 ER PT J AU Canellos, GP Abramson, JS Fisher, DC LaCasce, AS AF Canellos, George P. Abramson, Jeremy S. Fisher, David C. LaCasce, Ann S. TI Treatment of Favorable, Limited-Stage Hodgkin's Lymphoma With Chemotherapy Without Consolidation by Radiation Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INVOLVED-FIELD RADIOTHERAPY; COMBINED-MODALITY THERAPY; RANDOMIZED-TRIALS; 2 CYCLES; DISEASE; ABVD; VINBLASTINE; BLEOMYCIN; RISK; METAANALYSIS AB Purpose Limited-stage Hodgkin's lymphoma (HL) has been treated with radiation alone or radiation combined with chemotherapy. Although results in progression-free survival and overall survival have been excellent, the long-term, radiation-induced, toxic cardiac and secondary oncologic complications occurring in succeeding decades have compromised survival of young patients. This study examines the impact of chemotherapy alone in treatment of limited-stage, nonbulky HL, radiation therapy eliminated from primary treatment. Patients and Methods From 1992 to May 2008, 71 patients with a median age of 29 years (range, 17-44 years) with stages I and II HL without bulky nodes were treated with six cycles of classic combination doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Two patients received six cycles of ABVD-like modification. Two patients received four cycles of ABVD. The ABVD regimen was known to be curative in more advanced disease without radiation therapy. Results All patients achieved a clinical complete response (CR) or CR unconfirmed. After a median follow-up of at least 60 months (range, at least 12 to at least 204 months), six patients experienced relapse at 6, 10, 11, 16, 20, and 58 months. All relapses occurred at site of presenting disease. No patients have died. Salvage therapy was successful with second-line chemotherapy/radiation and autologous stem-cell transplantation. Conclusion Six cycles of ABVD is an effective and safe treatment for limited-stage, nonbulky HL and would spare young patients radiation toxicity. Interim positron emission tomography/computed tomography scans in current and future trials may identify those patients who require less than six cycles of chemotherapy. C1 [Canellos, George P.] Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Canellos, GP (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM george_canellos@dfci.harvard.edu NR 22 TC 27 Z9 29 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2010 VL 28 IS 9 BP 1611 EP 1615 DI 10.1200/JCO.2009.25.3260 PG 5 WC Oncology SC Oncology GA 572IR UT WOS:000275824600027 PM 20159818 ER PT J AU King, JC Lawrence, TS Murphy, SB Davidson, NE Mayer, RJ AF King, Jennifer C. Lawrence, Theodore S. Murphy, Sharon B. Davidson, Nancy E. Mayer, Robert J. TI The American Society of Clinical Oncology Cancer Foundation Grants Program: A 25-Year Report and a Look Toward the Future SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article AB The American Society of Clinical Oncology (ASCO) Grants Program began in 1984 with a single $16,000 grant to a young investigator for start-up research funding. In 2009, the Grants Program, now administered by The ASCO Cancer Foundation, awarded more than $6.5 million to 70 different investigators. This article, celebrating the 25th anniversary of this initiative, describes the history and evolution of the Grants Program, attempts to measure the impact of the program on clinical cancer research through an analysis of the career paths of past recipients, and addresses challenges that the program will face as it enters its second 25 years. C1 [Mayer, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. Amer Soc Clin Oncol Canc Fdn, Alexandria, VA USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. Natl Acad Sci, Inst Med, Washington, DC 20418 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. RP Mayer, RJ (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Robert_Mayer@dfci.harvard.edu RI King, Jennifer/F-8318-2010 NR 6 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2010 VL 28 IS 9 BP 1616 EP 1621 DI 10.1200/JCO.2009.27.4621 PG 6 WC Oncology SC Oncology GA 572IR UT WOS:000275824600028 PM 20177012 ER PT J AU Lee, JM Zhang, J Su, AI Walker, JR Wiltshire, T Kang, K Dragileva, E Gillis, T Lopez, ET Boily, MJ Cyr, M Kohane, I Gusella, JF MacDonald, ME Wheeler, VC AF Lee, Jong-Min Zhang, Jie Su, Andrew I. Walker, John R. Wiltshire, Tim Kang, Kihwa Dragileva, Ella Gillis, Tammy Lopez, Edith T. Boily, Marie-Josee Cyr, Michel Kohane, Isaac Gusella, James F. MacDonald, Marcy E. Wheeler, Vanessa C. TI HA novel approach to investigate tissue-specific trinucleotide repeat instability SO BMC SYSTEMS BIOLOGY LA English DT Article ID UNSTABLE TRIPLET REPEATS; KNOCK-IN MOUSE; CAG REPEAT; HUNTINGTONS-DISEASE; SOMATIC INSTABILITY; TRANSGENIC MICE; CTG REPEAT; EXPANSION; MUTATION; VULNERABILITY AB Background: In Huntington's disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors. Results: Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG repeat instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability. Conclusion: Our study clearly demonstrates that multiple tissue factors reflect the level of somatic instability in different tissues. In addition, our quantitative, genome-wide approach is readily applicable to high-throughput assays and opens the door to widespread applications with the potential to accelerate the discovery of drugs that alter tissue instability. C1 [Lee, Jong-Min; Dragileva, Ella; Gillis, Tammy; Lopez, Edith T.; Gusella, James F.; MacDonald, Marcy E.; Wheeler, Vanessa C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Zhang, Jie; Su, Andrew I.; Walker, John R.; Wiltshire, Tim] Novartis Res Fdn, Genom Inst, San Diego, CA USA. [Kang, Kihwa] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Boily, Marie-Josee; Cyr, Michel] Univ Quebec, Neurosci Res Grp, Trois Rivieres, PQ GA9 5H7, Canada. [Kohane, Isaac] Childrens Hosp, Informat Program, Boston, MA 02115 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM jlee51@partners.org; wheeler@helix.mgh.harvard.edu RI Kohane, Isaac Kohane/K-3716-2012; OI Kohane, Isaac Kohane/0000-0003-2192-5160; Su, Andrew I./0000-0002-9859-4104 FU NINDS [NS049206, NS16367, NS32765]; NCBC [LM008748]; Hereditary Disease Foundation; Canada Research Chair in Molecular Neuropharmacology; Huntington's Disease Society of America; Delta Squared FX We thank James W. MacDonald, Danh V. Nguyen, Jason M. Laramie, and Partners Research Computing (Jerry Xu and Dennis Gurgle) for technical assistance. Supported by NINDS grants NS049206 (to VCW), NS16367 (to JFG and MEM, HD Center Without Walls), and NS32765 (to MEM), NCBC grant LM008748 (to IK), the Hereditary Disease Foundation (to MC), Canada Research Chair in Molecular Neuropharmacology (to MC), and the Huntington's Disease Society of America (Coalition for the Cure, to JFG and MEM). We also thank Delta Squared for supporting this project. NR 31 TC 38 Z9 38 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD MAR 19 PY 2010 VL 4 AR 29 DI 10.1186/1752-0509-4-29 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 586AB UT WOS:000276871700001 PM 20302627 ER PT J AU Garrett, WS Gordon, JI Glimcher, LH AF Garrett, Wendy S. Gordon, Jeffrey I. Glimcher, Laurie H. TI Homeostasis and Inflammation in the Intestine SO CELL LA English DT Review ID EPITHELIAL TIGHT JUNCTIONS; GENOME-WIDE ASSOCIATION; MESENTERIC LYMPH-NODES; ILEAL CROHNS-DISEASE; T-BET DEFICIENCY; DENDRITIC CELLS; IMMUNE-SYSTEM; ENTEROENDOCRINE CELLS; ULCERATIVE-COLITIS; GUT MICROBIOTA AB The gut is home to our largest collection of microbes. The ability of the immune system to coevolve with the microbiota during postnatal life allows the host and microbiota to coexist in a mutually beneficial relationship. Failure to achieve or maintain equilibrium between a host and its microbiota has negative consequences for both intestinal and systemic health. In this Review, we consider the many cellular and molecular methods by which inflammatory responses are regulated to maintain intestinal homeostasis and the disease states that can ensue when this balance is lost. C1 [Garrett, Wendy S.; Glimcher, Laurie H.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Garrett, Wendy S.; Glimcher, Laurie H.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Gordon, Jeffrey I.] Washington Univ, Sch Med, Ctr Genome Sci, St Louis, MO 63108 USA. [Glimcher, Laurie H.] Massachusetts Gen Hosp East, Ragon Inst MGH Harvard MIT, Boston, MA 02129 USA. RP Garrett, WS (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. EM wgarrett@hsph.harvard.edu; lglimche@hsph.harvard.edu FU National Institutes of Health [AI32412, CA112663]; Burroughs Wellcome Fund; Crohn's and Colitis Foundation of America FX The authors thank the members of the Glimcher and Gordon labs for helpful discussions. This work was supported by National Institutes of Health grants AI32412 and CA112663 (L.H.G.), the Burroughs Wellcome Fund, and the Crohn's and Colitis Foundation of America. L. H. G. is a member of the Board of Directors of and holds equity in the Bristol Myers Squibb Corporation. NR 121 TC 271 Z9 280 U1 9 U2 69 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 19 PY 2010 VL 140 IS 6 BP 859 EP 870 DI 10.1016/j.cell.2010.01.023 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 571IX UT WOS:000275746600010 PM 20303876 ER PT J AU Zhang, C Browne, A Child, D DiVito, JR Stevenson, JA Tanzi, RE AF Zhang, Can Browne, Andrew Child, Daniel DiVito, Jason R. Stevenson, Jesse A. Tanzi, Rudolph E. TI Loss of Function of ATXN1 Increases Amyloid beta-Protein Levels by Potentiating beta-Secretase Processing of beta-Amyloid Precursor Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MICE LACKING ATAXIN-1; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASE; SPINOCEREBELLAR ATAXIA; APP; CELLS; SCA1; PRESENILIN-1; TRAFFICKING; ASSOCIATION AB Alzheimer disease (AD) is a devastating neurodegenerative disease with complex and strong genetic inheritance. Four genes have been established to either cause familial early onset AD (APP, PSEN1, and PSEN2) or to increase susceptibility for late onset AD (APOE). To date similar to 80% of the late onset AD genetic variance remains elusive. Recently our genome-wide association screen identified four novel late onset AD candidate genes. Ataxin 1 (ATXN1) is one of these four AD candidate genes and has been indicated to be the disease gene for spinocerebellar ataxia type 1, which is also a neurodegenerative disease. Mounting evidence suggests that the excessive accumulation of A beta, the proteolytic product of beta-amyloid precursor protein (APP), is the primary AD pathological event. In this study, we ask whether ATXN1 may lead to AD pathogenesis by affecting A beta and APP processing utilizing RNA interference in a human neuronal cell model and mouse primary cortical neurons. We show that knock-down of ATXN1 significantly increases the levels of both A beta 40 and A beta 42. This effect could be rescued with concurrent overexpression of ATXN1. Moreover, overexpression of ATXN1 decreased A beta levels. Regarding the underlying molecular mechanism, we show that the effect of ATXN1 expression on A beta levels is modulated via beta-secretase cleavage of APP. Taken together, ATXN1 functions as a genetic risk modifier that contributes to AD pathogenesis through a loss-of-function mechanism by regulating beta-secretase cleavage of APP and A beta levels. C1 [Zhang, Can; Browne, Andrew; Child, Daniel; DiVito, Jason R.; Stevenson, Jesse A.; Tanzi, Rudolph E.] Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Genet & Aging Res Unit,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Tanzi, RE (reprint author), Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Genet & Aging Res Unit,Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu FU NIMH; Cure Alzheimers Fund; Massachusetts General Hospital Fund for Medical Discovery (FMD) FX This work was supported, in whole or in part, by the NIMH, the Cure Alzheimers Fund, and the Massachusetts General Hospital Fund for Medical Discovery (FMD). NR 35 TC 25 Z9 25 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 19 PY 2010 VL 285 IS 12 BP 8515 EP 8526 DI 10.1074/jbc.M109.079079 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568VZ UT WOS:000275553700003 PM 20097758 ER PT J AU Sun, W Jin, JF Xu, RJ Hu, W Szulc, ZM Bielawski, J Obeid, LM Mao, CG AF Sun, Wei Jin, Junfei Xu, Ruijuan Hu, Wei Szulc, Zdzislaw M. Bielawski, Jacek Obeid, Lina M. Mao, Cungui TI Substrate Specificity, Membrane Topology, and Activity Regulation of Human Alkaline Ceramidase 2 (ACER2) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; MITOCHONDRIAL CERAMIDASE; SACCHAROMYCES-CEREVISIAE; MOLECULAR-CLONING; ACID CERAMIDASE; GOLGI-APPARATUS; SPHINGOSINE; DISEASE; ENZYME; CELLS AB Human alkaline ceramidase 2 (ACER2) plays an important role in cellular responses by regulating the hydrolysis of ceramides in cells. Here we report its biochemical characterization, membrane topology, and activity regulation. Recombinant ACER2 was expressed in yeast mutant cells (Delta ypc1 Delta ydc1) that lack endogenous ceramidase activity, and microsomes from ACER2-expressiong yeast cells were used to biochemically characterize ACER2. ACER2 catalyzed the hydrolysis of various ceramides and followed Michaelis-Menten kinetics. ACER2 required Ca(2+) for both its in vitro and cellular activities. ACER2 has 7 putative transmembrane domains, and its amino (N) and carboxyl (C) termini were found to be oriented in the lumen of the Golgi complex and cytosol, respectively. ACER2 mutant (ACER2 Delta N36) lacking the N-terminal tail (the first 36 amino acid residues) exhibited undetectable activity and was mislocalized to the endoplasmic reticulum, suggesting that the N-terminal tail is necessary for both ACER2 activity and Golgi localization. ACER2 mutant (ACER2 Delta N13) lacking the first 13 residues was also mislocalized to the endoplasmic reticulum although it retained ceramidase activity. Overexpression of ACER2, ACER2 Delta N13, but not ACER2 Delta N36 increased the release of sphingosine 1-phosphate from cells, suggesting that its mislocalization does not affect the ability of ACER2 to regulate sphingosine 1-phosphate secretion. However, overexpression of ACER2 but not ACER2 Delta N13 or ACER2 Delta N36 inhibited the glycosylation of integrin beta 1 subunit and Lamp1, suggesting that its mistargeting abolishes the ability of ACER2 to regulation protein glycosylation. These data suggest that ACER2 has broad substrate specificity and requires Ca(2+) for its activity and that ACER2 has the cytosolic C terminus and luminal N terminus, which are essential for its activity, correct cellular localization, and regulation for protein glycosylation. C1 [Sun, Wei; Jin, Junfei; Xu, Ruijuan; Hu, Wei; Obeid, Lina M.; Mao, Cungui] Med Univ S Carolina, Dept Med, Div Gen Internal Med, Charleston, SC 29425 USA. [Szulc, Zdzislaw M.; Bielawski, Jacek; Obeid, Lina M.; Mao, Cungui] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Obeid, Lina M.] Med Univ S Carolina, Ralph H Johnson Vet Affairs Hosp, Charleston, SC 29425 USA. RP Mao, CG (reprint author), Med Univ S Carolina, Dept Med, Div Gen Internal Med, 114 Doughty St,Rm 646,STB,POB 250779, Charleston, SC 29425 USA. EM maoc@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [R01CA104834]; Veterans Affairs Merit award FX This work was supported, in whole or in part, by National Institutes of Health Grant R01CA104834 (to C. M.) and a Veterans Affairs Merit award (to L.M.O.). NR 27 TC 22 Z9 24 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 19 PY 2010 VL 285 IS 12 BP 8995 EP 9007 DI 10.1074/jbc.M109.069203 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568VZ UT WOS:000275553700051 PM 20089856 ER PT J AU Lee, K Ambrose, Z Martin, TD Oztop, I Mulky, A Julias, JG Vandegraaff, N Baumann, JG Wang, R Yuen, W Takemura, T Shelton, K Taniuchi, I Li, Y Sodroski, J Littman, DR Coffin, JM Hughes, SH Unutmaz, D Engelman, A KewalRamani, VN AF Lee, KyeongEun Ambrose, Zandrea Martin, Thomas D. Oztop, Ilker Mulky, Alok Julias, John G. Vandegraaff, Nick Baumann, Joerg G. Wang, Rui Yuen, Wendy Takemura, Taichiro Shelton, Kenneth Taniuchi, Ichiro Li, Yuan Sodroski, Joseph Littman, Dan R. Coffin, John M. Hughes, Stephen H. Unutmaz, Derya Engelman, Alan KewalRamani, Vineet N. TI Flexible Use of Nuclear Import Pathways by HIV-1 SO CELL HOST & MICROBE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL DNA FLAP; FACTOR-I-M; NONDIVIDING CELLS; PREINTEGRATION COMPLEX; MATRIX PROTEIN; PORE COMPLEX; INFECTION; TYPE-1; LOCALIZATION AB HIV-1 replication requires transport of nascent viral DNA and associated virion proteins, the retroviral preintegration complex (PIG), into the nucleus. Too large for passive diffusion through nuclear pore complexes (NPCs), PICs use cellular nuclear transport mechanisms and nucleoporins (NUPs), the NPC components that permit selective nuclear-cytoplasmic exchange, but the details remain unclear. Here we identify a fragment of the cleavage and polyadenylation factor 6, CPSF6, as a potent inhibitor of HIV-1 infection. When enriched in the cytoplasm, CPSF6 prevents HIV-1 nuclear entry by targeting the viral capsid (CA). HIV-1 harboring the N74D mutation in CA fails to interact with CPSF6 and evades the nuclear import restriction. Interestingly, whereas wild-type HIV-1 requires NUP153, N74D HIV-1 mimics feline immunodeficiency virus nuclear import requirements and is more sensitive to NUP155 depletion. These findings reveal a remarkable flexibility in HIV-1 nuclear transport and highlight a single residue in CA as essential in regulating interactions with NUPs. C1 [Lee, KyeongEun; Ambrose, Zandrea; Martin, Thomas D.; Mulky, Alok; Baumann, Joerg G.; Yuen, Wendy; Takemura, Taichiro; Shelton, Kenneth; Hughes, Stephen H.; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Oztop, Ilker; Vandegraaff, Nick; Li, Yuan; Sodroski, Joseph; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Julias, John G.] SAIC Frederick, Frederick, MD 21702 USA. [Wang, Rui; Unutmaz, Derya] NYU, Sch Med, Dept Pathol & Microbiol, New York, NY 10016 USA. [Littman, Dan R.] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. [Littman, Dan R.] NYU, Sch Med, Mol Pathogenesis Program, Skirball Inst Biomol Med, New York, NY 10016 USA. [Taniuchi, Ichiro] Riken Res Ctr Allergy & Immunol, Lab Transcript Regulat, Yokohama, Kanagawa 2300045, Japan. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Sackler Sch Biomed Sci, Boston, MA 02111 USA. RP KewalRamani, VN (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM vineet@mail.nih.gov RI Li, Yuan/B-4098-2013; Taniuchi, Ichiro/N-6399-2015 OI Taniuchi, Ichiro/0000-0002-9853-9068 FU National Cancer Institute's intramural Center for Cancer Research; HIV Drug Resistance Program; National Institutes of Health [A152014, A1033303, A1033856, A149131, CA0894, A1063987, A107609441]; American Foundation for AIDS Research postdoctoral fellowship [106404-33-RFMC]; George Kirby Foundation FX We thank Eric Freed for manuscript comments; Paul Bieniasz, Michael Emerman, Eric Freed, and Masahiro Yamashita for discussions; Julie Tang for assistance; and Sabine Dettwiler, Michael Emerman, Eric Freed, John Kappes, Walter Keller, Ned Landau, Eric Poeschla, Wes Sundquist, and Uta von Schwedler for reagents. This work was supported by the National Cancer Institute's intramural Center for Cancer Research, which supports the HIV Drug Resistance Program (S.H.H., V.N.K.); National Institutes of Health (NH) grants to A.E. (A152014), D.R.L. (A1033303; A1033856), D.U. (A149131), J.M.C. (CA089441), and J.S. (A1063987; A1076094); and an American Foundation for AIDS Research postdoctoral fellowship to Z.A. (106404-33-RFMC). J.M.C. was a Research Professor of the American Cancer Society, with support from the George Kirby Foundation. The content of this publication 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 U.S. government. NR 51 TC 167 Z9 169 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAR 18 PY 2010 VL 7 IS 3 BP 221 EP 233 DI 10.1016/j.chom.2010.02.007 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 573XA UT WOS:000275947500007 PM 20227665 ER PT J AU Cichowski, K Janne, PA AF Cichowski, Karen Jaenne, Pasi A. TI DRUG DISCOVERY Inhibitors that activate SO NATURE LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMAS; BRAF C1 [Cichowski, Karen] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Cichowski, K (reprint author), Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM kcichowski@rics.bwh.harvard.edu; pjanne@partners.org NR 9 TC 48 Z9 48 U1 0 U2 5 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 MAR 18 PY 2010 VL 464 IS 7287 BP 358 EP 359 DI 10.1038/464358a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570FG UT WOS:000275657100029 PM 20237552 ER PT J AU Boudsocq, M Willmann, MR McCormack, M Lee, H Shan, LB He, P Bush, J Cheng, SH Sheen, J AF Boudsocq, Marie Willmann, Matthew R. McCormack, Matthew Lee, Horim Shan, Libo He, Ping Bush, Jenifer Cheng, Shu-Hua Sheen, Jen TI Differential innate immune signalling via Ca2+ sensor protein kinases SO NATURE LA English DT Article ID GENE-EXPRESSION ANALYSIS; PLANT DEFENSE; MOLECULAR-PATTERNS; ARABIDOPSIS; CALCIUM; PERCEPTION; RESISTANCE; FLAGELLIN; IDENTIFICATION; TRANSDUCTION AB Innate immunity represents the first line of inducible defence against microbial infection in plants and animals(1-3). In both kingdoms, recognition of pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs, respectively), such as flagellin, initiates convergent signalling pathways involving mitogen-activated protein kinase ( MAPK) cascades and global transcriptional changes to boost immunity(1-4). Although Ca2+ has long been recognized as an essential and conserved primary mediator in plant defence responses, how Ca2+ signals are sensed and relayed into early MAMP signalling is unknown(5,6). Using a functional genomic screen and genome-wide gene expression profiling, here we show that four calcium-dependent protein kinases (CDPKs) are Ca2+-sensor protein kinases critical for transcriptional reprogramming in plant innate immune signalling. Unexpectedly, CDPKs and MAPK cascades act differentially in four MAMP-mediated regulatory programs to control early genes involved in the synthesis of defence peptides and metabolites, cell wall modifications and redox signalling. Transcriptome profile comparison suggests that CDPKs are the convergence point of signalling triggered by most MAMPs. Double, triple and quadruple cpk mutant plants display progressively diminished oxidative burst and gene activation induced by the 22-amino-acid peptide flg22, as well as compromised pathogen defence. In contrast to negative roles of calmodulin and a calmodulin-activated transcription factor in plant defence(7,8), the present study reveals Ca2+ signalling complexity and demonstrates key positive roles of specific CDPKs in initial MAMP signalling. C1 [Boudsocq, Marie; Willmann, Matthew R.; McCormack, Matthew; Lee, Horim; Shan, Libo; He, Ping; Bush, Jenifer; Cheng, Shu-Hua; Sheen, Jen] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Boudsocq, Marie; Willmann, Matthew R.; McCormack, Matthew; Lee, Horim; Shan, Libo; He, Ping; Bush, Jenifer; Cheng, Shu-Hua; Sheen, Jen] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Boudsocq, Marie; Willmann, Matthew R.; McCormack, Matthew; Lee, Horim; Shan, Libo; He, Ping; Bush, Jenifer; Cheng, Shu-Hua; Sheen, Jen] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Boudsocq, M (reprint author), CNRS, UPR2355, Inst Sci Vegetal, 1 Ave Terrasse, F-91198 Gif Sur Yvette, France. EM boudsocq@molbio.mgh.harvard.edu; willmann@sas.upenn.edu OI Willmann, Matthew R./0000-0002-4146-8158 FU European Community; NSF; National Science Foundation; National Institute of Health; MGH CCIB FX We thank K. H. Liu and E. Baena-Gonzalez for contributing to the CPK clone collection, O.R. Patharkar for initial microarray data analysis, B. Mueller and G. Tena for offering qPCR primers, M. N. Soler and S. Bolte for assistance on confocal microscopy, C. Lauriere for discussions, S. P. Dinesh-Kumar for VIGS vectors, K. Schreiber and D. Desveaux for the seedling pathogen assay, and A. Gust and T. Nurnberger for the original PGN microarray data. Wethank the Salk Institute, Syngenta Biotechnology and A. Sessions for sharing the Arabidopsis T-DNA collections, and the Arabidopsis Biological Resource Center for providing Arabidopsis mutant seeds. This research has been supported by a Marie Curie International fellowship within the 6th European Community Framework Program to M. B., an NSF predoctoral fellowship to M. R. W., and grants from the National Science Foundation and the National Institute of Health, and the MGH CCIB fund to J. S. NR 38 TC 274 Z9 288 U1 12 U2 123 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 18 PY 2010 VL 464 IS 7287 BP 418 EP U116 DI 10.1038/nature08794 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570FG UT WOS:000275657100048 PM 20164835 ER PT J AU Young, RH Goodman, A Penson, RT Russell, AH Uppot, RN Tambouret, RH AF Young, Robert H. Goodman, Annekathryn Penson, Richard T. Russell, Anthony H. Uppot, Raul N. Tambouret, Rosemary H. TI Case 8-2010: A 22-Year-Old Woman with Hypercalcemia and a Pelvic Mass - Ovarian small-cell carcinoma, hypercalcemic type SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SERTOLI-LEYDIG CELL; CLINICOPATHOLOGICAL ANALYSIS; TUMORS; SURGERY; CANCER; CHEMOTHERAPY; PREGNANCY; ETOPOSIDE; WOMEN C1 [Young, Robert H.; Tambouret, Rosemary H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Goodman, Annekathryn] Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. [Penson, Richard T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Russell, Anthony H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Uppot, Raul N.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Young, Robert H.; Tambouret, Rosemary H.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. [Goodman, Annekathryn] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Cambridge, MA 02138 USA. [Penson, Richard T.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Russell, Anthony H.] Harvard Univ, Sch Med, Dept Radiat Oncol, Cambridge, MA 02138 USA. [Uppot, Raul N.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. RP Young, RH (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 21 TC 7 Z9 7 U1 1 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 MAR 18 PY 2010 VL 362 IS 11 BP 1031 EP 1040 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 570CY UT WOS:000275650400016 PM 20237350 ER PT J AU Curran, M AF Curran, Marjorie TI Haiti - A View from the Ship SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 MassGen Hosp Children, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 18 PY 2010 VL 362 IS 11 DI 10.1056/NEJMpv1002319 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 570CY UT WOS:000275650400041 PM 20200363 ER PT J AU Goodman, A AF Goodman, Annekathryn TI Ministry of Touch -- Reflections on Disaster Work after the Haitian Earthquake. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Goodman, A (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 18 PY 2010 VL 362 IS 11 DI 10.1056/NEJMp1002311 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 570CY UT WOS:000275650400005 PM 20200361 ER PT J AU Liang, MC Ma, J Chen, L Kozlowski, P Qin, W Li, D Goto, J Shimamura, T Hayes, DN Meyerson, M Kwiatkowski, DJ Wong, KK AF Liang, M-C Ma, J. Chen, L. Kozlowski, P. Qin, W. Li, D. Goto, J. Shimamura, T. Hayes, D. N. Meyerson, M. Kwiatkowski, D. J. Wong, K-K TI TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity SO ONCOGENE LA English DT Article DE lung cancer; TSC1; KRAS; TSC2; mTOR ID TUBEROUS SCLEROSIS COMPLEX; PEUTZ-JEGHERS-SYNDROME; ONCOGENIC K-RAS; TSC1-TSC2 COMPLEX; MAMMALIAN TARGET; MTOR INHIBITORS; BLADDER-CANCER; GENE TSC1; MODEL; LKB1 AB Germline TSC1 or TSC2 mutations cause tuberous sclerosis complex (TSC), a hamartoma syndrome with lung involvement. To explore the potential interaction between TSC1 and KRAS activation in lung cancer, mice in which Tsc1 loss and KrasG12D expression occur in a small fraction of lung epithelial cells were generated. Mice with a combined Tsc1-KrasG12D mutation had dramatically reduced tumor latency (median survival: 11.6-15.6 weeks) in comparison with KrasG12D alone mutant mice (median survival: 27.5 weeks). Tsc1-KrasG12D tumors showed consistent activation of mTOR (mammalian target of rapamycin) C1 and responded to treatment with rapamycin, leading to significantly improved survival, whereas rapamycin had minor effects on cancers in KrasG12D alone mice. Loss of heterozygosity for TSC1 or TSC2 was found in 22% of 86 human lung cancer specimens. However, none of the 80 lung cancer lines studied showed evidence of the lack of expression of either TSC1 or TSC2 or a signaling pattern corresponding to complete loss. These data indicate that Tsc1 loss synergizes with the Kras mutation to enhance lung tumorigenesis in the mouse, but that this is a rare event in human lung cancer. Rapamycin may have unique benefit for patients with lung cancer, for whom the TSC1/TSC2 function is limited. Oncogene (2010) 29, 1588-1597; doi:10.1038/onc.2009.452; published online 7 December 2009 C1 [Ma, J.; Kozlowski, P.; Qin, W.; Goto, J.; Kwiatkowski, D. J.] Brigham & Womens Hosp, Dept Med, Div Translat Med, Boston, MA 02115 USA. [Liang, M-C; Chen, L.; Li, D.; Wong, K-K] Harvard Canc Ctr, Ludwig Ctr Dana Farber, Boston, MA USA. [Liang, M-C; Chen, L.; Li, D.; Shimamura, T.; Meyerson, M.; Wong, K-K] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hayes, D. N.] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Med, Chapel Hill, NC USA. [Meyerson, M.] MIT, Cambridge, MA 02139 USA. [Meyerson, M.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. RP Kwiatkowski, DJ (reprint author), Brigham & Womens Hosp, Dept Med, Div Translat Med, 1 Blackfan Circle,Room 6-216, Boston, MA 02115 USA. EM dk@rics.bwh.harvard.edu RI Meyerson, Matthew/E-7123-2012; OI Hayes, D. Neil/0000-0001-6203-7771 FU NIH [R01 AG2400401, R01 CA122794, K08 AG024004, P01 CA120964]; Sidney Kimmel Foundation for Cancer Research; Joan Scarangello Foundation to Conquer Lung Cancer; Flight Attendant Medical Research Institute FX We thank Kate McNamara and Sara Zaghlul (Dana-Farber Cancer Institute, Boston), Christine Lam, Iza Malinowska-Kolodziej and Mei Zheng (Brigham and Women's Hospital, Boston) for their technical assistance and Roderick T. Bronson (Harvard Medical School, Boston) and Robert Padera and Lucian Chirieac (Brigham and Women's Hospital, Boston) for assistance with pathology review. This study was supported in part by the NIH Grant nos R01 AG2400401 (K-KW), R01 CA122794 (K-KW), K08 AG024004 (K-KW), P01 CA120964 (DJK), the Sidney Kimmel Foundation for Cancer Research (K-KW), the Joan Scarangello Foundation to Conquer Lung Cancer (K-KW and DJK) and the Flight Attendant Medical Research Institute (K-KW). NR 41 TC 26 Z9 27 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 18 PY 2010 VL 29 IS 11 BP 1588 EP 1597 DI 10.1038/onc.2009.452 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 570RC UT WOS:000275694700004 PM 19966866 ER PT J AU Worthley, DL Whitehall, VLJ Buttenshaw, RL Irahara, N Greco, SA Ramsnes, I Mallitt, KA Le Leu, RK Winter, J Hu, Y Ogino, S Young, GP Leggett, BA AF Worthley, D. L. Whitehall, V. L. J. Buttenshaw, R. L. Irahara, N. Greco, S. A. Ramsnes, I. Mallitt, K-A Le Leu, R. K. Winter, J. Hu, Y. Ogino, S. Young, G. P. Leggett, B. A. TI DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer SO ONCOGENE LA English DT Article DE DNA methylation; epigenetics; colorectal cancer; carcinogenesis ID NORMAL COLONIC-MUCOSA; MICROSATELLITE INSTABILITY; ULCERATIVE-COLITIS; BRAF MUTATION; CHROMOSOMAL INSTABILITY; PROMOTER METHYLATION; SERRATED ADENOMAS; MOLECULAR-ORIGINS; PHENOTYPE; POLYPS AB There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at 'type A' (ESR1, GATA5, HIC1, HPP1, SFRP1) and 'type C' markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEU-ROG1, SOCS1, RUNX3), and LINE-1. 'Type A' genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. 'Type C' methylation is more specific for neoplasia. The last five 'type C' markers comprise a CIMP panel. The mean 'type A' and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most 'type A' genes showed direct correlations between methylation and age (ESR1, rho = 0.66, P < 0.0001), with higher methylation distally (ESR1, P < 0.0001). On multivariate analysis, 'type A' methylation was inversely associated with colorectal adenomas (odds ratio 0.23, P < 0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio = 5.1, P = 0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice. Oncogene (2010) 29, 1653-1662; doi:10.1038/onc.2009.449; published online 7 December 2009 C1 [Worthley, D. L.; Whitehall, V. L. J.; Buttenshaw, R. L.; Greco, S. A.; Ramsnes, I.; Leggett, B. A.] Queensland Inst Med Res, Bancroft Ctr, Conjoint Gastroenterol Lab, Herston, Qld 4029, Australia. [Worthley, D. L.; Whitehall, V. L. J.; Buttenshaw, R. L.; Greco, S. A.; Ramsnes, I.; Leggett, B. A.] Royal Brisbane & Womens Hosp, Res Fdn Clin Res Ctr, Brisbane, Qld, Australia. [Irahara, N.; Ogino, S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mallitt, K-A] Queensland Inst Med Res, Stat Unit, Herston, Qld 4029, Australia. [Le Leu, R. K.; Winter, J.; Hu, Y.; Young, G. P.] Flinders Univ S Australia, Flinders Ctr Canc Prevent & Control, Adelaide, SA, Australia. [Ogino, S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, S.] Harvard Univ, Sch Med, Boston, MA USA. RP Worthley, DL (reprint author), Queensland Inst Med Res, Bancroft Ctr, Conjoint Gastroenterol Lab, Rm H07,PO RBH, Herston, Qld 4029, Australia. EM daniel.worthley@uqconnect.edu.au RI Mallitt, Kylie-Ann/E-2240-2011; Leggett, Barbara/D-3579-2011; Whitehall, Vicki/B-6262-2013; Le Leu, Richard/H-4555-2013 OI Mallitt, Kylie-Ann/0000-0002-5722-7287; Whitehall, Vicki/0000-0002-8285-2391; Le Leu, Richard/0000-0003-4704-4943 FU National Health and Medical Research Council [442965]; Gastroenterological Society of Australia; Royal Australasian College of Physicians Cottrell Fellowship; Royal Brisbane and Women's Hospital Foundation; Queensland Smart State PhD award FX We thank the gastroenterologists and gastroenterology nurses who helped to collect samples. This study was funded by a National Health and Medical Research Council project grant (442965), a Gastroenterological Society of Australia post-graduate medical scholarship (DLW), the Royal Australasian College of Physicians Cottrell Fellowship (DLW), a Royal Brisbane and Women's Hospital Foundation Research Grant (VLW, DLW, BAL) and a Queensland Smart State PhD award (DLW). NR 57 TC 53 Z9 57 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 18 PY 2010 VL 29 IS 11 BP 1653 EP 1662 DI 10.1038/onc.2009.449 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 570RC UT WOS:000275694700010 PM 19966864 ER PT J AU Kapoor, JR Kapoor, R AF Kapoor, John R. Kapoor, Roger TI Endovascular Aortic Aneurysm Repair SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID RANDOMIZED CONTROLLED-TRIAL; VASCULAR-SURGERY; MORTALITY C1 [Kapoor, John R.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Kapoor, Roger] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kapoor, JR (reprint author), Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. EM rkapoor4@partners.org NR 5 TC 0 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 17 PY 2010 VL 303 IS 11 BP 1035 EP 1035 DI 10.1001/jama.2010.154 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 569KC UT WOS:000275594100013 PM 20233820 ER PT J AU Kahn, KL Adams, JL Weeks, JC Chrischilles, EA Schrag, D Ayanian, JZ Kiefe, CI Ganz, PA Bhoopalam, N Potosky, AL Harrington, DP Fletcher, RH AF Kahn, Katherine L. Adams, John L. Weeks, Jane C. Chrischilles, Elizabeth A. Schrag, Deborah Ayanian, John Z. Kiefe, Catarina I. Ganz, Patricia A. Bhoopalam, Nirmala Potosky, Arnold L. Harrington, David P. Fletcher, Robert H. TI Adjuvant Chemotherapy Use and Adverse Events Among Older Patients With Stage III Colon Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MARGINAL STRUCTURAL MODELS; CARE OUTCOMES RESEARCH; COLORECTAL-CANCER; ELDERLY-PATIENTS; CLINICAL-TRIALS; RANDOMIZED-TRIAL; POOLED ANALYSIS; OF-LIFE; FLUOROURACIL; LEUCOVORIN AB Context Randomized trials suggest adjuvant chemotherapy is effective for older patients with stage III colon cancer. However, older patients are less likely to receive this therapy than younger patients, perhaps because of concern about adverse effects. Objective To evaluate adjuvant chemotherapy use and outcomes for older patients with stage III colon cancer from well-defined population-based settings and health care systems. Design Observational study of adjuvant chemotherapy use and outcomes by age using Poisson regression to estimate the number of adverse events adjusted for demographic and clinical factors, including comorbid illness and specific elements of chemotherapy regimens documented with clinically detailed medical record reviews and patient and surrogate surveys. Setting Five geographically defined regions (Alabama, Iowa, Los Angeles County, northern California, and North Carolina), 5 integrated health care delivery systems, and 15 Veterans Affairs hospitals. Patients Six hundred seventy-five patients diagnosed with stage III colon cancer from 2003 through 2005 who underwent surgical resection and were followed up for as long as 15 months postdiagnosis. Main Outcome Measures Chemotherapy regimen, dose, duration, and annualized mean number of adverse events stratified by age. Results Of 202 patients aged 75 years and older, 101 (50%) received adjuvant chemotherapy compared with 87% of 473 younger patients (difference, 37%; 95% confidence interval [CI], 30%-45%). Among patients who received adjuvant chemotherapy, 14 patients (14%) aged 75 years and older and 178 younger patients (44%) received a regimen containing oxaliplatin (difference, 30%; 95% CI, 21%-38%). Older patients were less likely to continue treatment, such that by 150 days, 99 patients (40%) aged 65 years and older and 68 younger patients (25%) had discontinued chemotherapy (difference, 15%; 95% CI, 7%-23%). Overall, 162 patients (24%) had at least 1 adverse clinical event, with more events among patients treated with vs without adjuvant chemotherapy (mean, 0.39 vs 0.16; difference, 0.23; 95% CI, 0.11-0.36; P<.001). Among patients receiving adjuvant chemotherapy, adjusted rates of late clinical adverse events were lower for patients 75 years and older (mean, 0.28) vs for younger patients (0.35 for ages 18-54 years, 0.52 for ages 55-64 years, and 0.45 for ages 65-74 years; P=.008 for any age effect). Conclusion Among patients with stage III colon cancer who underwent surgical resection and received adjuvant chemotherapy, older patients in the community received less-toxic and shorter chemotherapy regimens, and those treated had fewer adverse events than younger patients. JAMA. 2010; 303(11): 1037-1045 C1 [Kahn, Katherine L.; Adams, John L.] RAND Corp, Santa Monica, CA 90401 USA. [Kahn, Katherine L.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Div Hematol & Med Oncol, Los Angeles, CA USA. [Kahn, Katherine L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. [Weeks, Jane C.] Div Populat Sci, Boston, MA USA. [Harrington, David P.] Dept Biostat & Computat Biol, Boston, MA USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chrischilles, Elizabeth A.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Fletcher, Robert H.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02115 USA. [Kiefe, Catarina I.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Bhoopalam, Nirmala] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Control Program, Washington, DC 20007 USA. [Fletcher, Robert H.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Fletcher, Robert H.] Univ N Carolina, Dept Social Med, Chapel Hill, NC USA. RP Kahn, KL (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM kahn@rand.org FU National Cancer Institute (NCI) [U01 CA093344, U01 CA093348]; Harvard Medical School and Northern California Cancer Center [U01 CA093324]; Dana-Farber Cancer Institute and Cancer Research Network [U01 CA093332]; University of Alabama at Birmingham [U01 CA093329]; University of Iowa [U01 CA01013]; University of North Carolina [U01 CA093326]; Department of Veterans Affairs [U01 CDA093344 [MOU], HARQ 03-438MO-03] FX Funding/Support: The Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium was supported by grants from the National Cancer Institute (NCI) to the statistical coordinating center at the Dana-Farber Cancer Institute (U01 CA093344) and the primary data collection and research centers at RAND Corporation and University of California, Los Angeles (U01 CA093348); Harvard Medical School and Northern California Cancer Center (U01 CA093324); Dana-Farber Cancer Institute and Cancer Research Network (U01 CA093332); University of Alabama at Birmingham (U01 CA093329); University of Iowa (U01 CA01013); and University of North Carolina (U01 CA093326) and by a Department of Veterans Affairs grant to the Durham VA Medical Center (U01 CDA093344 [MOU] and HARQ 03-438MO-03). NR 38 TC 71 Z9 74 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 17 PY 2010 VL 303 IS 11 BP 1037 EP 1045 DI 10.1001/jama.2010.272 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 569KC UT WOS:000275594100016 PM 20233821 ER PT J AU Talcott, JA Rossi, C Shipley, WU Clark, JA Slater, JD Niemierko, A Zietman, AL AF Talcott, James A. Rossi, Carl Shipley, William U. Clark, Jack A. Slater, Jerry D. Niemierko, Andrzej Zietman, Anthony L. TI Patient-Reported Long-term Outcomes After Conventional and High-Dose Combined Proton and Photon Radiation for Early Prostate Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; OF-LIFE OUTCOMES; CONFORMAL RADIOTHERAPY; PATIENTS PERCEPTIONS; THERAPY; ADENOCARCINOMA; IRRADIATION; CARCINOMA; SEQUELAE; ESCALATION AB Context Increased radiation doses improve prostate cancer control but also increase toxicity to adjacent normal tissue. Proton radiation may attenuate adverse effects. Objective To determine long-term, patient-reported, dose-related toxicity. Design, Setting, and Patients We performed a post hoc cross-sectional survey of surviving participants in the Proton Radiation Oncology Group (PROG) 9509-a randomized trial comparing 70.2 Gy vs 79.2 Gy of combined photon and proton radiation for 393 men with clinically localized prostate cancer (stage T1b-T2b, prostate-specific antigen <15 ng/mL, and no radiographic evidence of metastasis). The estimated 10-year biochemical progression rate for patients receiving standard dose was 32% (95% confidence interval, 26%-39%) compared with 17% (95% confidence interval, 11%-23%) for patients receiving high dose (P<.001). We surveyed 280 of the surviving 337 patients (83%) from April 2007 to September 2008. Main Outcome Measures Prostate Cancer Symptom Indices, a validated measure of urinary incontinence, urinary obstruction and irritation, bowel problems, and sexual dysfunction, and related quality-of-life instruments. Results At a median of 9.4 years after treatment (range, 7.4-12.1 years), participants' demographic and clinical characteristics were similar. Patient-reported outcomes were reported as mean (SD) scale score for standard dose vs high dose: urinary obstruction/irritation (23.3 [13.7] vs 24.6 [14.0]; P=.36), urinary incontinence (10.6 [17.7] vs 9.7 [15.8]; P=.99), bowel problems (7.7 [7.8] vs 7.9 [9.1]; P=.70), sexual dysfunction (68.2 [34.6] vs 65.9 [34.7]; P=.65), and most other outcomes were also similar, although patients receiving standard dose whose cancers had more often progressed expressed less confidence that their cancers were under control (mean [SD] scale score for standard dose, 76.0 [25.4] vs high dose, 86.2 [17.9]; P<.001). Many patients characterized their urinary and bowel function as normal despite reporting symptoms that, for other prostate cancer patients before and early after cancer treatment, caused substantial distress. Conclusion Among men with clinically localized prostate cancer, treatment with higher-dose radiation compared with standard dose was not associated with an increase in patient-reported prostate cancer symptoms after a median of 9.4 years. JAMA. 2010; 303(11): 1046-1053 C1 [Talcott, James A.] Massachusetts Gen Hosp, MGH Canc Ctr, Ctr Outcomes Res, Boston, MA 02114 USA. [Rossi, Carl; Slater, Jerry D.] Loma Linda Univ, Med Ctr, Loma Linda, CA USA. [Shipley, William U.; Niemierko, Andrzej; Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Clark, Jack A.] Edith Nourse Rogers Mem Vet Adm Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA 01730 USA. [Clark, Jack A.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Talcott, James A.; Shipley, William U.; Niemierko, Andrzej; Zietman, Anthony L.] Harvard Univ, Sch Med, Boston, MA USA. RP Talcott, JA (reprint author), Ctr Outcomes Res, Charlestown Navy Yard,Bldg 120,6th St,2nd Floor, Charlestown, MA 02129 USA. EM jtalcott@partners.org OI Clark, Jack/0000-0002-7424-1670 FU Massachusetts General Hospital, Boston, MA FX Funding/Support: This research was supported by the Bertucci Genitourinary Cancer Research Fund, Massachusetts General Hospital, Boston, MA. NR 31 TC 58 Z9 59 U1 0 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 17 PY 2010 VL 303 IS 11 BP 1046 EP 1053 DI 10.1001/jama.2010.287 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 569KC UT WOS:000275594100017 PM 20233822 ER PT J AU Kim, SH Fraser, PE Westaway, D George-Hyslop, PHS Ehrlich, ME Gandy, S AF Kim, Soong Ho Fraser, Paul E. Westaway, David George-Hyslop, Peter H. St. Ehrlich, Michelle E. Gandy, Sam TI Group II Metabotropic Glutamate Receptor Stimulation Triggers Production and Release of Alzheimer's Amyloid beta(42) from Isolated Intact Nerve Terminals SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; PRECURSOR PROTEIN; TRANSGENIC MICE; IN-VIVO; SYNAPTIC PLASTICITY; CEREBRAL-CORTEX; DISEASE; ACTIVATION; PEPTIDE; KINASE AB Aberrant accumulation of amyloid beta (A beta) oligomers may underlie the cognitive failure of Alzheimer's disease (AD). All species of A beta peptides are produced physiologically during normal brain activity. Therefore, elucidation of mechanisms that interconnect excitatory glutamatergic neurotransmission, synaptic amyloid precursor protein (APP) processing and production of its metabolite, A beta, may reveal synapse-specific strategies for suppressing the pathological accumulation of A beta oligomers and fibrils that characterize AD. To study synaptic APP processing, we used isolated intact nerve terminals (cortical synaptoneurosomes) from TgCRND8 mice, which express a human APP with familial AD mutations. Potassium chloride depolarization caused sustained release from synaptoneurosomes of A beta(42) as well as A beta(40), and appeared to coactivate alpha-, beta-and gamma-secretases, which are known to generate a family of released peptides, including A beta(40) and A beta(42). Stimulation of postsynaptic group I metabotropic glutamate receptor (mGluRs) with DHPG (3,5-dihydroxyphenylglycine) induced a rapid accumulation of APP C-terminal fragments (CTFs) in the synaptoneurosomes, a family of membrane-bound intermediates generated from APP metabolized by alpha- and beta-secretases. Following stimulation with the group II mGluR agonist DCG-IV, levels of APP CTFs in the synaptoneurosomes initially increased but then returned to baseline by 10 min after stimulation. This APP CTF degradation phase was accompanied by sustained accumulation of A beta(42) in the releasate, which was blocked by the group IImGluR antagonist LY341495. These data suggest that group IImGluR may trigger synaptic activation of all three secretases and that suppression of group II mGluR signaling may be a therapeutic strategy for selectively reducing synaptic generation of A beta(42). C1 [Kim, Soong Ho; Ehrlich, Michelle E.; Gandy, Sam] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Gandy, Sam] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Ehrlich, Michelle E.] Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. [Fraser, Paul E.; George-Hyslop, Peter H. St.] Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Med Biophys, Toronto, ON M5S 1A1, Canada. [Fraser, Paul E.; George-Hyslop, Peter H. St.] Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Med Neurol, Toronto, ON M5S 1A1, Canada. [Westaway, David] Univ Alberta, Ctr Prions & Prot Folding Dis, Edmonton, AB T6G 2M8, Canada. [George-Hyslop, Peter H. St.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0XY, England. [Gandy, Sam] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Gandy, S (reprint author), Mt Sinai Sch Med, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM samuel.gandy@mssm.edu FU National Institutes of Health [AG10491]; Cure Alzheimer's Fund; Canadian Institutes of Health Research; Alzheimer Society of Ontario; Alberta Prion Research Institute; Canada Foundation for Innovation; Howard Hughes Medical Institute; Wellcome Trust FX This work was supported by National Institutes of Health Grant AG10491, Cure Alzheimer's Fund, Canadian Institutes of Health Research, the Alzheimer Society of Ontario, the Alberta Prion Research Institute, the Canada Foundation for Innovation, Howard Hughes Medical Institute, and The Wellcome Trust. We thank Loren Khan-Vaughan and Justine Bonet for assistance with mouse colony management. NR 51 TC 45 Z9 46 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 17 PY 2010 VL 30 IS 11 BP 3870 EP 3875 DI 10.1523/JNEUROSCI.4717-09.2010 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 571BT UT WOS:000275724800003 PM 20237257 ER PT J AU Ogino, S Stampfer, M AF Ogino, Shuji Stampfer, Meir TI Lifestyle Factors and Microsatellite Instability in Colorectal Cancer: The Evolving Field of Molecular Pathological Epidemiology SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ISLAND METHYLATOR PHENOTYPE; FATTY-ACID SYNTHASE; BODY-MASS INDEX; POPULATION-BASED SAMPLE; KI-RAS MUTATIONS; COLON-CANCER; DIETARY-FOLATE; RECTAL-CANCER; PHYSICAL-ACTIVITY; PATIENT SURVIVAL C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Mol Oncol Pathol,Sch Med,Dept Pathol, Boston, MA 02115 USA. [Stampfer, Meir] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji; Stampfer, Meir] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA USA. [Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Mol Oncol Pathol,Sch Med,Dept Pathol, 44 Binney St,Rm JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU NCI NIH HHS [K07 CA122826, P01 CA55075, P01 CA87969] NR 50 TC 87 Z9 89 U1 0 U2 5 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 MAR 17 PY 2010 VL 102 IS 6 BP 365 EP 367 DI 10.1093/jnci/djq031 PG 3 WC Oncology SC Oncology GA 573CB UT WOS:000275884900001 PM 20208016 ER PT J AU Goldfine, AB Fonseca, V Jablonski, KA Pyle, L Staten, MA Shoelson, SE AF Goldfine, Allison B. Fonseca, Vivian Jablonski, Kathleen A. Pyle, Laura Staten, Myrlene A. Shoelson, Steven E. CA TINSAL-T2D Targeting Inflammation TI The Effects of Salsalate on Glycemic Control in Patients With Type 2 Diabetes A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID NF-KAPPA-B; GLOMERULAR-FILTRATION-RATE; INDUCED INSULIN-RESISTANCE; SODIUM-SALICYLATE; IKK-BETA; NONACETYLATED SALICYLATE; CYSTATIN-C; URIC-ACID; ASPIRIN; INFLAMMATION AB Background: Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies. Objective: To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes. Design: Parallel randomized trial with computer-generated randomization and centralized allocation. Patients and investigators, including those assessing outcomes and performing analyses, were masked to group assignment. (ClinicalTrials.gov registration number: NCT00392678) Setting: 3 private practices and 14 universities in the United States. Patients: Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (<= 225 mg/dL) and hemoglobin A(1c) (HbA(1c)) levels of 7.0% to 9.5% treated by diet, exercise, and oral medication at stable doses for at least 8 weeks. Intervention: After a 4-week, single-masked run-in period, patients were randomly assigned to receive placebo or salsalate in dosages of 3.0, 3.5, or 4.0 g/d for 14 weeks (27 patients each) in addition to their current therapy. Measurements: Change in HbA(1c) was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes. Results: Higher proportions of patients in the 3 salsalate treatment groups experienced decreases in HbA(1c) levels of 0.5% or more from baseline (P = 0.009). Mean HbA(1c) changes were -0.36% (P = 0.02) at 3.0 g/d, -0.34% (P = 0.02) at 3.5 g/d, and -0.49% (P = 0.001) at 4.0 g/d compared with placebo. Other markers of glycemic control also improved in the 3 salsalate groups, as did circulating triglyceride and adiponectin concentrations. Mild hypoglycemia was more common with salsalate; documented events occurred only in patients taking sulfonylureas. Urine albumin concentrations increased in all salsalate groups compared with placebo. The drug was otherwise well tolerated. Limitation: The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for type 2 diabetes at this time. Conclusion: Salsalate lowers HbA(1c) levels and improves other markers of glycemic control in patients with type 2 diabetes and may therefore provide a new avenue for treatment. Renal and cardiac safety of the drug require further evaluation. C1 [Shoelson, Steven E.] Joslin Diabet Ctr, Boston, MA 02215 USA. Tulane Univ, New Orleans, LA 70118 USA. George Washington Univ, Rockville, MD USA. NIDDKD, Washington, DC USA. RP Shoelson, SE (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM steven.shoelson@joslin.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institutes of Health [U01 DK74556, P50 HL83813]; National Institutes of Health General Clinical Research Center; Clinical and Translational Science FX National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.; By National Institutes of Health grants U01 DK74556 and P50 HL83813, National Institutes of Health General Clinical Research Center and Clinical and Translational Science Award grants at multiple sites, and the Tullis-Tulane (Dr. Fonseca) and Helen and Morton Adler (Dr. Shoelson) Chairs. Caraco Pharmaceuticals (Detroit, Michigan) supplied drug and placebo, Lifescan (Miltipas, California; a division of Johnson & Johnson) supplied home glucose-monitoring kits, and Mercodia (Uppsala, Sweden) supplied insulin assay kits. NR 37 TC 198 Z9 201 U1 0 U2 13 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 MAR 16 PY 2010 VL 152 IS 6 BP 346 EP + DI 10.7326/0003-4819-152-6-201003160-00004 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 573IF UT WOS:000275905200002 PM 20231565 ER PT J AU Halpern, SD Raz, A Kohn, R Rey, M Asch, DA Reese, P AF Halpern, Scott D. Raz, Amelie Kohn, Rachel Rey, Michael Asch, David A. Reese, Peter TI Regulated Payments for Living Kidney Donation: An Empirical Assessment of the Ethical Concerns SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ORGAN DONATION; CONJOINT-ANALYSIS; HEALTH-CARE; CONFIDENCE-INTERVALS; COST-EFFECTIVENESS; CLINICAL-TRIALS; DONORS; INCENTIVES; TRANSPLANTATION; CONSEQUENCES AB Background: Although regulated payments to encourage living kidney donation could reduce morbidity and mortality among patients waiting for a kidney transplant, doing so raises several ethical concerns. Objective: To determine the extent to which the 3 main concerns with paying kidney donors might manifest if a regulated market were created. Design: Cross-sectional study of participants' willingness to donate a kidney in 12 scenarios. Setting: Regional rail and urban trolley lines in Philadelphia County, Philadelphia, Pennsylvania. Participants: Of 550 potential participants, 409 completed the questionnaire (response rate, 74.4%); 342 of these participants were medically eligible to donate. Intervention: Across scenarios, researchers experimentally manipulated the amount of money that participants would receive, the participants' risk for subsequently developing kidney failure themselves, and who would receive the donated kidney. Measurements: The researchers determined whether payment represents an undue inducement by evaluating participants' sensitivity to risk in relation to the payment offered or an unjust inducement by evaluating participants' sensitivity to payment as a function of their annual income. The researchers also evaluated whether introducing payment would hinder altruistic donations by comparing participants' willingness to donate altruistically before versus after the introduction of payments. Results: Generalized estimating equation models revealed that participants' willingness to donate increased significantly as their risk for kidney failure decreased, as the payment offered increased, and when the kidney recipient was a family member rather than a patient on a public waiting list (P < 0.001 for each). No statistical interactions were identified between payment and risk (odds ratio, 1.00 [95% CI, 0.96 to 1.03]) or between payment and income (odds ratio, 1.01 [CI, 0.99 to 1.03]). The proximity of these estimates to 1.0 and narrowness of the CIs suggest that payment is neither an undue nor an unjust inducement, respectively. Alerting participants to the possibility of payment did not alter their willingness to donate for altruistic reasons (P = 0.40). Limitation: Choices revealed in hypothetical scenarios may not reflect real-world behaviors. Conclusion: Theoretical concerns about paying persons for living kidney donation are not corroborated by empirical evidence. A real-world test of regulated payments for kidney donation is needed to definitively show whether payment provides a viable and ethical method to increase the supply of kidneys available for transplantation. C1 [Halpern, Scott D.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Halpern, SD (reprint author), Univ Penn, Sch Med, 724 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM scott.halpern@uphs.upenn.edu OI Asch, David/0000-0002-7970-286X FU Greenwall Foundation Faculty Scholar Award in Bioethics; National Institutes of Health [K23-078688-01]; University of Pennsylvania Center for Bioethics FX By a Greenwall Foundation Faculty Scholar Award in Bioethics (Dr. Halpern), the National Institutes of Health (Dr. Reese; grant K23-078688-01), and internships from the University of Pennsylvania Center for Bioethics (Ms. Raz, Ms. Kohn, and Mr. Rey). NR 43 TC 27 Z9 27 U1 1 U2 11 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 MAR 16 PY 2010 VL 152 IS 6 BP 358 EP + DI 10.7326/0003-4819-152-6-201003160-00005 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 573IF UT WOS:000275905200003 PM 20231566 ER PT J AU Sboner, A Demichelis, F Calza, S Pawitan, Y Setlur, SR Hoshida, Y Perner, S Adami, HO Fall, K Mucci, LA Kantoff, PW Stampfer, M Andersson, SO Varenhorst, E Johansson, JE Gerstein, MB Golub, TR Rubin, MA Andren, O AF Sboner, Andrea Demichelis, Francesca Calza, Stefano Pawitan, Yudi Setlur, Sunita R. Hoshida, Yujin Perner, Sven Adami, Hans-Olov Fall, Katja Mucci, Lorelei A. Kantoff, Philip W. Stampfer, Meir Andersson, Swen-Olof Varenhorst, Eberhard Johansson, Jan-Erik Gerstein, Mark B. Golub, Todd R. Rubin, Mark A. Andren, Ove TI Molecular sampling of prostate cancer: a dilemma for predicting disease progression SO BMC MEDICAL GENOMICS LA English DT Article ID TMPRSS2-ERG GENE FUSION; CIRCULATING TUMOR-CELLS; POPULATION-BASED COHORT; RADICAL PROSTATECTOMY; INTEROBSERVER REPRODUCIBILITY; INTRAEPITHELIAL NEOPLASIA; CLINICAL-IMPLICATIONS; SYSTEMIC PROGRESSION; TISSUE MICROARRAYS; TRANSITION ZONE AB Background: Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. Methods: We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases. Results: Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors. Conclusions: The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging. C1 [Demichelis, Francesca; Perner, Sven; Rubin, Mark A.] Weill Cornell Med Ctr, Dept Pathol & Lab Med, New York, NY USA. [Sboner, Andrea; Gerstein, Mark B.] Yale Univ, Dept Biochem & Mol Biophys, New Haven, CT 06520 USA. [Demichelis, Francesca] Weill Cornell Med Ctr, Inst Computat Biomed, New York, NY USA. [Calza, Stefano; Pawitan, Yudi; Adami, Hans-Olov; Fall, Katja] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Calza, Stefano] Univ Brescia, Dept Biomed Sci & Biotechnol, Brescia, Italy. [Setlur, Sunita R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hoshida, Yujin; Kantoff, Philip W.; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Adami, Hans-Olov; Fall, Katja; Mucci, Lorelei A.; Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Andersson, Swen-Olof; Johansson, Jan-Erik; Andren, Ove] Orebro Univ Hosp, Dept Urol, SE-70185 Orebro, Sweden. [Mucci, Lorelei A.; Kantoff, Philip W.; Stampfer, Meir] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mucci, Lorelei A.; Stampfer, Meir] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Varenhorst, Eberhard] Linkoping Univ Hosp, Dept Urol, SE-58185 Linkoping, Sweden. [Gerstein, Mark B.] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Gerstein, Mark B.] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA. [Golub, Todd R.] Broad Inst MIT & Harvard, Howard Hughes Med Inst, Cambridge, MA 02142 USA. RP Rubin, MA (reprint author), Weill Cornell Med Ctr, Dept Pathol & Lab Med, New York, NY USA. EM asbmgmr@gersteinlab.org RI Fall, Katja/A-9186-2012; Calza, Stefano/B-1915-2010; OI Calza, Stefano/0000-0003-4996-7995; Sboner, Andrea/0000-0001-6915-3070; Rubin, Mark/0000-0002-8321-9950; Demichelis, Francesca/0000-0002-8266-8631; Fall, Katja/0000-0002-3649-2639 FU National Cancer Institute (NCI) [P50 90381]; Dana Farber/Harvard Cancer Center Prostate S.P.O.R.E; National Institute of Health (NIH) [RR19895] FX We would like to acknowledge the National Cancer Institute (NCI) grant P50 90381 support for the Dana Farber/Harvard Cancer Center Prostate S.P.O.R.E. and the National Institute of Health (NIH) grant RR19895 for the Yale University Biomedical High Performance Computing Center. NR 55 TC 86 Z9 86 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD MAR 16 PY 2010 VL 3 AR 8 DI 10.1186/1755-8794-3-8 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 585SA UT WOS:000276848100001 PM 20233430 ER PT J AU Sheng, Q Liu, XG Fleming, E Yuan, K Piao, HY Chen, JY Moustafa, Z Thomas, RK Greulich, H Schinzel, A Zaghlul, S Batt, D Ettenberg, S Meyerson, M Schoeberl, B Kung, AL Hahn, WC Drapkin, R Livingston, DM Liu, JF AF Sheng, Qing Liu, Xinggang Fleming, Eleanor Yuan, Karen Piao, Huiying Chen, Jinyun Moustafa, Zeinab Thomas, Roman K. Greulich, Heidi Schinzel, Anna Zaghlul, Sara Batt, David Ettenberg, Seth Meyerson, Matthew Schoeberl, Birgit Kung, Andrew L. Hahn, William C. Drapkin, Ronny Livingston, David M. Liu, Joyce F. TI An Activated ErbB3/NRG1 Autocrine Loop Supports In Vivo Proliferation in Ovarian Cancer Cells SO CANCER CELL LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; PHASE-II TRIAL; ONCOGENE ADDICTION; PHOSPHATIDYLINOSITOL 3-KINASE; MONOCLONAL-ANTIBODY; LUNG-CANCER; EXPRESSION; RECEPTOR; THERAPY; CARCINOMA AB Ovarian cancer is a leading cause of death from gynecologic malignancies. Treatment for advanced-stage disease remains limited and, to date, targeted therapies have been incompletely explored. By systematically suppressing each human tyrosine kinase in ovarian cancer cell lines by RNAi, we found that an autocrine signal-transducing loop involving NRG1 and activated ErbB3 operates in a subset of primary ovarian cancers and ovarian cancer cell lines. Perturbation of this circuit with ErbB3-directed RNAi decreased cell growth in three-dimensional culture and resulted in decreased disease progression and prolonged survival in a xenograft mouse model of ovarian cancer. Furthermore, a monoclonal ErbB3-directed antibody (MM-121) also significantly inhibited tumor growth in vivo. These findings identify ErbB3 as a potential therapeutic target in ovarian cancer. C1 [Sheng, Qing; Liu, Xinggang; Fleming, Eleanor; Yuan, Karen; Zaghlul, Sara; Livingston, David M.; Liu, Joyce F.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Piao, Huiying; Greulich, Heidi; Schinzel, Anna; Meyerson, Matthew; Hahn, William C.; Drapkin, Ronny; Liu, Joyce F.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sheng, Qing; Liu, Xinggang; Fleming, Eleanor; Yuan, Karen; Piao, Huiying; Greulich, Heidi; Schinzel, Anna; Zaghlul, Sara; Meyerson, Matthew; Kung, Andrew L.; Hahn, William C.; Drapkin, Ronny; Livingston, David M.; Liu, Joyce F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Piao, Huiying; Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Greulich, Heidi] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Chen, Jinyun; Moustafa, Zeinab; Batt, David; Ettenberg, Seth] Novartis Oncol, Cambridge, MA 02139 USA. [Thomas, Roman K.] Univ Cologne, Fac Med, D-50931 Cologne, Germany. [Thomas, Roman K.] Univ Cologne, Max Planck Soc, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany. [Thomas, Roman K.] Univ Cologne, Dept Internal Med 1, D-50937 Cologne, Germany. [Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol, D-50937 Cologne, Germany. [Thomas, Roman K.] Max Planck Soc, Chem Genom Ctr, D-44227 Dortmund, Germany. [Greulich, Heidi; Schinzel, Anna; Meyerson, Matthew; Hahn, William C.] MIT, Cambridge, MA 02142 USA. [Greulich, Heidi; Schinzel, Anna; Meyerson, Matthew; Hahn, William C.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Schoeberl, Birgit] Merrimack Pharmaceut, Cambridge, MA 02139 USA. [Kung, Andrew L.] Childrens Hosp, Boston, MA 02115 USA. [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Livingston, DM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM david_livingston@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Drapkin, Ronny/E-9944-2016; OI Drapkin, Ronny/0000-0002-6912-6977; Kung, Andrew/0000-0002-9091-488X FU NIH [U54CA112962, W81XWH-07-0408, R33CA128625, K12CA08772307, P50-CA105009, K08CA108748]; DFCI; Ovarian Cancer Research Fund; ASCO Young Investigator Award and Prevent Cancer Foundation; Deborah and Robert First; Joel and Randi Cutler Ovarian Research Fund; Aaron Foundation FX We thank R. Wright and B. Ospina for expert technical assistance in mouse imaging. We would also like to thank Dr. S. Mok for providing human ovarian surface epithelial cells. This work was supported by NIH grants U54CA112962 (W.C.H.), W81XWH-07-0408 (W.C.H.), R33CA128625 (W.C.H.), and K12CA08772307 (J.F.L.); by NCI grants P50-CA105009 SPORE in Ovarian Cancer (Q.S., R.D.) and K08CA108748 (R.D.); by the DFCI/Novartis Program in Drug Discovery; by generous funding from the Women's Cancer Programs of DFCI; from the Ovarian Cancer Research Fund (R.D.); from the ASCO Young Investigator Award and Prevent Cancer Foundation (J.F.L.); from Deborah and Robert First (D.M.L., R.D.); the Joel and Randi Cutler Ovarian Research Fund (R.D.); and from the Aaron Foundation (D.M.L.). D.M.L., W.C.H., R.D., M.M., and A.L.K. are grantees of and consultants to the Novartis Institute of Biomedical Research. J.C., Z.M., D.B., and S.E. are employees and shareholders of the Novartis Institute of Biomedical Research. B.S. is an employee and shareholder of Merrimack Pharmaceuticals. NR 44 TC 112 Z9 115 U1 0 U2 5 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 MAR 16 PY 2010 VL 17 IS 3 BP 298 EP 310 DI 10.1016/j.ccr.2009.12.047 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 572CK UT WOS:000275804200011 PM 20227043 ER PT J AU Gianni, D Li, AR Tesco, G Mckay, KM Moore, J Raygor, K Rota, M Gwathmey, JK Dec, GW Aretz, T Leri, A Semigran, MJ Anversa, P Macgillivray, TE Tanzi, RE del Monte, F AF Gianni, Davide Li, Airong Tesco, Giuseppina Mckay, Kenneth M. Moore, John Raygor, Kunal Rota, Marcello Gwathmey, Judith K. Dec, G. William Aretz, Thomas Leri, Annarosa Semigran, Marc J. Anversa, Piero Macgillivray, Thomas E. Tanzi, Rudolph E. del Monte, Federica TI Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy SO CIRCULATION LA English DT Article DE calcium; cardiomyopathy; genetics; heart failure; myocytes ID SOLUBLE AMYLOID OLIGOMERS; ALZHEIMERS-DISEASE; HEART-FAILURE; MUTATIONS; CALCIUM; CELL; ACCUMULATION; POPULATION; MECHANISM; FREQUENCY AB Background-Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death. Methods and Results-We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca2+ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions-On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca2+ handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function. (Circulation. 2010; 121: 1216-1226.) C1 [Gianni, Davide; Gwathmey, Judith K.; del Monte, Federica] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02125 USA. [Li, Airong; Tesco, Giuseppina; Mckay, Kenneth M.; Moore, John; Raygor, Kunal; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Genet & Aging Res Unit, Boston, MA 02114 USA. [Aretz, Thomas] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dec, G. William; Semigran, Marc J.] Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. [Macgillivray, Thomas E.] Massachusetts Gen Hosp, Cardiac Surg Div, Boston, MA 02114 USA. [Rota, Marcello; Leri, Annarosa; Anversa, Piero] Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. [Rota, Marcello; Leri, Annarosa; Anversa, Piero] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP del Monte, F (reprint author), Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02125 USA. EM tanzi@helix.harvard.edu; fdelmont@bidmc.harvard.edu FU National Institutes of Health [K08-HL69842, R01AG014713, R01MH60009]; Beth Israel Deaconess Medical Center discretional funds; Cure Alzheimer's fund; Neuroscience Education and Research Foundation FX This work was supported by funds from the National Institutes of Health (K08-HL69842 to Dr del Monte, R01AG014713, R01MH60009 to Dr Tanzi), Beth Israel Deaconess Medical Center discretional funds (to Dr del Monte), the Cure Alzheimer's fund ( to Dr Tanzi), and the Neuroscience Education and Research Foundation (to Dr Li). NR 42 TC 33 Z9 33 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 16 PY 2010 VL 121 IS 10 BP 1216 EP U81 DI 10.1161/CIRCULATIONAHA.109.879510 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 569NQ UT WOS:000275604400008 PM 20194882 ER PT J AU Januzzi, JL Bamberg, F Lee, H Truong, QA Nichols, JH Karakas, M Mohammed, AA Schlett, CL Nagurney, JT Hoffmann, U Koenig, W AF Januzzi, James L., Jr. Bamberg, Fabian Lee, Hang Truong, Quynh A. Nichols, John H. Karakas, Mahir Mohammed, Asim A. Schlett, Christopher L. Nagurney, John T. Hoffmann, Udo Koenig, Wolfgang TI High-Sensitivity Troponin T Concentrations in Acute Chest Pain Patients Evaluated With Cardiac Computed Tomography SO CIRCULATION LA English DT Article DE myocardial infarction; troponin; diagnosis; imaging ID ACUTE CORONARY SYNDROME; ACUTE MYOCARDIAL-INFARCTION; I ASSAY; EARLY-DIAGNOSIS; ADVERSE EVENTS; HEART-FAILURE; ISCHEMIA; RISK; PREDICTION; ELEVATION AB Background-For evaluation of patients with chest pain and suspected acute coronary syndrome (ACS), consensus guidelines recommend use of a cardiac troponin cut point that corresponds to the 99th percentile of a healthy population. Most conventional troponin methods lack sufficient precision at this low level. Methods and Results-In a cross-sectional study, 377 patients (mean age 53.7 years, 64.2% male) with chest pain and low to intermediate likelihood for ACS were enrolled in the emergency department. Blood was tested with a precommercial high-sensitivity troponin T assay (hsTnT) and compared with a conventional cardiac troponin T method. Patients underwent a 64-slice coronary computed tomography coronary angiogram at the time of phlebotomy, on average 4 hours from initial presentation. Among patients with acute chest pain, 37 (9.8%) had an ACS. Using the 99th percentile cut point for a healthy population (13 pg/mL), hsTnT had 62% sensitivity, 89% specificity, 38% positive predictive value, and 96% negative predictive value for ACS. Compared with the cardiac troponin T method, hsTnT detected 27% more ACS cases (P=.001), and an hsTnT above the 99th percentile strongly predicted ACS (odds ratio 9.0, 95% confidence interval 3.9 to 20.9, P<0.001). Independent of ACS diagnosis, computed tomography angiography demonstrated that concentrations of hsTnT were determined by numerous factors, including the presence and severity of coronary artery disease, left ventricular mass, left ventricular ejection fraction, and regional left ventricular dysfunction. Conclusions-Among low-to intermediate-risk patients with chest pain, hsTnT provides good sensitivity and specificity for ACS. Elevation of hsTnT identifies patients with myocardial injury and significant structural heart disease, irrespective of the diagnosis of ACS. (Circulation. 2010; 121: 1227-1234.) C1 [Bamberg, Fabian; Truong, Quynh A.; Nichols, John H.; Schlett, Christopher L.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. [Januzzi, James L., Jr.; Truong, Quynh A.; Mohammed, Asim A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Karakas, Mahir; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med & Cardiol 2, Ulm, Germany. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, 165 Charles River Plaza,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org FU National Institutes of Health [RO1 HL080053, T32HL076136, L30HL093896]; Dennis and Marilyn Barry Cardiology Fellowship; German Federal Ministry of Education and Research; Foundation of German Business FX This study was sponsored in part by the National Institutes of Health (RO1 HL080053). Dr Januzzi is supported in part by the Balson Scholar Fund. Dr Truong is supported by National Institutes of Health grants T32HL076136 and L30HL093896. Dr Mohammed is supported by the Dennis and Marilyn Barry Cardiology Fellowship, and Mr Schlett is supported in part by grants from the German Federal Ministry of Education and Research, as well as the Foundation of German Business. NR 25 TC 117 Z9 118 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 16 PY 2010 VL 121 IS 10 BP 1227 EP U91 DI 10.1161/CIRCULATIONAHA.109.893826 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 569NQ UT WOS:000275604400009 PM 20194879 ER PT J AU Samuel, SM Thirunavukkarasu, M Penumathsa, SV Koneru, S Zhan, LJ Maulik, G Sudhakaran, PR Maulik, N AF Samuel, Samson Mathews Thirunavukkarasu, Mahesh Penumathsa, Suresh Varma Koneru, Srikanth Zhan, Lijun Maulik, Gautam Sudhakaran, Perumana R. Maulik, Nilanjana TI Thioredoxin-1 Gene Therapy Enhances Angiogenic Signaling and Reduces Ventricular Remodeling in Infarcted Myocardium of Diabetic Rats SO CIRCULATION LA English DT Article DE myocardial infarction; diabetes mellitus; angiogenesis; oxidative stress; thioredoxins; gene therapy; echocardiograpy ID ENDOTHELIAL GROWTH-FACTOR; HEME OXYGENASE-1; OXIDATIVE STRESS; CARDIOMYOCYTE APOPTOSIS; MAMMALIAN THIOREDOXIN; REACTIVE OXYGEN; NITRIC-OXIDE; MAP-KINASE; NEOVASCULARIZATION; EXPRESSION AB Background-The present study evaluated the reversal of diabetes-mediated impairment of angiogenesis in a myocardial infarction model of type 1 diabetic rats by intramyocardial administration of an adenoviral vector encoding thioredoxin-1 (Ad.Trx1). Various studies have linked diabetes-mediated impairment of angiogenesis to dysfunctional antioxidant systems in which thioredoxin-1 plays a central role. Methods and Results-Ad.Trx1 was administered intramyocardially in nondiabetic and diabetic rats immediately after myocardial infarction. Ad. LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. Myocardial function was measured by echocardiography 30 days after the intervention. The Ad.Trx1-administered group exhibited reduced fibrosis, oxidative stress, and cardiomyocyte and endothelial cell apoptosis compared with the diabetic myocardial infarction group, along with increased capillary and arteriolar density. Western blot and immunohistochemical analysis demonstrated myocardial overexpression of thioredoxin-1, heme oxygenase-1, vascular endothelial growth factor, and p38 mitogen-activated protein kinase-beta, as well as decreased phosphorylated JNK and p38 mitogen-activated protein kinase-alpha, in the Ad.Trx1-treated diabetic group. Conversely, we observed a significant reduction in the expression of vascular endothelial growth factor in nondiabetic and diabetic animals treated with tin protoporphyrin (SnPP, a heme oxygenase-1 enzyme inhibitor), even after Ad.Trx1 therapy. Echocardiographic analysis after 4 weeks of myocardial infarction revealed significant improvement in myocardial functional parameters such as ejection fraction, fractional shortening, and E/A ratio in the Ad.Trx1-administered group compared with the diabetic myocardial infarction group. Conclusions-This study demonstrates for the first time that impairment of angiogenesis and myocardial dysfunction can be regulated by Ad.Trx1 gene therapy in streptozotocin-induced diabetic rats subjected to infarction. (Circulation. 2010; 121: 1244-1255.) C1 [Samuel, Samson Mathews; Thirunavukkarasu, Mahesh; Penumathsa, Suresh Varma; Koneru, Srikanth; Zhan, Lijun; Maulik, Nilanjana] Univ Connecticut, Ctr Hlth, Mol Cardiol & Angiogenesis Lab, Dept Surg, Farmington, CT 06030 USA. [Samuel, Samson Mathews; Sudhakaran, Perumana R.] Univ Kerala, Dept Biochem, Trivandrum 695581, Kerala, India. [Maulik, Gautam] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Maulik, N (reprint author), Univ Connecticut, Ctr Hlth, Mol Cardiol & Angiogenesis Lab, Dept Surg, 263 Farmington Ave, Farmington, CT 06030 USA. EM nmaulik@neuron.uchc.edu FU National Institutes of Health [HL-56803, HL-69910] FX This study was supported by National Institutes of Health grants HL-56803 and HL-69910 to Dr Maulik. NR 40 TC 57 Z9 61 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 16 PY 2010 VL 121 IS 10 BP 1244 EP U129 DI 10.1161/CIRCULATIONAHA.109.872481 PG 27 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 569NQ UT WOS:000275604400011 PM 20194885 ER PT J AU van Kimmenade, RRJ Crijns, HJGM Januzzi, JL AF van Kimmenade, Roland R. J. Crijns, Harry J. G. M. Januzzi, James L. TI Letter by van Kimmenade et al Regarding Article, "Urinary N-Terminal Prohormone Brain Natriuretic Peptide Excretion in Patients With Chronic Heart Failure" SO CIRCULATION LA English DT Letter ID TRANSPORT; PROTEINS C1 [van Kimmenade, Roland R. J.; Crijns, Harry J. G. M.] Maastricht Univ, Med Ctr, Dept Cardiol, Maastricht, Netherlands. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP van Kimmenade, RRJ (reprint author), Maastricht Univ, Med Ctr, Dept Cardiol, Maastricht, Netherlands. RI Kimmenade, R.R.J./L-4432-2015 NR 5 TC 0 Z9 0 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 MAR 16 PY 2010 VL 121 IS 10 BP E242 EP E242 DI 10.1161/CIR.0b013e3181d78116 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 569NQ UT WOS:000275604400018 PM 20231541 ER PT J AU Deo, AJ Costa, R DeLisi, LE DeSalle, R Haghighi, F AF Deo, Anthony J. Costa, Ramiro DeLisi, Lynn E. DeSalle, Rob Haghighi, Fatemeh TI A Novel Analytical Framework for Dissecting the Genetic Architecture of Behavioral Symptoms in Neuropsychiatric Disorders SO PLOS ONE LA English DT Article ID GENOME-WIDE SCAN; SCHIZOAFFECTIVE DISORDER; DEPRESSIVE-DISORDERS; MAJOR DEPRESSION; BIPOLAR-DISORDER; LINKAGE ANALYSIS; EARLY-ONSET; SCHIZOPHRENIA SUSCEPTIBILITY; PSYCHIATRIC-DISORDERS; LOCI AB Background: For diagnosis of neuropsychiatric disorders, a categorical classification system is often utilized as a simple way for conceptualizing an often complex clinical picture. This approach provides an unsatisfactory model of mental illness, since in practice patients do not conform to these prototypical diagnostic categories. Family studies show notable familial co-aggregation between schizophrenia and bipolar illness and between schizoaffective disorders and both bipolar disorder and schizophrenia, revealing that mental illness does not conform to such categorical models and is likely to follow a continuum encompassing a spectrum of behavioral symptoms. Results and Methodology: We introduce an analytic framework to dissect the phenotypic heterogeneity present in complex psychiatric disorders based on the conceptual paradigm of a continuum of psychosis. The approach identifies subgroups of behavioral symptoms that are likely to be phenotypically and genetically homogenous. We have evaluated this approach through analysis of simulated data with simulated behavioral traits and predisposing genetic factors. We also apply this approach to a psychiatric dataset of a genome scan for schizophrenia for which extensive behavioral information was collected for each individual patient and their families. With this approach, we identified significant evidence for linkage among depressed individuals with two distinct symptom profiles, that is individuals with sleep disturbance symptoms with linkage on chromosome 2q13 and also a mutually exclusive group of individuals with symptoms of concentration problems with linkage on chromosome 2q35. In addition we identified a subset of individuals with schizophrenia defined by language disturbances with linkage to chromosome 2p25.1 and a group of patients with a phenotype intermediate between those of schizophrenia and schizoaffective disorder with linkage to chromosome 2p21. Conclusions: The findings presented are novel and demonstrate the efficacy of this approach in detection of genes underlying such complex human disorders as schizophrenia and depression. C1 [Deo, Anthony J.] NYU, Dept Biol, New York, NY 10003 USA. [Deo, Anthony J.; DeSalle, Rob] Amer Museum Nat Hist, Ctr Comparat Genom, New York, NY 10024 USA. [Deo, Anthony J.; DeSalle, Rob] Amer Museum Nat Hist, Dept Invertebrate Zool, New York, NY 10024 USA. [Deo, Anthony J.; Haghighi, Fatemeh] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Costa, Ramiro; Haghighi, Fatemeh] New York State Psychiat Inst & Hosp, Div Mol Imaging & Neuropathol, New York, NY 10032 USA. [DeLisi, Lynn E.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02401 USA. RP Deo, AJ (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. EM fgh3@columbia.edu FU NSF [DEB0508584]; National Science Foundation; [HG002915]; [MH074118] FX This work was supported by HG002915, MH074118, and NSF DEB0508584. The analyses were conducted on computing resources supported by the National Science Foundation under the following NSF programs: Partnerships for Advanced Computational Infrastructure, Distributed Terascale Facility (DTF) and Terascale Extensions: Enhancements to the Extensible Terascale Facility. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 5 Z9 5 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 16 PY 2010 VL 5 IS 3 AR e9714 DI 10.1371/journal.pone.0009714 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570ZC UT WOS:000275716400012 PM 20300526 ER PT J AU Zhou, YB Ramachandran, S Oh-hora, M Rao, A Hogan, PG AF Zhou, Yubin Ramachandran, Sweta Oh-hora, Masatsugu Rao, Anjana Hogan, Patrick G. TI Pore architecture of the ORAI1 store-operated calcium channel SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cross-linking; membrane protein; store-operated calcium entry; stromal interaction molecule; structure ID ACTIVATES CRAC CHANNELS; DISULFIDE CROSS-LINKING; PLASMA-MEMBRANE; CA2+ ENTRY; BACTERIAL CHEMORECEPTOR; TRANSMEMBRANE DOMAIN; PROTEIN-STRUCTURE; ION PERMEATION; MICE LACKING; STIM1 AB ORAI1 is the pore-forming subunit of the calcium release-activated calcium (CRAC) channel, a store-operated channel that is central to Ca(2+) signaling in mammalian cells. Electrophysiological data have shown that the acidic residues E106 in transmembrane helix 1 (TM1) and E190 in TM3 contribute to the high selectivity of ORAI1 channels for Ca(2+). We have examined the pore architecture of the ORAI1 channel using ORAI1 proteins engineered to contain either one or two cysteine residues. Disulfide cross-linking shows that ORAI1 assembles as a tetramer or a higher oligomer with TM1 centrally located. Cysteine side chains projecting from TM1 at position 88, 95, 102, or 106 cross-link efficiently to the corresponding side chain in a second ORAI1 monomer. Cysteine residues at position 190 or at surrounding positions in TM3 do not cross-link. We conclude that E106 residues in wild-type ORAI1 are positioned to form a Ca(2+) binding site in the channel pore and that E190 interacts less directly with ions traversing the pore. The cross-linking data further identify a relatively rigid segment of TM1 adjacent to E106 that is likely to contribute to the selectivity filter. C1 [Zhou, Yubin; Ramachandran, Sweta; Oh-hora, Masatsugu; Rao, Anjana; Hogan, Patrick G.] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Zhou, Yubin; Ramachandran, Sweta; Oh-hora, Masatsugu; Rao, Anjana; Hogan, Patrick G.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Zhou, Yubin; Oh-hora, Masatsugu; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hogan, PG (reprint author), Childrens Hosp, Immune Dis Inst, 200 Longwood Ave, Boston, MA 02115 USA. EM hogan@idi.harvard.edu RI Zhou, Yubin/D-4748-2011 OI Zhou, Yubin/0000-0001-7962-0517 FU NIH [AI84167, AI40127]; Cancer Research Institute; Leukemia and Lymphoma Society FX This work was funded by NIH grants AI84167 and AI40127 (to A. R. and P. G. H.). Y.Z. was supported by an Irvington Fellowship from the Cancer Research Institute and a postdoctoral fellowship from the Leukemia and Lymphoma Society. NR 43 TC 69 Z9 70 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 MAR 16 PY 2010 VL 107 IS 11 BP 4896 EP 4901 DI 10.1073/pnas.1001169107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570YI UT WOS:000275714300020 PM 20194792 ER PT J AU Vallet, S Mukherjee, S Vaghela, N Hideshima, T Fulciniti, M Pozzi, S Santo, L Cirstea, D Patel, K Sohani, AR Guimaraes, A Xie, WL Chauhan, D Schoonmaker, JA Attar, E Churchill, M Weller, E Munshi, N Seehra, JS Weissleder, R Anderson, KC Scadden, DT Raje, N AF Vallet, Sonia Mukherjee, Siddhartha Vaghela, Nileshwari Hideshima, Teru Fulciniti, Mariateresa Pozzi, Samantha Santo, Loredana Cirstea, Diana Patel, Kishan Sohani, Aliyah R. Guimaraes, Alex Xie, Wanling Chauhan, Dharminder Schoonmaker, Jesse A. Attar, Eyal Churchill, Michael Weller, Edie Munshi, Nikhil Seehra, Jasbir S. Weissleder, Ralph Anderson, Kenneth C. Scadden, David T. Raje, Noopur TI Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE osteoblasts; osteoclasts; tumor niche ID MARROW STROMAL CELLS; OSTEOBLAST DIFFERENTIATION; IN-VIVO; MODEL; INHIBIN; SYSTEM; BETA; DLX5; OSTEOCLASTOGENESIS; SUPPRESSION AB Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distalless homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials. C1 [Vallet, Sonia; Vaghela, Nileshwari; Pozzi, Samantha; Patel, Kishan; Sohani, Aliyah R.; Attar, Eyal; Raje, Noopur] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol & Oncol, Boston, MA 02114 USA. [Mukherjee, Siddhartha; Schoonmaker, Jesse A.; Churchill, Michael; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, MGH Ctr Regenerat Med, Cambridge, MA 02138 USA. [Hideshima, Teru; Fulciniti, Mariateresa; Santo, Loredana; Cirstea, Diana; Chauhan, Dharminder; Munshi, Nikhil; Anderson, Kenneth C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fulciniti, Mariateresa; Munshi, Nikhil] Vet Affairs Boston Hlth Care Syst, Dept Med, Boston, MA 02130 USA. [Guimaraes, Alex; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Simches Res Facil, Boston, MA 02114 USA. [Xie, Wanling; Weller, Edie] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Seehra, Jasbir S.] Acceleron Pharma, Cambridge, MA 02139 USA. RP Raje, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol & Oncol, Boston, MA 02114 USA. EM nraje@partners.org RI Pozzi, Samantha/A-7617-2012 OI Pozzi, Samantha/0000-0001-7917-1774 FU International Myeloma Foundation [K08]; NIH; ASCO CDA; MMRF; LLS CDA; NIH SPORE FX Grant support for this study was received in the form of an International Myeloma Foundation junior award (S.V., L.S., S.P.), K08 (S.M.), NIH (D.T.S.), ASCO CDA, MMRF, LLS CDA, and NIH SPORE (N.R.). NR 31 TC 92 Z9 94 U1 1 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 MAR 16 PY 2010 VL 107 IS 11 BP 5124 EP 5129 DI 10.1073/pnas.0911929107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570YI UT WOS:000275714300059 PM 20194748 ER PT J AU Westreich, D Cole, SR Tien, PC Chmiel, JS Kingsley, L Funk, MJ Anastos, K Jacobson, LP AF Westreich, Daniel Cole, Stephen R. Tien, Phyllis C. Chmiel, Joan S. Kingsley, Lawrence Funk, Michele Jonsson Anastos, Kathryn Jacobson, Lisa P. TI Time Scale and Adjusted Survival Curves for Marginal Structural Cox Models SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE acquired immunodeficiency syndrome; antiretroviral therapy; highly active; bias (epidemiology); causal inference; confounding factors (epidemiology); proportional hazards model; survival curve; survival time ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; INVERSE PROBABILITY WEIGHTS; LOGISTIC-REGRESSION; CAUSAL INFERENCE; HIV; AIDS; MORTALITY; CHOICE; DEATH AB Typical applications of marginal structural time-to-event (e.g., Cox) models have used time on study as the time scale. Here, the authors illustrate use of time on treatment as an alternative time scale. In addition, a method is provided for estimating Kaplan-Meier-type survival curves for marginal structural models. For illustration, the authors estimate the total effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome (AIDS) or death in 1,498 US men and women infected with human immunodeficiency virus and followed for 6,556 person-years between 1995 and 2002; 323 incident cases of clinical AIDS and 59 deaths occurred. Of the remaining 1,116 participants, 77% were still under observation at the end of follow-up. By using time on study, the hazard ratio for AIDS or death comparing always with never using highly active antiretroviral therapy from the marginal structural model was 0.52 (95% confidence interval: 0.35, 0.76). By using time on treatment, the analogous hazard ratio was 0.44 (95% confidence interval: 0.32, 0.60). In time-to-event analyses, the choice of time scale may have a meaningful impact on estimates of association and precision. In the present example, use of time on treatment yielded a hazard ratio further from the null and more precise than use of time on study as the time scale. C1 [Westreich, Daniel; Cole, Stephen R.; Funk, Michele Jonsson] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 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. [Chmiel, Joan S.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Kingsley, Lawrence] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [Anastos, Kathryn] Montefiore Med Ctr, Bronx, NY 10467 USA. [Anastos, Kathryn] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Cole, SR (reprint author), McGavran Greenberg Hall,CB7435, Chapel Hill, NC 27599 USA. EM cole@unc.edu RI Jonsson Funk, Michele/F-6885-2011 OI Jonsson Funk, Michele/0000-0002-3756-7540 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [T32-AI-07001, R03-AI-071763, R01-AA-01759, UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Cancer Institute; National Heart, Lung, and Blood Institute [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]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources [UL1 RR024131] FX This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant T32-AI-07001 to D. W.; R03-AI-071763 and R01-AA-01759 to S. R. C.). Data in this article were collected by the Multicenter AIDS Cohort Study (MACS) funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung, and Blood Institute (UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041). Data in this article were also collected by the Women's Interagency HIV Study Collaborative Study Group funded by the National Institute of Allergy and Infectious Diseases (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 (UO1-HD-32632). The Women's Interagency HIV Study is jointly funded 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). NR 41 TC 25 Z9 25 U1 0 U2 8 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 MAR 15 PY 2010 VL 171 IS 6 BP 691 EP 700 DI 10.1093/aje/kwp418 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 568ZJ UT WOS:000275565100009 PM 20139124 ER PT J AU Gradus, JL Qin, P Lincoln, AK Miller, M Lawler, E Sorensen, HT Lash, TL AF Gradus, Jaimie L. Qin, Ping Lincoln, Alisa K. Miller, Matthew Lawler, Elizabeth Sorensen, Henrik Toft Lash, Timothy L. TI Posttraumatic Stress Disorder and Completed Suicide SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; stress disorders; post-traumatic; suicide ID ANXIETY DISORDERS; MAJOR DEPRESSION; REGISTER; RISK; ASSOCIATION; BEHAVIOR; SCHIZOPHRENIA; DIAGNOSES; MORTALITY; VALIDITY AB Most research regarding posttraumatic stress disorder (PTSD) and suicide has focused on suicidal ideation or attempts; no known study of the association between PTSD and completed suicide in a population-based sample has been reported. This study examined the association between PTSD and completed suicide in a population-based sample. Data were obtained from the nationwide Danish health and administrative registries, which include data on all 5.4 million residents of Denmark. All suicides between January 1, 1994, and December 31, 2006, were included, and controls were selected from a sample of all Danish residents. Using this nested case-control design, the authors examined 9,612 suicide cases and 199,306 controls matched to cases on gender, date of birth, and time. Thirty-eight suicide cases (0.40%) and 95 controls (0.05%) were diagnosed with PTSD. The odds ratio associating PTSD with suicide was 9.8 (95% confidence interval: 6.7, 15). The association between PTSD and completed suicide remained after controlling for psychiatric and demographic confounders (odds ratio = 5.3, 95% confidence interval: 3.4, 8.1). Additionally, persons with PTSD and depression had a greater rate of suicide than expected based on their independent effects. In conclusion, a registry-based diagnosis of PTSD based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, is a risk factor for completed suicide. C1 [Gradus, Jaimie L.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Gradus, Jaimie L.; Sorensen, Henrik Toft; Lash, Timothy L.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Qin, Ping] Aarhus Univ, Ctr Registry Based Res, Aarhus, Denmark. [Lincoln, Alisa K.] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Lincoln, Alisa K.] Northeastern Univ, Dept Sociol, Boston, MA 02115 USA. [Miller, Matthew] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Lawler, Elizabeth] Harvard Univ, Dept Med, Boston, MA 02115 USA. [Sorensen, Henrik Toft; Lash, Timothy L.] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. RP Gradus, JL (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave,116B-3, Boston, MA 02130 USA. EM jaimie.gradus@va.gov OI Gradus, Jaimie/0000-0003-1459-5327 NR 30 TC 60 Z9 61 U1 3 U2 11 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 MAR 15 PY 2010 VL 171 IS 6 BP 721 EP 727 DI 10.1093/aje/kwp456 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 568ZJ UT WOS:000275565100012 PM 20160171 ER PT J AU Mularski, RA Campbell, ML Asch, SM Reeve, BB Basch, E Maxwell, TL Hoverman, JR Cuny, J Clauser, SB Snyder, C Seow, H Wu, AW Dy, S AF Mularski, Richard A. Campbell, Margaret L. Asch, Steven M. Reeve, Bryce B. Basch, Ethan Maxwell, Terri L. Hoverman, J. Russell Cuny, Joanne Clauser, Steve B. Snyder, Claire Seow, Hsien Wu, Albert W. Dy, Sydney TI A Review of Quality of Care Evaluation for the Palliation of Dyspnea SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE dyspnea; quality of health care; quality indicators; health care; assessment ID CLINICAL METHODS; LIFE CARE; DISEASE; BREATHLESSNESS; QUESTIONNAIRE; END; INDICATORS; CANCER; DESCRIPTORS; SHORTNESS AB Assessment and management of dyspnea has emerged as a priority topic for quality evaluation and improvement. Evaluating dyspnea quality of care requires valid, reliable, and responsive measures of the care provided to patients across settings and diseases. As part of an Agency for Healthcare Research and Quality Symposium, we reviewed quality of care measures for dyspnea by compiling quality measures identified in systematic searches and reviews. Systematic reviews identified only three existing quality measurement sets that included quality measures for dyspnea care. The existing dyspnea quality measures reported by retrospective evaluations of care assess only four aspects: dyspnea assessment within 48 hours of hospital admission, use of objective scales to rate dyspnea severity, identification of management plans, and evidence of dyspnea reduction. To begin to improve care, clinicians need to assess and regularly document patient's experiences of dyspnea. There is no consensus on how dyspnea should be characterized for quality measurement, and although over 40 tools exist to assess dyspnea, no rating scale or instrument is ideal for palliative care. The panel recommended that dyspnea assessment should include a measure of intensity and some inquiry into the associated bother or distress experienced by the patient. A simple question into the presence or absence of dyspnea would be unlikely to help guide therapy, as complete relief of dyspnea in advanced disease would not be anticipated. Additional knowledge gaps include standards for clinical dyspnea care, assessment in the cognitively impaired, and evaluation of effectiveness of dyspnea care for patients with advanced disease. C1 [Mularski, Richard A.] Oregon Hlth & Sci Univ, Ctr Hlth Res, Portland, OR 97227 USA. [Campbell, Margaret L.] Wayne State Univ, Detroit Receiving Hosp Ctr Hlth Res, Detroit, MI USA. [Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Reeve, Bryce B.; Clauser, Steve B.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Basch, Ethan] Mem Sloan Kettering Canc Ctr, Hlth Outcomes Grp, New York, NY 10021 USA. [Maxwell, Terri L.] ExcelleRx Inc, Philadelphia, PA USA. [Hoverman, J. Russell] Texas Oncol, Dallas, TX USA. [Cuny, Joanne] Univ HealthSyst Consortium, Oak Brook, IL USA. [Snyder, Claire; Dy, Sydney] Johns Hopkins Sch Publ Hlth, Dept Hlth Policy & Management, Johns Hopkins Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Seow, Hsien] McMaster Univ, Dept Oncol, Hamilton, ON, Canada. RP Mularski, RA (reprint author), Oregon Hlth & Sci Univ, Ctr Hlth Res, 3800 N Interstate,WIN 1060, Portland, OR 97227 USA. EM Richard.A.Mularski@kpchr.org OI Campbell, Margaret/0000-0003-4517-690X FU Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services [290-2005-00341]; Spiration, Inc.; Novartis; Amgen; Wyeth Pharmaceuticals; United Healthcare FX Supported by Contract No. 290-2005-00341 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program. The Symposium on Developing a Framework to Assess Cancer Quality Indicators for End-of-Life Care was held in Baltimore, MD on April 28, 2008. The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.; R.A.M. received 850,001-$100,000 from Spiration, Inc., and 850,001-8100,001 from Novartis in industry-sponsored grants. M.L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.M.A. received more than 8100,001 from Amgen in grants. B.B.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.L.M. is a full-time employee of excelleRx, Inc., and received S10,001-850,000 from Wyeth Pharmaceuticals in industry-sponsored grants for database analysis related to constipation prevalence at the end of life. J.R.H. received $1,001-85,000 from United Healthcare in advisory board fees. j.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.B.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.S. does not have a financial relationship with a commercial I. entity that has an interest in the subject of this manuscript. H.S. does not NR 50 TC 20 Z9 20 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 15 PY 2010 VL 181 IS 6 BP 534 EP 538 DI 10.1164/rccm.200903-0462PP PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 632RX UT WOS:000280446500005 PM 20056904 ER PT J AU Sarosy, GA Hussain, MM Seiden, MV Fuller, AF Nikrui, N Goodman, A Minasian, L Reed, E Steinberg, SM Kohn, EC AF Sarosy, Gisele A. Hussain, Mahrukh M. Seiden, Michael V. Fuller, Arlan F. Nikrui, Najmosama Goodman, Annekathryn Minasian, Lori Reed, Eddie Steinberg, Seth M. Kohn, Elise C. TI Ten-Year Follow-Up of a Phase 2 Study of Dose-Intense Paclitaxel With Cisplatin and Cyclophosphamide as Initial Therapy for Poor-Prognosis, Advanced-Stage Epithelial Ovarian Cancer SO CANCER LA English DT Article DE ovarian neoplasms; paclitaxel; cyclophosphamide; cisplatin; antineoplastic combined chemotherapy protocols; filgrastim; drug dose-response relation ID GYNECOLOGIC-ONCOLOGY-GROUP; CARCINOMA CELL-LINES; 1ST-LINE TREATMENT; IV; PACLITAXEL/CARBOPLATIN; CYTOTOXICITY AB BACKGROUND: The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced-stage epithelial ovarian cancer (EOC) who were receiving dose-intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule. METHODS: Patients with stage III/IV EOC received cyclophosphamide 750 mg/m(2), followed by a 24-hour infusion of paclitaxel 250 mg/m(2) and cisplatin 75 mg/m(2) on Day 2. Filgrastim began on Day 3 at 10 mu g/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel. RESULTS: Sixty-two patients were enrolled. Thirty-two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent-to-treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow-up of 11.4 years, the median progression-free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel. CONCLUSIONS: The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Cincology Group suggest that further study is warranted of dose-dense or dose-intense paclitaxel regimens in women with newly diagnosed, advanced-stage EOC. Cancer 2010;116:1476-84. (C) 2070 American Cancer Society. C1 [Sarosy, Gisele A.; Hussain, Mahrukh M.; Minasian, Lori; Reed, Eddie; Kohn, Elise C.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Seiden, Michael V.] Massachusetts Gen Hosp, Div Canc Biol, Boston, MA 02114 USA. [Fuller, Arlan F.; Nikrui, Najmosama; Goodman, Annekathryn] Massachusetts Gen Hosp, Div Gynecol Oncol, Boston, MA 02114 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 10 Ctr Dr,MSC 1906, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov FU National Institutes of Health; National Cancer Institute, Center for Cancer Research; Amgen Corporation FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Patient care Support was provided to the Massachusetts General Hospital investigators from Amgen Corporation. NR 24 TC 13 Z9 13 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2010 VL 116 IS 6 BP 1476 EP 1484 DI 10.1002/cncr.24861 PG 9 WC Oncology SC Oncology GA 564SY UT WOS:000275238800015 PM 20091841 ER PT J AU Richards, WG Godleski, JJ Yeap, BY Corson, JM Chirieac, LR Zellos, L Mujoomdar, A Jaklitsch, MT Bueno, R Sugarbaker, DJ AF Richards, William G. Godleski, John J. Yeap, Beow Y. Corson, Joseph M. Chirieac, Lucian R. Zellos, Lambros Mujoomdar, Aneil Jaklitsch, Michael T. Bueno, Raphael Sugarbaker, David J. TI Proposed Adjustments to Pathologic Staging of Epithelial Malignant Pleural Mesothelioma Based on Analysis of 354 Cases SO CANCER LA English DT Article DE diffuse malignant pleural mesothelioma; pathologic staging; extrapleural pneumonectomy; epithelial mesothelioma; TNM staging ID MULTIMODALITY THERAPY; PROGNOSTIC-FACTORS; EXPERIENCE; SYSTEM; RESECTION; SURVIVAL; DIFFUSE AB BACKGROUND: Several pathologic staging systems for malignant pleural mesothelioma (MPM) have been published, but none of them provide optimal survival stratification or stage distribution among patients treated with surgery. Interpretation of prior studies that correlate pathologic factors with outcome has been confounded by the inclusion of patients undergoing differing surgical procedures and with varied tumor histology. METHODS: We examined pathologic characteristics, previously included in published studies, and explored correlations with outcome among patients with epithelioid MPM who underwent extrapleural pneumonectomy (EPP) at Brigham and Women's Hospital (BWH). Comparisons of survival among patients with and without each tumor or lymph node feature guided adjustments to the American Joint Commission on Cancer (AJCC)/International Union Against Cancer (UICC) classification criteria. Proportional hazards modeling of TN combinations guided adjustments to stage groupings. RESULTS: Three hundred fifty-four patients were resectable by EPP and had complete pathologic data. Overall median survival was 18 months from surgery. By AJCC/UICC criteria, 233 (66%) patients were stage 111, whereas by BWH criteria, 194 (SS%) patients were stage III. T classification criteria were adjusted-based on prevalence and relation to survival. N status correlated significantly with survival. Regrouping of TN combinations based on relative hazard and Kaplan-Meier survival analysis resulted in improved stage distribution (stage I-IV: 8%, 43%, 33%, 16%, respectively) and survival stratification (SI, 26, 15, 8 months, respectively). CONCLUSIONS: Proposed adjustments to TNM staging criteria improved outcome stratification of patients with epithelial tumor histology who received surgical therapy by EPP and complete pathologic assessment. Determining relevance to other treatment or staging modalities will require verification in additional cohorts. Cancer 2010;116:1510-7. (C) 2070 American Cancer Society. C1 [Richards, William G.; Zellos, Lambros; Mujoomdar, Aneil; Jaklitsch, Michael T.; Bueno, Raphael; Sugarbaker, David J.] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02115 USA. [Richards, William G.; Godleski, John J.; Yeap, Beow Y.; Corson, Joseph M.; Chirieac, Lucian R.; Zellos, Lambros; Mujoomdar, Aneil; Jaklitsch, Michael T.; Bueno, Raphael; Sugarbaker, David J.] Brigham & Womens Hosp, Int Mesothelioma Program, Boston, MA 02115 USA. [Godleski, John J.; Corson, Joseph M.; Chirieac, Lucian R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Richards, WG (reprint author), Brigham & Womens Hosp, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. EM wrichards@partners.org FU International Mesothelionia Program FX Supported by the International Mesothelionia Program. The authors made no further disclosures. NR 22 TC 30 Z9 31 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2010 VL 116 IS 6 BP 1510 EP 1517 DI 10.1002/cncr.24886 PG 8 WC Oncology SC Oncology GA 564SY UT WOS:000275238800019 PM 20108310 ER PT J AU Rothenberg, SM Mohapatra, G Rivera, MN Winokur, D Greninger, P Nitta, M Sadow, PM Sooriyakumar, G Brannigan, BW Ulman, MJ Perera, RM Wang, R Tam, A Ma, XJ Erlander, M Sgroi, DC Rocco, JW Lingen, MW Cohen, EEW Louis, DN Settleman, J Haber, DA AF Rothenberg, S. Michael Mohapatra, Gayatry Rivera, Miguel N. Winokur, Daniel Greninger, Patricia Nitta, Mai Sadow, Peter M. Sooriyakumar, Gaya Brannigan, Brian W. Ulman, Matthew J. Perera, Rushika M. Wang, Rui Tam, Angela Ma, Xiao-Jun Erlander, Mark Sgroi, Dennis C. Rocco, James W. Lingen, Mark W. Cohen, Ezra E. W. Louis, David N. Settleman, Jeffrey Haber, Daniel A. TI A Genome-Wide Screen for Microdeletions Reveals Disruption of Polarity Complex Genes in Diverse Human Cancers SO CANCER RESEARCH LA English DT Article ID REPRESENTATIONAL DIFFERENCE ANALYSIS; COPY-NUMBER; CELL POLARITY; ARRAY; HYBRIDIZATION; CARCINOMA; MICROARRAYS; EXPRESSION; DROSOPHILA; PATTERNS AB In a genome-wide screen of 684 cancer cell lines, we identified homozygous intragenic microdeletions involving genes encoding components of the apical-basal cell polarity complexes. Among these, PARD3 is disrupted in cell lines and primary tumors from squamous carcinomas and glioblastomas. Reconstituting PARD3 expression in both cell types restores tight junctions and retards contact-dependent proliferation. Searching specifically for small intragenic microdeletions using high-resolution genomic arrays may be complementary to other genomic deletion screens and resequencing efforts in identifying new tumor suppressor genes. Cancer Res; 70(6); 2158-64. (C) 2010 AACR. C1 [Rothenberg, S. Michael; Mohapatra, Gayatry; Rivera, Miguel N.; Winokur, Daniel; Greninger, Patricia; Nitta, Mai; Sooriyakumar, Gaya; Brannigan, Brian W.; Ulman, Matthew J.; Perera, Rushika M.; Tam, Angela; Sgroi, Dennis C.; Rocco, James W.; Louis, David N.; Settleman, Jeffrey; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Greninger, Patricia; Tam, Angela; Settleman, Jeffrey] Harvard Univ, Ctr Mol Therapeut, Sch Med, Charlestown, MA USA. [Rothenberg, S. Michael; Rivera, Miguel N.; Haber, Daniel A.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Rothenberg, S. Michael] Massachusetts Gen Hosp, Ctr Head & Neck Canc, Boston, MA 02114 USA. [Mohapatra, Gayatry; Rivera, Miguel N.; Nitta, Mai; Sadow, Peter M.; Sgroi, Dennis C.; Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Wang, Rui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Ma, Xiao-Jun; Erlander, Mark] Biotheranostics, San Diego, CA USA. [Lingen, Mark W.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Cohen, Ezra E. W.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, CNY7 Bldg 149,13th St, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu; haber@helix.mgh.harvard.edu FU Howard Hughes Medical Institute; NIH [RO1 CA207186, RO1 CA57683, K08 DK080175]; T32 Institutional Ruth L. Kirschstein National Research Service Award; MGH; Burroughs Wellcome Fund FX Grant Support; Howard Hughes Medical Institute (D. A. Haber, M.N. Rivera) and NIH grants RO1 CA207186 (D. A. Haber) and RO1 CA57683 (D.N. Louis). S. M. Rothenberg is supported by a T32 Institutional Ruth L. Kirschstein National Research Service Award and the MGH Tosteson Postdoctoral Fellowship. M.N. Rivera is supported by NIH grant K08 DK080175, MGH, and the Burroughs Wellcome Fund. NR 21 TC 41 Z9 41 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2010 VL 70 IS 6 BP 2158 EP 2164 DI 10.1158/0008-5472.CAN-09-3458 PG 7 WC Oncology SC Oncology GA 607GA UT WOS:000278485900003 PM 20215515 ER PT J AU Yang, XWH Flores, LM Li, QL Zhou, PC Xu, FH Krop, IE Hemler, ME AF Yang, Xiuwei H. Flores, Ludmila M. Li, Qinglin Zhou, Pengcheng Xu, Fenghui Krop, Ian E. Hemler, Martin E. TI Disruption of Laminin-Integrin-CD151-Focal Adhesion Kinase Axis Sensitizes Breast Cancer Cells to ErbB2 Antagonists SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; ALPHA-6-BETA-4 INTEGRIN; LUNG-CANCER; IN-VITRO; TRASTUZUMAB RESISTANCE; CLINICAL-SIGNIFICANCE; TETRASPANIN PROTEINS; LAPATINIB RESISTANCE; DRUG-RESISTANCE; CARCINOMA CELLS AB Resistance to anti-ErbB2 agents is a significant problem in the treatment of human ErbB2+ breast cancers. We show here that adhesion of human ErbB2+ breast cancer cells to basement membrane laminin-5 provides substantial resistance to trastuzumab and lapatinib, agents that respectively target the extracellular and kinase domains of ErbB2. Knockdown of laminin-binding integrins (alpha 6 beta 4, alpha 3 beta 1) or associated tetraspanin protein CD151 reversed laminin-5 resistance and sensitized ErbB2+ cells to trastuzumab and lapatinib. CD151 knockdown, together with trastuzumab treatment, inhibited ErbB2 activation and downstream signaling through Akt, Erk1/2, and focal adhesion kinase (FAK). Hence, ErbB2 function in mammary tumor cells is promoted by integrin-mediated adhesion to laminin-5, with strong support by CD151, leading to signaling through FAK. Consequently, removal or inhibition of any of these components (laminin-5, integrin, CD151, FAK) markedly sensitizes cells to anti-ErbB2 agents. These new insights should be useful when devising strategies for overcoming drug resistance in ErbB2+ cancers. Cancer Res; 70(6); 2256-63. (C) 2010 AACR. C1 [Yang, Xiuwei H.; Li, Qinglin; Xu, Fenghui; Hemler, Martin E.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Flores, Ludmila M.; Krop, Ian E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhou, Pengcheng] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Flores, Ludmila M.] Univ Massachusetts, Dept Biol, Boston, MA 02125 USA. RP Hemler, ME (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Room D1430,44 Binney St, Boston, MA 02115 USA. EM Martin_Hemler@DFCI.Harvard.EDU RI Li, Qinglin/K-2570-2015 OI Li, Qinglin/0000-0002-4125-1944 FU NIH [CA42368]; S.G. Komen Career Catalyst Award; DOD [W81XWH-06-BCRP-CA]; Center for Clinical and Translational Research at Dana-Farber Cancer Institute FX Grant Support; NIH grant CA42368 (M. E. Hemler), S.G. Komen Career Catalyst Award, and DOD W81XWH-06-BCRP-CA Concept Award (X. H. Yang) and Center for Clinical and Translational Research at Dana-Farber Cancer Institute. NR 51 TC 61 Z9 63 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2010 VL 70 IS 6 BP 2256 EP 2263 DI 10.1158/0008-5472.CAN-09-4032 PG 8 WC Oncology SC Oncology GA 607GA UT WOS:000278485900013 PM 20197472 ER PT J AU Zhang, X Gejman, R Mahta, A Zhong, Y Rice, KA Zhou, YL Cheunsuchon, P Louis, DN Klibanski, A AF Zhang, Xun Gejman, Roger Mahta, Ali Zhong, Ying Rice, Kimberley A. Zhou, Yunli Cheunsuchon, Pornsuk Louis, David N. Klibanski, Anne TI Maternally Expressed Gene 3, an Imprinted Noncoding RNA Gene, Is Associated with Meningioma Pathogenesis and Progression SO CANCER RESEARCH LA English DT Article ID MOUSE-CHROMOSOME 12; PITUITARY-ADENOMAS; EXPRESSION; TUMOR; MEG3; GTL2; P53; MUTATION; GROWTH; REGION AB Meningiomas are common tumors, representing 15% to 25% of all central nervous system tumors. NF2 gene inactivation on chromosome 22 has been shown as an early event in tumorigenesis; however, few factors underlying tumor growth and progression have been identified. The chromosomal abnormalities of 14q32 are often associated with meningioma pathogenesis and progression; therefore, it has been proposed that an as yet unidentified tumor suppressor is present at this locus. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 which encodes a noncoding RNA with an antiproliferative function. We found that MEG3 mRNA is highly expressed in normal arachnoidal cells. However, MEG3 is not expressed in the majority of human meningiomas or the human meningioma cell lines IOMM-Lee and CH157-MN. There is a strong association between loss of MEG3 expression and tumor grade. Allelic loss at the MEG3 locus is also observed in meningiomas, with increasing prevalence in higher grade tumors. In addition, there is an increase in CpG methylation within the promoter and the imprinting control region of MEG3 gene in meningiomas. Functionally, MEG3 suppresses DNA synthesis in both IOMM-Lee and CH157-MN cells by similar to 60% in bromodeoxyuridine incorporation assays. Colony-forming efficiency assays show that MEG3 inhibits colony formation in CH157-MN cells by similar to 80%. Furthermore, MEG3 stimulates p53-mediated transactivation in these cell lines. Therefore, these data are consistent with the hypothesis that MEG3, which encodes a noncoding RNA, may be a tumor suppressor gene at chromosome 14q32 involved in meningioma progression via a novel mechanism. Cancer Res; 70(6); 2350-8. (C) 2010 AACR. C1 [Zhang, Xun; Gejman, Roger; Mahta, Ali; Zhong, Ying; Rice, Kimberley A.; Zhou, Yunli; Cheunsuchon, Pornsuk; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Gejman, Roger; Cheunsuchon, Pornsuk; Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL457,55 Fruit St, Boston, MA 02114 USA. EM aklibanski@partners.org RI Cheunsuchon, Pornsuk/O-7915-2015 OI Cheunsuchon, Pornsuk/0000-0001-8851-3553 FU NIH [R01-DK-40947]; Guthart Family Foundation FX Grant Support; NIH R01-DK-40947 (A. Klibanski) and The Guthart Family Foundation. NR 50 TC 131 Z9 147 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2010 VL 70 IS 6 BP 2350 EP 2358 DI 10.1158/0008-5472.CAN-09-3885 PG 9 WC Oncology SC Oncology GA 607GA UT WOS:000278485900022 PM 20179190 ER PT J AU Schoeberl, B Faber, AC Li, DN Liang, MC Crosby, K Onsum, M Burenkova, O Pace, E Walton, Z Nie, L Fulgham, A Song, Y Nielsen, UB Engelman, JA Wong, KK AF Schoeberl, Birgit Faber, Anthony C. Li, Danan Liang, Mei-Chih Crosby, Katherine Onsum, Matthew Burenkova, Olga Pace, Emily Walton, Zandra Nie, Lin Fulgham, Aaron Song, Youngchul Nielsen, Ulrik B. Engelman, Jeffrey A. Wong, Kwok-Kin TI An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation SO CANCER RESEARCH LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; CELL LUNG-CANCER; BREAST-CANCER; PHOSPHATIDYLINOSITOL 3-KINASE; ANTITUMOR ACTION; FACTOR RECEPTOR; IN-VIVO; EGFR; KINASE; HER3 AB ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3. Cancer Res; 70(6); 2485-94. (C)2010 AACR. C1 [Faber, Anthony C.; Song, Youngchul; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Schoeberl, Birgit; Onsum, Matthew; Burenkova, Olga; Pace, Emily; Nie, Lin; Fulgham, Aaron; Nielsen, Ulrik B.] Merrimack Pharmaceut Inc, Cambridge, MA USA. [Li, Danan; Liang, Mei-Chih; Walton, Zandra; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, Danan; Liang, Mei-Chih; Walton, Zandra; Wong, Kwok-Kin] Harvard Canc Ctr, Ludwig Ctr Dana Farber, Boston, MA USA. [Engelman, Jeffrey A.; Wong, Kwok-Kin] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Crosby, Katherine] Cell Signaling Technol, Danvers, MA USA. RP Engelman, JA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM jengelman@partners.org; kwong1@partners.org OI wong, kwok kin/0000-0001-6323-235X FU Dana-Farber-Harvard Cancer Center Lung Cancer [P50 CA090578]; NIH [K08 AG024004, R01 AG2400401, R01 CA122794, R01 CA140594, K08 CA120060, R01CA137008, R01CA140594]; DF/HCC Gastrointestinal Cancer SPORE [P50 CA127003]; American Association for Cancer Research; American Cancer Society [RSG-06102- 01-CCE]; Ellison Foundation FX Grant Support; Dana-Farber-Harvard Cancer Center Lung Cancer Specialized Program of Research Excellence (SPORE) grant P50 CA090578 (J.A. Engelman and K-K. Wong); NIH grants K08 AG024004 (K-K. Wong), R01 AG2400401 (K-K. Wong), R01 CA122794 (K-K. Wong), R01 CA140594 (J.A. Engelman and K-K. Wong), K08 grant CA120060 (J.A. Engelman), R01CA137008 (J.A. Engelman), and R01CA140594 (J.A. Engelman); DF/HCC Gastrointestinal Cancer SPORE P50 CA127003 (J.A. Engelman); American Association for Cancer Research (J.A. Engelman); V Foundation (J.A. Engelman); American Cancer Society RSG-06102- 01-CCE (J.A. Engelman); and Ellison Foundation Scholar (J.A. Engelman). NR 25 TC 151 Z9 155 U1 2 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 MAR 15 PY 2010 VL 70 IS 6 BP 2485 EP 2494 DI 10.1158/0008-5472.CAN-09-3145 PG 10 WC Oncology SC Oncology GA 607GA UT WOS:000278485900036 PM 20215504 ER PT J AU Chan, SY Loscalzo, J AF Chan, Stephen Y. Loscalzo, Joseph TI MicroRNA-210 A unique and pleiotropic hypoxamir SO CELL CYCLE LA English DT Review DE microRNA; hypoxia; miR-210; hypoxia inducible factor; metabolism; proliferation; angiogenesis; apoptosis; cell cycle; Pasteur effect ID SULFUR CLUSTER BIOGENESIS; RECEPTOR TYROSINE KINASE; REPAIR GENE-EXPRESSION; NITRIC-OXIDE; MICROPROCESSOR COMPLEX; ESCHERICHIA-COLI; MESSENGER-RNAS; CELL-CARCINOMA; BREAST-CANCER; HUMAN-DISEASE AB Inadequate oxygen availability or hypoxia induces a complex and still incompletely understood set of adaptations that influence cellular survival and function. Many of these adaptations are directly controlled by a master transcription factor, hypoxia inducible factor-alpha (HIF-alpha). In response to hypoxia, HIF-alpha levels increase and directly induce the transcription of > 100 genes, influencing functions ranging from metabolism, survival, proliferation, migration, to angiogenesis, among others. Recently, it has been demonstrated that a specific set of microRNA molecules are upregulated by hypoxia, which we denote here as "hypoxamirs." In particular, the HIF-responsive hypoxamir microRNA-210 (miR-210) is a unique microRNA that is evolutionarily conserved and ubiquitously expressed in hypoxic cell and tissue types. A number of direct targets of miR-210 have been identified by in silico, transcriptional and biochemical methods, a subset of which have been extensively validated. As a result, miR-210 has been mechanistically linked to the control of a wide range of cellular responses known to influence normal developmental physiology as well as a number of hypoxia-dependent disease states, including tissue ischemia, inflammation and tumorigenesis. Thus, reflecting the pleiotropic actions of HIF-alpha, miR-210 appears to function as a "master microRNA" relevant for the control of diverse functions in the hypoxic state. C1 [Loscalzo, Joseph] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA. [Chan, Stephen Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. RP Loscalzo, J (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA. EM jloscalzo@partners.org FU AHA [0825906D]; NIH [HL 61795, NO1 HV 28178, PO1 81587, U54 HL 70819] FX This work was supported by AHA grant 0825906D (S.Y.C.), and NIH grants HL 61795, NO1 HV 28178, PO1 81587, U54 HL 70819 (J.L.). No conflicts of interest are reported. We apologize to those authors whose work is not cited due to space restrictions. We thank the Loscalzo laboratory for fruitful discussions; T. Lis for graphic design; S. K. Chan and J.W. Snow for critical reading of the manuscript; and S. Tribuna for expert administrative assistance. NR 99 TC 125 Z9 134 U1 2 U2 13 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2010 VL 9 IS 6 BP 1072 EP 1083 PG 12 WC Cell Biology SC Cell Biology GA 569XT UT WOS:000275636900013 PM 20237418 ER PT J AU Gomez-Baldo, L Schmidt, S Maxwell, CA Bonifaci, N Gabaldon, T Vidalain, PO Senapedis, W Kletke, A Rosing, M Barnekow, A Rottapel, R Capella, G Vidal, M Astrinidis, A Piekorz, RP Pujana, MA AF Gomez-Baldo, Laia Schmidt, Stephan Maxwell, Christopher A. Bonifaci, Nuria Gabaldon, Toni Vidalain, Pierre-Olivier Senapedis, William Kletke, Anja Rosing, Mechthild Barnekow, Angelika Rottapel, Robert Capella, Gabriel Vidal, Marc Astrinidis, Aristotelis Piekorz, Roland P. Angel Pujana, Miguel TI TACC3-TSC2 maintains nuclear envelope structure and controls cell division SO CELL CYCLE LA English DT Article DE TSC; TACC3; centrosome; nuclear envelope; mitosis ID TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR; GENE-PRODUCT; ACTIN CYTOSKELETON; PRIMARY CILIUM; C-ELEGANS; EXPRESSION PROFILES; INTERACTOME NETWORK; MUTATIONAL ANALYSIS; BINDING PARTNER AB Studies of the role of tuberous sclerosis complex (TSC) proteins (TSC1/TSC2) in pathology have focused mainly on their capacity to regulate translation and cell growth, but their relationship with alterations of cellular structures and the cell cycle is not yet fully understood. The transforming acidic coiled-coil (TACC) domain-containing proteins are central players in structures and processes connected to the centrosome. Here, TACC3 interactome mapping identified TSC2 and 15 other physical interactors, including the evolutionary conserved interactions with ch-TOG/CKAP5 and FAM161B. TACC3 and TSC2 co-localize and co-purify with components of the nuclear envelope, and their deficiency causes morphological alterations of this structure. During cell division, TACC3 is necessary for the proper localization of phospho-Ser939 TSC2 at spindle poles and cytokinetic bridges. Accordingly, abscission alterations and increased frequency of binucleated cells were observed in Tacc3- and Tsc2-deficient cells relative to controls. In regulating cell division, TSC2 acts epistatically to TACC3 and, in addition to canonical TSC/mTOR signaling and cytokinetic associations, converges to the early mitotic checkpoint mediated by CHFR, consistently with nuclear envelope associations. Our findings link TACC3 to novel structural and cell division functions of TSC2, which may provide additional explanations for the clinical and pathological manifestations of lymphangioleiomyomatosis (LAM) disease and TSC syndrome, including the greater clinical severity of TSC2 mutations compared to TSC1 mutations. C1 [Gomez-Baldo, Laia; Maxwell, Christopher A.; Capella, Gabriel; Angel Pujana, Miguel] Bellvitge Inst Biomed Res, Catalan Inst Oncol, Translat Res Lab, Barcelona, Spain. [Bonifaci, Nuria; Angel Pujana, Miguel] Bellvitge Inst Biomed Res, Catalan Inst Oncol, Bioinformat & Biostat Unit, Barcelona, Spain. [Schmidt, Stephan; Kletke, Anja; Piekorz, Roland P.] Univ Dusseldorf, Dept Biochem & Mol Biol 2, Dusseldorf, Germany. [Gabaldon, Toni] Ctr Genom Regulat, Bioinformat & Genom Program, Barcelona, Spain. [Vidalain, Pierre-Olivier] Inst Pasteur, Ctr Natl Rech Sci, Lab Genom Viral & Vaccinat, Paris, France. [Senapedis, William; Astrinidis, Aristotelis] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Rosing, Mechthild; Barnekow, Angelika] Univ Munster, Dept Expt Tumorbiol, Munster, Germany. [Rottapel, Robert] Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. [Vidal, Marc] Harvard Univ, Sch Med, CCSB, Boston, MA USA. [Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Astrinidis, Aristotelis] Drexel Univ, Dept Biochem & Mol Biol, Coll Med, Philadelphia, PA 19104 USA. RP Pujana, MA (reprint author), Bellvitge Inst Biomed Res, Catalan Inst Oncol, Translat Res Lab, Barcelona, Spain. EM aristotelis.astreinidis@drexelmed.edu; roland.piekorz@uniduesseldorf.de; mapujana@ico.scs.es RI Gabaldon, Toni/A-7336-2008; Astrinidis, Aristotelis/A-1396-2010; Maxwell, Christopher/B-3044-2011; pujana, Miguel Angel/N-3127-2014 OI Gabaldon, Toni/0000-0003-0019-1735; Maxwell, Christopher/0000-0002-0860-4031; pujana, Miguel Angel/0000-0003-3222-4044 NR 101 TC 24 Z9 25 U1 0 U2 9 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2010 VL 9 IS 6 BP 1143 EP 1155 PG 13 WC Cell Biology SC Cell Biology GA 569XT UT WOS:000275636900021 PM 20237422 ER PT J AU El Jamali, A Valente, AJ Clark, RA AF El Jamali, Amina Valente, Anthony J. Clark, Robert A. TI Regulation of phagocyte NADPH oxidase by hydrogen peroxide through a Ca2+/c-Abl signaling pathway SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE NADPH oxidase; NOX2; Neutrophil; Superoxide; Hydrogen peroxide; Signaling; c-Abl, Calcium; Free radicals ID ABL TYROSINE KINASE; NEUTROPHIL RESPIRATORY BURST; SMOOTH-MUSCLE-CELLS; C-DELTA; OXIDATIVE STRESS; GROWTH-FACTOR; HEMATOPOIETIC-CELLS; CALCIUM IONOPHORE; HUMAN MONOCYTES; MYC EXPRESSION AB The importance of H2O2 as a cellular signaling molecule has been demonstrated in a number of cell types and pathways. Here we explore a positive feedback mechanism of H2O2-mediated regulation of the phagocyte respiratory burst NADPH oxidase (NOX2). H2O2 induced a dose-dependent stimulation of superoxide production in human neutrophils, as well as in K562 leukemia cells overexpressing NOX2 system components. Stimulation was abrogated by the addition of catalase, the extracellular Ca2+ chelator BAPTA, the T-type Ca2+ channel inhibitor mibefradil, the PKC delta inhibitor rottlerin, or the c-Abl nonreceptor tyrosine kinase inhibitor imatinib mesylate or by overexpression of a dominant-negative form of c-Abl. H2O2 induced phosphorylation of tyrosine 311 on PKC delta and this activating phosphorylation was blocked by treatment with rottlerin, imatinib mesylate, or BAPTA. Rac GTPase activation in response to H2O2 was abrogated by BAPTA, imatinib mesylate, or rottlerin. In conclusion, H2O2 stimulates NOX2-mediated superoxide generation in neutrophils and K562/NOX2 cells via a signaling pathway involving Ca2+ influx and c-Abl tyrosine kinase acting upstream of PKC delta. This positive feedback regulatory pathway has important implications for amplifying the innate immune response and contributing to oxidative stress in inflammatory disorders. (c) 2009 Elsevier Inc. All rights reserved. C1 [El Jamali, Amina] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. RP El Jamali, A (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM AkoulouzeBik@uthscsa.edu FU National Institutes of Health [R01-Al020866, T32 HL07446, P30-CA054174, P30-AG013319, P01-AG019316]; Department of Veterans Affairs FX This work was supported by grants from the National Institutes of Health (R01-Al020866 and T32 HL07446) and the Department of Veterans Affairs. The confocal microscopy studies were performed in the University of Texas Health Science Center Institutional Optical Imaging Facility, which is supported by NIH Grants P30-CA054174 (Cancer Therapy and Research Center), P30-AG013319 (Nathan Shock Center), and P01-AG019316 (Aging, Oxidative Stress and Cell Death). The authors thank Alain Virion and Yves Gorin for helpful discussion and critical review of the manuscript, Victoria Frohlich for expert guidance on the confocal microscope image acquisition and analysis, John Cornell for insightful advice on statistical analysis, and Maria Gamez and Doran Pearson for expert technical assistance. Dr. Clark is a scientific cofounder member of the Scientific Advisory Board and equity holder in GenKyoTex SA, a Swiss biotechnology start-up company with a primary goal of developing clinically useful inhibitors of the NOX family of NADPH oxidases. No other competing financial interests exist. NR 62 TC 19 Z9 19 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR 15 PY 2010 VL 48 IS 6 BP 798 EP 810 DI 10.1016/j.freeradbiomed.2009.12.018 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 561WS UT WOS:000275011400006 PM 20043988 ER PT J AU Charest-Marcotte, A Dufour, CR Wilson, BJ Tremblay, AM Eichner, LJ Arlow, DH Mootha, VK Giguere, V AF Charest-Marcotte, Alexis Dufour, Catherine R. Wilson, Brian J. Tremblay, Annie M. Eichner, Lillian J. Arlow, Daniel H. Mootha, Vamsi K. Giguere, Vincent TI The homeobox protein Prox1 is a negative modulator of ERR alpha/PGC-1 alpha bioenergetic functions SO GENES & DEVELOPMENT LA English DT Article DE ChIP-on-chip; homeobox; mitochondrial respiration; nuclear receptor; regulon ID ERR-ALPHA; ENERGY HOMEOSTASIS; LIVER DEVELOPMENT; RECEPTOR-ALPHA; REQUIRES PROX1; COUP-TFII; GAMMA; GENE; TRANSCRIPTION; EXPRESSION AB Estrogen-related receptor alpha (ERR alpha) and proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. Here we identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERRa and PGC-1 alpha, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERR alpha/PGC-1 alpha complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERR alpha and other factors. Importantly, ablation of Prox1 and ERR alpha have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis. C1 [Charest-Marcotte, Alexis; Dufour, Catherine R.; Wilson, Brian J.; Tremblay, Annie M.; Eichner, Lillian J.; Giguere, Vincent] McGill Univ, Goodman Canc Ctr, Montreal, PQ H3A 1A3, Canada. [Charest-Marcotte, Alexis; Tremblay, Annie M.; Eichner, Lillian J.; Giguere, Vincent] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada. [Arlow, Daniel H.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Syst Biol, Cambridge, MA 02142 USA. [Arlow, Daniel H.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Cambridge, MA 02142 USA. [Arlow, Daniel H.; Mootha, Vamsi K.] MIT Harvard, Broad Inst, Cambridge, MA 02142 USA. [Giguere, Vincent] McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. [Giguere, Vincent] McGill Univ, Dept Oncol, Montreal, PQ H3G 1Y6, Canada. RP Giguere, V (reprint author), McGill Univ, Goodman Canc Ctr, Montreal, PQ H3A 1A3, Canada. EM vincent.giguere@mcgill.ca FU Canadian Institutes for Health Research [MOP-84227, MOP-77763]; American Diabetes Association/Smith Family Foundation FX We thank Carlo Ouellet for skillful technical assistance and Dr. Julie St- Pierre for careful reading of the manuscript. This work was supported by grants from the Canadian Institutes for Health Research (MOP-84227 and MOP-77763) and the American Diabetes Association/Smith Family Foundation. NR 25 TC 57 Z9 58 U1 2 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAR 15 PY 2010 VL 24 IS 6 BP 537 EP 542 DI 10.1101/gad.1871610 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 569LU UT WOS:000275599400003 PM 20194433 ER PT J AU Kirsch, DG Grimm, J Guimaraes, AR Wojtkiewicz, GR Perez, BA Santiago, PM Anthony, NK Forbes, T Doppke, K Weissleder, R Jacks, T AF Kirsch, David G. Grimm, Jan Guimaraes, Alexander R. Wojtkiewicz, Gregory R. Perez, Bradford A. Santiago, Philip M. Anthony, Nikolas K. Forbes, Thomas Doppke, Karen Weissleder, Ralph Jacks, Tyler TI IMAGING PRIMARY LUNG CANCERS IN MICE TO STUDY RADIATION BIOLOGY SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Genetically engineered mouse models of cancer; Lung cancer; Micro computed tomography; K-Ras; p53 ID RADIOTHERAPY; EXPRESSION AB Purpose: To image a genetically engineered mouse model of non small-cell lung cancer with micro computed tomography (micro-CT) to measure tumor response to radiation therapy. Methods and Materials: The Cre-loxP system was used to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT, and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT. Results: The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers fivefold. Conclusions: Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer. (C) 2010 Elsevier Inc. C1 [Kirsch, David G.; Perez, Bradford A.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27708 USA. [Kirsch, David G.; Perez, Bradford A.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27708 USA. [Kirsch, David G.; Santiago, Philip M.; Jacks, Tyler] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Kirsch, David G.; Anthony, Nikolas K.; Forbes, Thomas; Doppke, Karen] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Grimm, Jan; Guimaraes, Alexander R.; Wojtkiewicz, Gregory R.] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. [Grimm, Jan; Guimaraes, Alexander R.; Wojtkiewicz, Gregory R.] Harvard Univ, Sch Med, Charlestown, MA USA. [Grimm, Jan] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Guimaraes, Alexander R.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Guimaraes, Alexander R.; Weissleder, Ralph] Harvard Univ, Sch Med, Boston, MA USA. [Guimaraes, Alexander R.; Weissleder, Ralph] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Jacks, Tyler] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Kirsch, DG (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, Box 91006, Durham, NC 27708 USA. EM david.kirsch@duke.edu RI Grimm, Jan/B-1937-2008 FU Howard Hughes Medical Institute; American Cancer Society Institutional Research [K08 CA 114176, P50 CA86355, R24 CA92782, U24 CA 092782]; NCI [5-U01-CA84306, P30-CA14051]; RSNA FX Supported by the Howard Hughes Medical Institute (Ti., B.A.P.), American Cancer Society Institutional Research Grant, K08 CA 114176 (D.G.K.), P50 CA86355 (D.G.K., R.W.), R24 CA92782 (R.W.), U24 CA 092782 (R.W., Ti.), NCI grant 5-U01-CA84306 (T.J.), partially by Cancer Center Support (core) grant P30-CA14051 from the NCI (Ti.) and by a medical student seed grant from the RSNA (B.A.P.). Dr. Jacks is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. NR 14 TC 28 Z9 28 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2010 VL 76 IS 4 BP 973 EP 977 DI 10.1016/j.ijrobp.2009.11.038 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 573OO UT WOS:000275923900002 PM 20206017 ER PT J AU Mutyala, S Stewart, A Khan, AJ Cormack, RA O'Farrell, D Sugarbaker, D Devlin, PM AF Mutyala, Subhakar Stewart, Alexandra Khan, Atif J. Cormack, Robert A. O'Farrell, Desmond Sugarbaker, David Devlin, Phillip M. TI PERMANENT IODINE-125 INTERSTITIAL PLANAR SEED BRACHYTHERAPY FOR CLOSE OR POSITIVE MARGINS FOR THORACIC MALIGNANCIES SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Thoracic tumors; Mediastinal tumors; Thoracic surgery; Brachytherapy seed implant; Lung brachytherapy ID LUNG; CANCER; CARCINOMA; TUMORS; TRIAL; JAPAN AB Purpose: To assess toxicity and outcome following permanent iodine-125 seed implant as an adjunct to surgical resection in cases of advanced thoracic malignancy. Methods and Materials: An institutional review board-approved retrospective review was performed. Fifty-nine patients were identified as having undergone thoracic brachytherapy seed implantation between September 1999 and December 2006. Data for patient demographics, tumor details, and morbidity and mortality were recorded. Results: Fifty-nine patients received 64 implants. At a median follow-up of 17 months, 1-year and 2-year Kaplan-Meier rates of estimated overall survival were 94.1% and 82.0%, respectively. The 1-year and 2-year local control rates were 80.1% and 67.4%, respectively. The median time to develop local recurrence was 11 months. Grades 3 and 4 toxicity rates were 12% at 1 year. Conclusions: This review shows relatively low toxicity for interstitial planar seed implantation after thoracic surgical resection. The high local control results suggest that an incomplete oncologic surgery plus a brachytherapy implant for treating advanced thoracic malignancy merit further investigation. (C) 2010 Elsevier Inc. C1 [Mutyala, Subhakar] Montefiore Med Ctr, Dept Radiat Oncol, New York, NY USA. [Mutyala, Subhakar] Albert Einstein Coll Med Bronx, New York, NY USA. [Stewart, Alexandra] Royal Surrey Cty Hosp, St Lukes Canc Ctr, Guildford, Surrey, England. [Khan, Atif J.] Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ USA. [Cormack, Robert A.; O'Farrell, Desmond; Devlin, Phillip M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Radiat Oncol, Boston, MA 02115 USA. [Sugarbaker, David] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Thorac Surg, Boston, MA 02115 USA. RP Mutyala, S (reprint author), Montefiore Med Ctr, Dept Radiat Oncol, 1625 Poplar St, Bronx, NY 10461 USA. EM smutyala@montefiore.org OI Cormack, Robert/0000-0001-5553-9984; Khan, Atif/0000-0001-8640-8530 NR 15 TC 18 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2010 VL 76 IS 4 BP 1114 EP 1120 DI 10.1016/j.ijrobp.2009.02.067 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 573OO UT WOS:000275923900022 PM 19540065 ER PT J AU Nanda, A Chen, MH D'Amico, AV AF Nanda, Akash Chen, Ming-Hui D'Amico, Anthony V. TI RESPONSE TO "PREDICTORS OF PROSTATE CANCER-SPECIFIC MORTALITY IN ELDERLY MEN WITH INTERMEDIATE-RISK PROSTATE CANCER TREATED WITH BRACHYTHERAPY WITH OR WITHOUT EXTERNAL BEAM RADIATION THERAPY" (INT J RADIAT ONCOL BIOL PHYS 2009, IN PRESS) IN REPLY SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter C1 [Nanda, Akash] Brigham & Womens Hosp, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nanda, A (reprint author), Brigham & Womens Hosp, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2010 VL 76 IS 4 BP 1275 EP 1275 DI 10.1016/j.ijrobp.2009.11.051 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 573OO UT WOS:000275923900045 ER PT J AU Zolopa, AR Berger, DS Lampiris, H Zhong, LJ Chuck, SL Enejosa, JV Kearney, BP Cheng, AK AF Zolopa, Andrew R. Berger, Daniel S. Lampiris, Harry Zhong, Lijie Chuck, Steven L. Enejosa, Jeffrey V. Kearney, Brian P. Cheng, Andrew K. TI Activity of Elvitegravir, a Once-Daily Integrase Inhibitor, against Resistant HIV Type 1: Results of a Phase 2, Randomized, Controlled, Dose-Ranging Clinical Trial SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; EXPERIENCED HIV-1-INFECTED PATIENTS; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; TMC125 ETRAVIRINE; RALTEGRAVIR; INFECTION; EFFICACY; SAFETY; RITONAVIR AB Background. This phase 2, randomized, active-controlled, 48-week study assessed the noninferiority of the human immunodeficiency virus (HIV) integrase inhibitor elvitegravir to comparator ritonavir-boosted protease inhibitor (CPI/r) in treatment-experienced subjects. Methods. Subjects had HIV RNA levels >= 1000 copies/mL and >= 1 protease resistance mutation. Subjects received nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs) with or without T-20 and either CPI/r or once- daily elvitegravir at a dose of 20 mg, 50 mg, or 125 mg (blinded to dose) with ritonavir. After week 8, the independent data monitoring committee stopped the elvitegravir 20 mg arm and allowed subjects in the elvitegravir 50 mg and 125 mg arms to add protease inhibitors. The primary end point was the time-weighted average change from baseline in HIV RNA level through week 24 (DAVG(24)). Results. A total of 278 subjects with a median of 11 protease and 3 thymidine analog mutations were randomized and treated. One-half of subjects received NRTIs without expected antiviral activity. Compared with the DAVG(24) for the CPI/r arm (-1.19 log(10) copies/mL), the elvitegravir 50 mg arm was noninferior (-1.44 log(10) copies/mL), and the elvitegravir 125 mg arm was superior (-1.66 log(10) copies/mL; P = . 021). Efficacy was impacted by activity of background agents. There was no relationship between elvitegravir dosage and adverse events. Conclusions. Elvitegravir was well-tolerated and produced rapid virologic suppression that was durable with active background therapy. C1 [Zolopa, Andrew R.] Stanford Univ, Div Infect Dis & Geog Med, Stanford, CA 94305 USA. [Lampiris, Harry] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lampiris, Harry] San Francisco VA Med Ctr, San Francisco, CA USA. [Zhong, Lijie; Chuck, Steven L.; Enejosa, Jeffrey V.; Kearney, Brian P.; Cheng, Andrew K.] Gilead Sci Inc, Foster City, CA 94404 USA. [Berger, Daniel S.] Northstar Med Ctr, Chicago, IL USA. RP Zolopa, AR (reprint author), Stanford Univ, Div Infect Dis & Geog Med, 300 Pasteur Dr,Rm S-156,Grant Bldg, Stanford, CA 94305 USA. EM azolopa@stanford.edu FU Gilead Sciences FX Potential conflicts of interest: A.Z. has received grant support from Gilead Sciences and is on the National Advisory Board for Gilead Sciences; D.B. has received compensation for conducting clinical trials sponsored by Gilead Sciences and is a stockholder; H.L. has received grant support from Gilead Sciences; L.Z., S.C., J.E., B.K., and A.C. are employees and stockholders of Gilead Sciences.; Financial support: Gilead Sciences. NR 14 TC 80 Z9 81 U1 0 U2 4 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 MAR 15 PY 2010 VL 201 IS 6 BP 814 EP 822 DI 10.1086/650698 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 557JH UT WOS:000274664900004 PM 20146631 ER PT J AU Kovacs, A Karim, R Mack, WJ Xu, JA Chen, Z Operskalski, E Frederick, T Landay, A Voris, J Spencer, L Young, MA Tien, PC Augenbraun, M Strickler, HD Al-Harthi, L AF Kovacs, Andrea Karim, Roksana Mack, Wendy J. Xu, Jiaao Chen, Zhi Operskalski, Eva Frederick, Toni Landay, Alan Voris, John Spencer, La Shonda Young, Mary A. Tien, Phyllis C. Augenbraun, Michael Strickler, Howard D. Al-Harthi, Lena TI Activation of CD8 T Cells Predicts Progression of HIV Infection in Women Coinfected with Hepatitis C Virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CENTRAL-NERVOUS-SYSTEM; IMMUNE ACTIVATION; DISEASE PROGRESSION; MICROBIAL TRANSLOCATION; LYMPHOCYTE-ACTIVATION; CLINICAL PROGRESSION; BACTERIAL PNEUMONIA; VIRAL LOAD AB Background. Because activation of T cells is associated with human immunodeficiency virus (HIV) pathogenesis, CD4 and CD8 activation levels in patients coinfected with HIV and hepatitis C virus (HCV) may explain conflicting reports regarding effects of HCV on HIV disease progression. Methods. Kaplan-Meier and multivariate Cox regression models were used to study the risk of incident clinical AIDS and AIDS-related deaths among 813 HCV-negative women with HIV infection, 87 HCV-positive nonviremic women with HIV coinfection, and 407 HCV-positive viremic women with HIV coinfection (median follow-up time, 5.2 years). For 592 women, the percentages of activated CD4 and CD8 T cells expressing HLA-DR (DR) and/or CD38 were evaluated. Results. HCV-positive viremic women had a statistically significantly higher percentage of activated CD8 T cells (P<.001) and a statistically significantly higher incidence of AIDS compared with HCV-negative women (P<.001 [log-rank test]). The AIDS risk was greater among HCV-positive viremic women in the highest tertile compared with the lowest tertile (>43% vs <26%) of CD8(+)CD38(+)DR(+) T cells (hazard ratio, 2.94 [95% confidence interval, 1.50-5.77]; P<.001). This difference was not observed in the HCV-negative women (hazard ratio, 1.87 [95% confidence interval, 0.80-4.35]; P = .16). In contrast, CD4 activation predicted AIDS in both groups similarly. Increased percentages of CD8(+)CD38(-)DR(+), CD4(+)CD38(-)DR(-), and CD8(+)CD38(-)DR(-) T cells were associated with a 160% decreased risk of AIDS for HCV-positive viremic women and HCV-negative women. Conclusion. HCV-positive viremic women with HIV coinfection who have high levels of T cell activation may have increased risk of AIDS. Earlier treatment of HIV and HCV infection may be beneficial. C1 [Kovacs, Andrea] Univ So Calif, Maternal Child & Adolescent Ctr Infect Dis & Viro, Keck Sch Med, HRA 300, Los Angeles, CA 90033 USA. [Karim, Roksana; Mack, Wendy J.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90033 USA. [Tien, Phyllis C.; Al-Harthi, Lena] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Tien, Phyllis C.; Al-Harthi, Lena] San Francisco VA Med Ctr, San Francisco, CA USA. [Landay, Alan; Voris, John] Rush Univ, Dept Immunol & Microbiol, Med Ctr, Chicago, IL 60612 USA. [Young, Mary A.] Georgetown Univ, Div Infect Dis, Washington, DC USA. [Augenbraun, Michael] Suny Downstate Coll Med, Dept Med, Brooklyn, NY USA. [Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Kovacs, A (reprint author), Univ So Calif, Maternal Child & Adolescent Ctr Infect Dis & Viro, Keck Sch Med, HRA 300, 1640 Marengo St, Los Angeles, CA 90033 USA. EM akovacs@usc.edu FU National Institute of Allergy and Infectious Diseases [R01-A1052065-04, R01-AI057006]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01-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]; [U01-AI-35004]; [U01-AI-31834]; [U01-AI-34994]; [U01-AI-34989]; [U01-AI-34993]; [U01-AI-42590]; [K23 AI-66943] FX Financial support: National Institute of Allergy and Infectious Diseases (grant R01-A1052065-04 to A. K.; grant R01-AI057006 to H. S.; grants U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, and U01-AI-42590 to the Women's Interagency HIV Study [WIHS]; and grant K23 AI-66943 to P. C. T.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant U01-HD-32632 to the WIHS); National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI grant UL1 RR024131). NR 50 TC 46 Z9 48 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 MAR 15 PY 2010 VL 201 IS 6 BP 823 EP 834 DI 10.1086/650997 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 557JH UT WOS:000274664900005 PM 20151840 ER PT J AU Singh, A Ye, M Bucur, O Zhu, SD Santos, MT Rabinovitz, I Wei, WY Gao, DM Hahn, WC Khosravi-Far, R AF Singh, Amrik Ye, Min Bucur, Octavian Zhu, Shudong Santos, Maria Tanya Rabinovitz, Isaac Wei, Wenyi Gao, Daming Hahn, William C. Khosravi-Far, Roya TI Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; PROMOTES TUMORIGENESIS; NUCLEAR EXCLUSION; SURVIVAL SIGNALS; KINASE B; PHOSPHORYLATION; PP2A; INHIBITION; APOPTOSIS; FAMILY AB Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, the role of protein phosphatases (PP) in the control of FOXO3a subcellular localization and function is unknown. In this study, we detected a robust interaction between FOXO3a and PP2A. We further demonstrate that 14-3-3, while not impeding the interaction between PP2A and FOXO3a, restrains its activity toward AKT phosphorylation sites T32/S253. Disruption of PP2A function revealed that after AKT inhibition, PP2A-mediated dephosphorylation of T32/S253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of FOXO3a. Our findings reveal that distinct phosphatases dephosphorylate conserved AKT motifs within the FOXO family and that PP2A is entwined in a dynamic interplay with AKT and 14-3-3 to directly regulate FOXO3a subcellular localization and transcriptional activation. C1 [Singh, Amrik; Ye, Min; Bucur, Octavian; Zhu, Shudong; Santos, Maria Tanya; Rabinovitz, Isaac; Wei, Wenyi; Gao, Daming; Khosravi-Far, Roya] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Singh, Amrik; Ye, Min; Bucur, Octavian; Zhu, Shudong; Santos, Maria Tanya; Rabinovitz, Isaac; Wei, Wenyi; Gao, Daming; Khosravi-Far, Roya] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Hahn, William C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hahn, William C.] MIT, Cambridge, MA 02142 USA. [Hahn, William C.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. RP Khosravi-Far, R (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM rkhosrav@bidmc.harvard.edu RI Bucur, Octavian/G-2823-2010 OI Bucur, Octavian/0000-0002-8501-588X FU U.S. Public Health Service [CA131664, CA105306, 2-T32-HL07623-22, 5-F32-CA132365-02]; Lady Tata Memorial Trust FX We thank Joseph Avruch (Massachusetts General Hospital/Harvard Medical School), Azad Bonni (Harvard Medical School), Boudewijn Burgering (University Medical Center Utrecht), James Griffin (Dana Farber Cancer Institute/Harvard Medical School), Kun-Liang Guan (University of California, San Diego Medical Center), Marc Mumby (University of Texas Southwestern Medical Center), and William Sellers (Novartis Institutes for BioMedical Research) for reagents. We are grateful to Jack Lawler and Susan Glueck for critical reading of the manuscript. This work was supported by U.S. Public Health Service grants CA131664 and CA105306 (to R. K.), 2-T32-HL07623-22 and 5-F32-CA132365-02 (to A. S.), and a Lady Tata Memorial Trust Award (to O. B.). NR 41 TC 45 Z9 46 U1 2 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 15 PY 2010 VL 21 IS 6 BP 1140 EP 1152 DI 10.1091/mbc.E09-09-0795 PG 13 WC Cell Biology SC Cell Biology GA 567GQ UT WOS:000275433500026 PM 20110348 ER PT J AU Nelson, KP Edwards, D AF Nelson, Kerrie P. Edwards, Don TI Improving the reliability of diagnostic tests in population-based agreement studies SO STATISTICS IN MEDICINE LA English DT Article DE agreement, model-based kappa, Cohen's kappa; intraclass kappa, generalized linear mixed model; crossed random effects ID INTERRATER AGREEMENT; MAMMOGRAPHY; KAPPA; MODEL; VARIABILITY; CLASSIFICATIONS; ASSOCIATION; PERFORMANCE; CARCINOMA; RATINGS AB Many large-scale studies have recently been carried out to assess the reliability of diagnostic procedures, such as mammography for the detection of breast cancer. The large numbers of raters and subjects involved raise new challenges in how to measure agreement in these types of studies. An important motivator of these studies is the identification of factors that contribute to the often wide discrepancies observed between raters' classifications, such as a rater's experience, in order to improve the reliability of the diagnostic process of interest. Incorporating covariate information into the agreement model is a key component in addressing these questions. Few agreement models are currently available that jointly model larger numbers of raters and subjects and incorporate covariate information. In this paper, we extend a recently developed population-based model and measure of agreement for binary ratings to incorporate covariate information using the class of generalized linear mixed models with a probit link function. Important information on factors related to the subjects and raters can be included as fixed and/or random effects in the model. We demonstrate how agreement can be assessed between subgroups of the raters and/or subjects, for example, comparing agreement between experienced and less experienced raters. Simulation studies are carried out to test the performance of the proposed models and measures of agreement. Application to a large-scale breast cancer study is presented. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Nelson, Kerrie P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nelson, Kerrie P.] Harvard Univ, Sch Med, Ctr Biostat, Boston, MA 02114 USA. [Edwards, Don] Univ S Carolina, Dept Stat, Columbia, SC 29208 USA. RP Nelson, KP (reprint author), Massachusetts Gen Hosp, 50 Staniford St,Suite 560, Boston, MA 02114 USA. FU United States' Institutes of Health [R03CA114783-01A1] FX Contract/grant sponsor United States' Institutes of Health, contract/grant number R03CA114783-01A1 NR 34 TC 1 Z9 1 U1 4 U2 11 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 MAR 15 PY 2010 VL 29 IS 6 BP 617 EP 626 DI 10.1002/sim.3819 PG 10 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 570PW UT WOS:000275691200001 PM 20128018 ER PT J AU Reszka, N Zhou, CH Song, B Sodroski, JG Knipe, DM AF Reszka, Natalia Zhou, Changhong Song, Byeongwoon Sodroski, Joseph G. Knipe, David M. TI Simian TRIM5 alpha proteins reduce replication of herpes simplex virus SO VIROLOGY LA English DT Article DE HSV; TRIM5; Restriction ID PML NUCLEAR-BODIES; PROMYELOCYTIC LEUKEMIA PROTEIN; INFECTED-CELL PROTEIN-0; IMMUNODEFICIENCY-VIRUS; RETROVIRAL RESTRICTION; ANTIVIRAL DEFENSE; VIRAL REPLICATION; BINDING PROTEIN; AIDS VACCINE; MONKEY CELLS AB Old World monkey TRIM5 alpha proteins are known to block the replication of human immunodeficiency virus and other retroviruses in a species-specific fashion. In this report, we show that specific forms of simian TRIM5 alpha proteins can restrict herpes simplex virus (HSV) infection. To define the effect of TRIM5 alpha on HSV replication, we examined HSV infection in HeLa cell lines that stably express simian and human orthologs of TRIM5 alpha proteins. We demonstrated that several simian TRIM5 alpha proteins can restrict HSV replication, with the TRIM5a protein of rhesus macaques showing the strongest inhibition of HSV infection. We also found that the level of the inhibition of virus replication was viral strain-specific. TRIM5 alpha is likely to inhibit HSV at the early stage of infection; however, at later times of infection, the levels of TRIM5 alpha are significantly decreased. Thus, some TRIM5 alpha proteins exhibit antiviral effects that extend beyond retroviral infections, but HSV may be able to reduce this restriction by reducing TRIM5 alpha levels during the later phases of virus replication. Our results also argue that TRIM5 alpha is only part of the reduced level of HSV replication in rhesus macaques, which are known to be less susceptible to HSV infection than other primates. (C) 2009 Elsevier Inc. All rights reserved. C1 [Reszka, Natalia; Zhou, Changhong; Knipe, David M.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Song, Byeongwoon; Sodroski, Joseph G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Div AIDS, Boston, MA 02115 USA. RP Knipe, DM (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. EM david_knipe@hms.harvard.edu FU NIH HIVRAD [AI46006]; NIH [AI63987] FX We thank Anna Cliffe for comments on the manuscript. This research was supported by NIH HIVRAD grant AI46006 (DMK) and NIH grant AI63987 (JS). NR 57 TC 6 Z9 6 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2010 VL 398 IS 2 BP 243 EP 250 DI 10.1016/j.virol.2009.11.041 PG 8 WC Virology SC Virology GA 557KZ UT WOS:000274669300012 PM 20060996 ER PT J AU Kennerson, ML Nicholson, GA Kaler, SG Kowalski, B Mercer, JFB Tang, JR Llanos, RM Chu, SN Takata, RI Speck-Martins, CE Baets, J Almeida-Souza, L Fischer, D Timmerman, V Taylor, PE Scherer, SS Ferguson, TA Bird, TD De Jonghe, P Feely, SME Shy, ME Garbern, JY AF Kennerson, Marina L. Nicholson, Garth A. Kaler, Stephen G. Kowalski, Bartosz Mercer, Julian F. B. Tang, Jingrong Llanos, Roxana M. Chu, Shannon Takata, Reinaldo I. Speck-Martins, Carlos E. Baets, Jonathan Almeida-Souza, Leonardo Fischer, Dirk Timmerman, Vincent Taylor, Philip E. Scherer, Steven S. Ferguson, Toby A. Bird, Thomas D. De Jonghe, Peter Feely, Shawna M. E. Shy, Michael E. Garbern, James Y. TI Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SPINAL MUSCULAR-ATROPHY; OCCIPITAL-HORN-SYNDROME; MARIE-TOOTH-DISEASE; MENKES-DISEASE; NEURON DISEASE; CANDIDATE GENE; DEFICIENCY MYELONEUROPATHY; WILSON-DISEASE; PROTEIN; TRAFFICKING AB Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T9941) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function. C1 [Kennerson, Marina L.; Nicholson, Garth A.; Kowalski, Bartosz; Chu, Shannon] Univ Sydney, ANZAC Res Inst, Northcott Neurosci Lab, Concord, Australia. [Kennerson, Marina L.; Nicholson, Garth A.] Concord Hosp, Mol Med Lab, Concord, Australia. [Kaler, Stephen G.; Tang, Jingrong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bethesda, MD USA. [Mercer, Julian F. B.; Llanos, Roxana M.; Taylor, Philip E.] Deakin Univ, Sch Life & Environm Sci, Ctr Cellular & Mol Biol, Burwood, Australia. [Takata, Reinaldo I.; Speck-Martins, Carlos E.] Sarah Network Rehabil Hosp, Brasilia, DF, Brazil. [Baets, Jonathan; Almeida-Souza, Leonardo; Timmerman, Vincent; De Jonghe, Peter] Flanders Inst Biotechnol, Dept Mol Genet, Antwerp, Belgium. [Baets, Jonathan; Almeida-Souza, Leonardo; Timmerman, Vincent; De Jonghe, Peter] Univ Antwerp, B-2020 Antwerp, Belgium. [Fischer, Dirk] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Fischer, Dirk] Univ Childrens Hosp Basel, Dept Neuropediat, Basel, Switzerland. [Scherer, Steven S.; Ferguson, Toby A.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Bird, Thomas D.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Bird, Thomas D.] Univ Washington, Sch Med, Dept Med Genet, Seattle, WA USA. [Bird, Thomas D.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Feely, Shawna M. E.; Shy, Michael E.; Garbern, James Y.] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Feely, Shawna M. E.; Shy, Michael E.; Garbern, James Y.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Kennerson, ML (reprint author), Univ Sydney, ANZAC Res Inst, Northcott Neurosci Lab, Concord, Australia. EM marinak@anzac.edu.au RI Almeida-Souza, Leonardo/C-3437-2011; Kennerson, Marina/B-5058-2014 FU Motor Neuron Disease Research Institute of Australia; National Health and Medical Research Council of Australia; Intramural Research program of the National Institute of Child Health and Human Development; Methusalem project of the University of Antwerp; Fund for Scientific Research (FWO-Flanders); Medical Foundation Queen Elisabeth (GSKE); Interuniversity Attraction Poles program [P6/43]; Belgian Federal Science Policy Office (BELSPO) FX We thank the patients and family members for their participation in this study. We thank Rabia Chaudhry and Alison Blake for their assistance with Cell Cultures and Jose Centeno for fibroblast copper measurements. This work was supported by grants from the Motor Neuron Disease Research Institute of Australia, the National Health and Medical Research Council of Australia, the Intramural Research program of the National Institute of Child Health and Human Development, the Methusalem project of the University of Antwerp, the Fund for Scientific Research (FWO-Flanders), the Medical Foundation Queen Elisabeth (GSKE), and the Interuniversity Attraction Poles program (P6/43) of the Belgian Federal Science Policy Office (BELSPO). J.B. and L.S. are Supported by PhD fellowships of the FWO-Flanders and the University of Antwerp, respectively. We thank Professor David Handelsman for his useful constructive comments on the manuscript. NR 47 TC 79 Z9 81 U1 0 U2 4 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 MAR 12 PY 2010 VL 86 IS 3 BP 343 EP 352 DI 10.1016/j.ajhg.2010.01.027 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 570LG UT WOS:000275678800006 PM 20170900 ER PT J AU Hu, W Xu, RJ Sun, W Szulc, ZM Bielawski, J Obeid, LM Mao, CG AF Hu, Wei Xu, Ruijuan Sun, Wei Szulc, Zdzislaw M. Bielawski, Jacek Obeid, Lina M. Mao, Cungui TI Alkaline Ceramidase 3 (ACER3) Hydrolyzes Unsaturated Long-chain Ceramides, and Its Down-regulation Inhibits Both Cell Proliferation and Apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; MOLECULAR-CLONING; ACID CERAMIDASE; FUNCTIONAL-CHARACTERIZATION; MITOCHONDRIAL CERAMIDASE; SACCHAROMYCES-CEREVISIAE; FARBER-DISEASE; CANCER CELLS; SPHINGOSINE; GENERATION AB Ceramides with different fatty acyl chains may vary in their physiological or pathological roles; however, it remains unclear how cellular levels of individual ceramide species are regulated. Here, we demonstrate that our previously cloned human alkaline ceramidase 3 (ACER3) specifically controls the hydrolysis of ceramides carrying unsaturated long acyl chains, unsaturated long-chain (ULC) ceramides. In vitro, ACER3 only hydrolyzed C(18:1)-, C(20:1)-, C(20:4)-ceramides, dihydroceramides, and phytoceramides. In cells, ACER3 overexpression decreased C(18:1)- and C(20:1)-ceramides and dihydroceramides, whereas ACER3 knockdown by RNA interference had the opposite effect, suggesting that ACER3 controls the catabolism of ULC ceramides and dihydroceramides. ACER3 knockdown inhibited cell proliferation and up-regulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1). Blocking p21(CIP1/WAF1) up-regulation attenuated the inhibitory effect of ACER3 knockdown on cell proliferation, suggesting that ACER3 knockdown inhibits cell proliferation because of p21(CIP1/WAF1) up-regulation. ACER3 knockdown inhibited cell apoptosis in response to serum deprivation. ACER3 knockdown up-regulated the expression of the alkaline ceramidase 2 (ACER2), and the ACER2 up-regulation decreased non-ULC ceramide species while increasing both sphingosine and its phosphate. Collectively, these data suggest that ACER3 catalyzes the hydrolysis of ULC ceramides and dihydroceramides and that ACER3 coordinates with ACER2 to regulate cell proliferation and survival. C1 [Mao, Cungui] Med Univ S Carolina, Div Gen Internal Med, Dept Med, Charleston, SC 29425 USA. [Szulc, Zdzislaw M.; Bielawski, Jacek; Obeid, Lina M.; Mao, Cungui] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Obeid, Lina M.] Ralph H Johnson Vet Affairs Hosp, Charleston, SC 29425 USA. RP Mao, CG (reprint author), Med Univ S Carolina, Div Gen Internal Med, Dept Med, 114 Doughty St,Rm 646,STB,POB 250779, Charleston, SC 29425 USA. EM maoc@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [P20RR017677, R01CA104834, R01GM062887]; Veterans Affairs Merit award FX This work was supported, in whole or in part, by National Institutes of Health Grants P20RR017677 (to C.M.), R01CA104834 (to C.M.), and R01GM062887 (to L.M.O.). This work was also supported by a Veterans Affairs Merit award (to L.M.O.). NR 42 TC 31 Z9 31 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 12 PY 2010 VL 285 IS 11 BP 7964 EP 7976 DI 10.1074/jbc.M109.063586 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AE UT WOS:000275413800014 PM 20068046 ER PT J AU Zlotoff, DA Sambandam, A Logan, TD Bell, JJ Schwarz, BA Bhandoola, A AF Zlotoff, Daniel A. Sambandam, Arivazhagan Logan, Theodore D. Bell, J. Jeremiah Schwarz, Benjamin A. Bhandoola, Avinash TI CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus SO BLOOD LA English DT Article ID T-CELL DEVELOPMENT; COMMON LYMPHOID PROGENITORS; MOUSE BONE-MARROW; STEM-CELLS; LINEAGE COMMITMENT; UP-REGULATION; PRECURSORS; IDENTIFICATION; EXPRESSION; BLOOD AB T lymphopoiesis requires settling of the thymus by bone marrow-derived precursors throughout adult life. Progenitor entry into the thymus is selective, but the molecular basis of this selectivity is incompletely understood. The chemokine receptor CCR9 has been demonstrated to be important in this process. However, progenitors lacking CCR9 can still enter the thymus, suggesting a role for additional molecules. Here we report that the chemokine receptor CCR7 is also required for efficient thymic settling. CCR7 is selectively expressed on bone marrow progenitors previously shown to have the capacity to settle the thymus, and CCR7(-/-) progenitors are defective in settling the thymus. We further demonstrate that CCR7 sustains thymic settling in the absence of CCR9. Mice deficient for both CCR7 and CCR9 have severe reductions in the number of early thymic progenitors, and in competitive assays CCR7(-/-) CCR9(-/-) double knockout progenitors are almost completely restricted from thymic settling. However, these mice possess near-normal thymic cellularity. Compensatory expansion of intrathymic populations can account for at least a part of this recovery. Together our results illustrate the critical role of chemokine receptor signaling in thymic settling and help to clarify the cellular identity of the physiologic thymic settling progenitors. (Blood. 2010; 115: 1897-1905) C1 [Zlotoff, Daniel A.; Logan, Theodore D.; Bell, J. Jeremiah; Bhandoola, Avinash] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Sambandam, Arivazhagan] Genentech Inc, San Francisco, CA 94080 USA. [Schwarz, Benjamin A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Bhandoola, A (reprint author), 266 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM bhandooa@mail.med.upenn.edu FU NIH [AI080091, AI059621, HL086900, RC1HL099758]; Leukemia & Lymphoma Society FX This work was supported by NIH grants AI080091 (J.J.B.), AI059621, HL086900, and RC1HL099758 (A. B.), and a Scholar Award from the Leukemia & Lymphoma Society (A. B.). NR 50 TC 99 Z9 100 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 MAR 11 PY 2010 VL 115 IS 10 BP 1897 EP 1905 DI 10.1182/blood-2009-08-237784 PG 9 WC Hematology SC Hematology GA 571KS UT WOS:000275751300011 PM 19965655 ER PT J AU Hasserjian, RP Zuo, Z Garcia, C Tang, GL Kasyan, A Luthra, R Abruzzo, LV Kantarjian, HM Medeiros, LJ Wang, SA AF Hasserjian, Robert P. Zuo, Zhuang Garcia, Christine Tang, Guilin Kasyan, Armen Luthra, Rajyalakshmi Abruzzo, Lynne V. Kantarjian, Hagop M. Medeiros, L. Jeffrey Wang, Sa A. TI Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MYELODYSPLASTIC SYNDROMES; ACUTE ERYTHROLEUKEMIA; REFRACTORY-ANEMIA; BONE-MARROW; BLASTS; RECLASSIFICATION; PROPOSALS; MUTATIONS; PROGNOSIS AB Acute erythroid leukemia (AEL) is a rare type of acute myeloid leukemia (AML) for which diagnostic criteria have been refined in the 2008 World Health Organization (WHO) classification of AML. The relationship of AEL to myelodysplastic syndromes (MDSs) and to AML with myelodysplasia-related changes (AMLMRC) is not clearly defined. We conducted a retrospective, multi-institutional study of patients with AEL and compared them with patients with MDS or AML-MRC with erythroid hyperplasia (>= 50% erythroid cells). Among a total of 124 patients with AEL, 32% had a history of MDS or chronic cytopenia, 32% had therapy-related disease, and 35% had de novo disease. Sixty-four percent of patients had unfavorable AML risk-group karyotypes. FLT3 and RAS mutations were infrequent, occurring in 6% and 2%, respectively. The median overall survival (OS) of all AEL patients was 8 months, comparable with that of patients with MDS or AML-MRC with erythroid hyperplasia. The OS was related to cytogenetic risk group, but not blast count or morphologic dysplasia. Our findings suggest that AEL is in the continuum of MDS and AML with erythroid hyperplasia, where karyotype rather than an arbitrary blast cutoff represents the most important prognostic factor. (Blood. 2010; 115: 1985-1992) C1 [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zuo, Zhuang; Kasyan, Armen; Luthra, Rajyalakshmi; Abruzzo, Lynne V.; Medeiros, L. Jeffrey; Wang, Sa A.] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Garcia, Christine] Univ Pittsburgh, Sch Med, Dept Pathol, Div Hematopathol, Pittsburgh, PA 15260 USA. [Tang, Guilin] Univ Massachusetts, Mem Med Ctr, Dept Pathol, Worcester, MA 01605 USA. [Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, Dept Hematol, Houston, TX 77030 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM rhasserjian@partners.org FU National Center for Research Resources (NCRR) [UL1 RR024153]; National Institutes of Health (NIH); NIH Roadmap for Medical Research FX This publication was made possible by grant no. UL1 RR024153 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. NR 26 TC 48 Z9 50 U1 0 U2 7 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 MAR 11 PY 2010 VL 115 IS 10 BP 1985 EP 1992 DI 10.1182/blood-2009-09-243964 PG 8 WC Hematology SC Hematology GA 571KS UT WOS:000275751300021 PM 20040759 ER PT J AU Virgin, HW Walker, BD AF Virgin, Herbert W. Walker, Bruce D. TI Immunology and the elusive AIDS vaccine SO NATURE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CHRONIC VIRAL-INFECTION; T-CELL RESPONSES; HIV-1 INFECTION; NEUTRALIZING ANTIBODIES; HETEROLOGOUS CHALLENGE; ANTIRETROVIRAL THERAPY; RETROVIRUS INFECTION; DISEASE PROGRESSION; LYMPHOCYTE ESCAPE AB Developing a human immunodeficiency virus (HIV) vaccine is critical to end the global acquired immunodeficiency syndrome (AIDS) epidemic, but many question whether this goal is achievable. Natural immunity is not protective, and despite immunogenicity of HIV vaccine candidates, human trials have exclusively yielded disappointing results. Nevertheless, there is an indication that success may be possible, but this will be dependent on understanding the antiviral immune response in unprecedented depth to identify and engineer the types of immunity required. Here we outline fundamental immunological questions that need to be answered to develop a protective HIV vaccine, and the immediate need to harness a much broader scientific community to achieve this goal. C1 [Virgin, Herbert W.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Virgin, Herbert W.] Washington Univ, Midwest Reg Ctr Excellence Biodef & Emerging Infe, St Louis, MO 63110 USA. [Walker, Bruce D.] Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. [Walker, Bruce D.] Harvard Univ, Howard Hughes Med Inst, Charlestown, MA 02129 USA. RP Virgin, HW (reprint author), Washington Univ, Sch Med, Campus Box 8118,660 S Euclid Ave, St Louis, MO 63110 USA. EM virgin@wustl.edu; bwalker@partners.org FU National Institutes of Health; Bill and Melinda Gates Foundation; Mark and Lisa Schwartz Foundation FX We would like to acknowledge, while accepting full responsibility for the content and opinions expressed, open discussions and correspondence with: M. Altfeld, D. Brooks, D. Burton, M. Colonna, L. Corey, B. Beutler, D. Barouch, A. Chakraborty, F. Chisari, R. Desrosiers, M. Diamond, A. Garcia-Sastre, L. Glimcher, P. Goulder, H. Greenberg, A. Haase, K. Hasenkrug, B. Haynes, M. Hirsch, S. Abdool-Karim, W. Koff, B. Lamb, J. Lifson, J. Loh, R. Medzhitov, J. Moore, M. Nussenzweig, M. Oldstone, L. Picker, B. Roizman, R. Siliciano, G. Silvestri, S. Wain-Hobson, D. Watkins, R. Weiss, J. Wherry and O. Yang. This work was supported by grants from the National Institutes of Health (H. W. V. and B. D. W.), the Bill and Melinda Gates Foundation (B. D. W.), and a gift from the Mark and Lisa Schwartz Foundation (B. D. W.). NR 101 TC 108 Z9 109 U1 3 U2 11 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 MAR 11 PY 2010 VL 464 IS 7286 BP 224 EP 231 DI 10.1038/nature08898 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566JO UT WOS:000275366100036 PM 20220841 ER PT J AU Hare, S Gupta, SS Valkov, E Engelman, A Cherepanov, P AF Hare, Stephen Gupta, Saumya Shree Valkov, Eugene Engelman, Alan Cherepanov, Peter TI Retroviral intasome assembly and inhibition of DNA strand transfer SO NATURE LA English DT Article ID AUTOMATED STRUCTURE SOLUTION; SARCOMA-VIRUS INTEGRASE; HIV-1 INTEGRASE; CRYSTAL-STRUCTURE; ACTIVE-SITE; ENZYMATIC-ACTIVITY; TERMINAL DOMAINS; STRUCTURAL BASIS; BINDING DOMAIN; PROTEIN AB Integrase is an essential retroviral enzyme that binds both termini of linear viral DNA and inserts them into a host cell chromosome. The structure of full-length retroviral integrase, either separately or in complex with DNA, has been lacking. Furthermore, although clinically useful inhibitors of HIV integrase have been developed, their mechanism of action remains speculative. Here we present a crystal structure of full-length integrase from the prototype foamy virus in complex with its cognate DNA. The structure shows the organization of the retroviral intasome comprising an integrase tetramer tightly associated with a pair of viral DNA ends. All three canonical integrase structural domains are involved in extensive protein-DNA and protein-protein interactions. The binding of strand-transfer inhibitors displaces the reactive viral DNA end from the active site, disarming the viral nucleoprotein complex. Our findings define the structural basis of retroviral DNA integration, and will allow modelling of the HIV-1 intasome to aid in the development of antiretroviral drugs. C1 [Hare, Stephen; Gupta, Saumya Shree; Valkov, Eugene; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Med, London W2 1PG, England. [Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Cherepanov, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Med, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM p.cherepanov@imperial.ac.uk RI Valkov, Eugene/C-1554-2010; Cherepanov, Peter/F-6859-2010; OI Cherepanov, Peter/0000-0002-0634-538X; Hare, Stephen/0000-0003-2951-1595 FU UK Medical Research Council; US National Institutes of Health FX We thank F. Dyda for critical reading of the manuscript, R. Clayton and M. Cummings for the generous gift of InSTIs and helpful discussions, T. Sorensen and the staff of the I02 and I04 beamlines of the Diamond Light Source for assistance with X-ray data collection. P. C. and co-workers are funded by the UK Medical Research Council, and A. E. by the US National Institutes of Health. NR 50 TC 363 Z9 376 U1 5 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 11 PY 2010 VL 464 IS 7286 BP 232 EP U108 DI 10.1038/nature08784 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566JO UT WOS:000275366100037 PM 20118915 ER PT J AU Agarwal, S Loh, YH McLoughlin, EM Huang, JJ Park, IH Miller, JD Huo, HG Okuka, M dos Reis, RM Loewer, S Ng, HH Keefe, DL Goldman, FD Klingelhutz, AJ Liu, L Daley, GQ AF Agarwal, Suneet Loh, Yuin-Han McLoughlin, Erin M. Huang, Junjiu Park, In-Hyun Miller, Justine D. Huo, Hongguang Okuka, Maja dos Reis, Rosana Maria Loewer, Sabine Ng, Huck-Hui Keefe, David L. Goldman, Frederick D. Klingelhutz, Aloysius J. Liu, Lin Daley, George Q. TI Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients SO NATURE LA English DT Article ID REPLICATIVE LIFE-SPAN; HUMAN SOMATIC-CELLS; HUMAN BONE-MARROW; HEMATOPOIETIC-CELLS; HUMAN FIBROBLASTS; GENE-EXPRESSION; DEFINED FACTORS; RNA COMPONENT; MAINTENANCE; MUTATIONS AB Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues(1-3). Patient-specific induced pluripotent stem (iPS) cells(4) represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT)(5-7). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3' deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients. C1 [Agarwal, Suneet; Loh, Yuin-Han; McLoughlin, Erin M.; Park, In-Hyun; Miller, Justine D.; Huo, Hongguang; Loewer, Sabine; Daley, George Q.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Agarwal, Suneet; Loh, Yuin-Han; McLoughlin, Erin M.; Park, In-Hyun; Miller, Justine D.; Huo, Hongguang; Loewer, Sabine; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Agarwal, Suneet; Loh, Yuin-Han; McLoughlin, Erin M.; Park, In-Hyun; Miller, Justine D.; Huo, Hongguang; Loewer, Sabine; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Agarwal, Suneet; Loh, Yuin-Han; McLoughlin, Erin M.; Park, In-Hyun; Miller, Justine D.; Huo, Hongguang; Loewer, Sabine; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Agarwal, Suneet; Loh, Yuin-Han; McLoughlin, Erin M.; Park, In-Hyun; Miller, Justine D.; Huo, Hongguang; Loewer, Sabine; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Agarwal, Suneet; Loh, Yuin-Han; McLoughlin, Erin M.; Park, In-Hyun; Miller, Justine D.; Huo, Hongguang; Loewer, Sabine; Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Huang, Junjiu; Okuka, Maja; dos Reis, Rosana Maria; Keefe, David L.; Liu, Lin] Univ S Florida, Coll Med, Dept Obstet & Gynecol, MDC 3125, Tampa, FL 33612 USA. [Huang, Junjiu] Sun Yat Sen Univ, Sch Life Sci, State Key Lab Biocontrol, Guangzhou 510275, Guangdong, Peoples R China. [Ng, Huck-Hui] Genome Inst Singapore, Gene Regulatory Lab, Singapore 138672, Singapore. [Ng, Huck-Hui] Natl Univ Singapore, Dept Biol Sci, Singapore 138672, Singapore. [Goldman, Frederick D.] Childrens Hosp Alabama, Dept Pediat, Birmingham, AL 35233 USA. [Klingelhutz, Aloysius J.] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Liu, Lin] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China. [Daley, George Q.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu RI Reis, Rosana/E-3346-2012; Ng, Huck Hui/A-1135-2009; Saude da mulher, Inct/J-9403-2013; Loh, Yuin-Han/E-1096-2014; OI Reis, Rosana/0000-0001-9631-4167; Loh, Yuin-Han/0000-0002-4715-6454; NG, HUCK HUI/0000-0001-6352-8417 FU National Institutes of Health (NIH) [K08HL089150, R01AG0227388]; Manton Center for Orphan Disease Research; Amy Clare Potter Fellowship; Agency of Science, Technology and Research; Institute of Medical Biology, Singapore; James and Esther King Biomedical Research Program; MOST 973 project [2009CB941000] FX This work was funded by grants from the National Institutes of Health (NIH) and the Manton Center for Orphan Disease Research (G. Q. D.); NIH K08HL089150, Amy Clare Potter Fellowship and Manton Center for Orphan Disease Research (S. A.); the Agency of Science, Technology and Research and the Institute of Medical Biology, Singapore (Y.-H. L.); NIH R01AG0227388 (F. D. G. and A. J. K.); and the James and Esther King Biomedical Research Program and MOST 973 project (2009CB941000) (D. L. K and L. L). NR 38 TC 162 Z9 165 U1 4 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 11 PY 2010 VL 464 IS 7286 BP 292 EP U176 DI 10.1038/nature08792 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566JO UT WOS:000275366100050 PM 20164838 ER PT J AU Ropper, AH Raje, NS Lawrimore, TM Camelo-Piragua, S Sohani, AR AF Ropper, Allan H. Raje, Noopur S. Lawrimore, Tara M. Camelo-Piragua, Sandra Sohani, Aliyah R. TI A Man with Peripheral Neuropathy and Ascites The POEMS syndrome, with demyelinating neuropathy and solitary plasmacytoma of bone SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; STEM-CELL TRANSPLANTATION; CROW-FUKASE-SYNDROME; OF-THE-LITERATURE; BEVACIZUMAB THERAPY; POLYNEUROPATHY; DYSCRASIA; VEGF C1 [Ropper, Allan H.] Brigham & Womens Hosp, Dept Neurol, Boston, MA USA. [Raje, Noopur S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lawrimore, Tara M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Camelo-Piragua, Sandra; Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ropper, Allan H.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Raje, Noopur S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lawrimore, Tara M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Camelo-Piragua, Sandra; Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Ropper, AH (reprint author), Brigham & Womens Hosp, Dept Neurol, Boston, MA USA. NR 23 TC 7 Z9 9 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 MAR 11 PY 2010 VL 362 IS 10 BP 929 EP 940 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 566JM UT WOS:000275365900015 PM 20220188 ER PT J AU Drazen, JM Weinstein, DF AF Drazen, Jeffrey M. Weinstein, Debra F. TI Considering Recertification SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Drazen, Jeffrey M.; Weinstein, Debra F.] Partners HealthCare Syst, Off Grad Med Educ, Boston, MA USA. [Weinstein, Debra F.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Weinstein, Debra F.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Weinstein, Debra F.] Harvard Univ, Sch Med, Boston, MA USA. RP Drazen, JM (reprint author), Partners HealthCare Syst, Off Grad Med Educ, Boston, MA USA. OI Drazen, Jeffrey/0000-0003-2715-9890 NR 2 TC 30 Z9 30 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 11 PY 2010 VL 362 IS 10 BP 946 EP 947 DI 10.1056/NEJMe1000174 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 566JM UT WOS:000275365900018 PM 20220191 ER PT J AU Levinson, W King, TE Goldman, L Goroll, AH Kessler, B AF Levinson, Wendy King, Talmadge E., Jr. Goldman, Lee Goroll, Allan H. Kessler, Bruce TI American Board of Internal Medicine Maintenance of Certification Program SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ACUTE MYOCARDIAL-INFARCTION; QUALITY IMPROVEMENT; SELF-ASSESSMENT; UNITED-STATES; HEALTH-CARE; PHYSICIANS; EXPERIENCE; RECERTIFICATION; EDUCATION; ADULTS C1 [Levinson, Wendy] Univ Toronto, Dept Med, Toronto, ON, Canada. [King, Talmadge E., Jr.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Goldman, Lee] Columbia Univ, Med Ctr, New York, NY USA. [Goroll, Allan H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goroll, Allan H.] Harvard Univ, Sch Med, Boston, MA USA. [Kessler, Bruce] Eureka Internal Med, Eureka, CA USA. RP Levinson, W (reprint author), Univ Toronto, Dept Med, Toronto, ON, Canada. NR 17 TC 40 Z9 40 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 11 PY 2010 VL 362 IS 10 BP 948 EP 952 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 566JM UT WOS:000275365900019 PM 20220192 ER PT J AU Choy, E AF Choy, Edwin TI A Man with Cough, Hoarseness, and Abnormalities on Chest Imaging REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID EWING SARCOMA; TEMOZOLOMIDE; IRINOTECAN C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Choy, E (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 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 MAR 11 PY 2010 VL 362 IS 10 BP 961 EP 961 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 566JM UT WOS:000275365900033 ER PT J AU Poage, GM Christensen, BC Houseman, EA McClean, MD Wiencke, JK Posner, MR Clark, JR Nelson, HH Marsit, CJ Kelsey, KT AF Poage, Graham M. Christensen, Brock C. Houseman, E. Andres McClean, Michael D. Wiencke, John K. Posner, Marshall R. Clark, John R. Nelson, Heather H. Marsit, Carmen J. Kelsey, Karl T. TI Genetic and Epigenetic Somatic Alterations in Head and Neck Squamous Cell Carcinomas Are Globally Coordinated but Not Locally Targeted SO PLOS ONE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; DNA METHYLATION; COPY NUMBER; PROMOTER METHYLATION; HIGH-RESOLUTION; CANCER PATIENTS; POOR-PROGNOSIS; BREAST-CANCER; SURVIVAL; ARRAY AB Background: Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Little work has been done that simultaneously examines the spectrum of both types of changes in human tumors on a genome-wide scale and results so far have been limited and mixed. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Methodology/Principal Findings: We have extended a prior analysis of 1,413 cancer-associated loci for epigenetic changes in HNSCC by integrating DNA copy number alterations, measured at 500,000 polymorphic loci, in a case series of 19 primary HNSCC tumors. We have previously demonstrated that local copy number does not bias methylation measurements in this array platform. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles (p<0.002). However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation (lowest q = 0.3), and the spectrum of genes affected by each type of alteration was unique. Conclusion/Significance: This work, using a novel and robust statistical approach demonstrates that, although a "second hit'' mechanism is not likely the predominant mode of action for epigenetic dysregulation in cancer, the patterns of methylation events are associated with the patterns of allele loss. Our work further highlights the utility of integrative genomics approaches in exploring the driving somatic alterations in solid tumors. C1 [Poage, Graham M.; Kelsey, Karl T.] Brown Univ, Dept Mol Pharmacol, Providence, RI 02912 USA. [Poage, Graham M.; Kelsey, Karl T.] Brown Univ, Dept Physiol, Providence, RI 02912 USA. [Christensen, Brock C.; Marsit, Carmen J.; Kelsey, Karl T.] Brown Univ, Dept Pathol, Providence, RI 02912 USA. [Christensen, Brock C.; Marsit, Carmen J.; Kelsey, Karl T.] Brown Univ, Dept Lab Med, Providence, RI 02912 USA. [Christensen, Brock C.; Houseman, E. Andres; Kelsey, Karl T.] Brown Univ, Dept Community Hlth, Ctr Environm Hlth & Technol, Providence, RI 02912 USA. [Houseman, E. Andres] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [McClean, Michael D.] Boston Univ, Dept Environm Hlth, Boston, MA 02215 USA. [Wiencke, John K.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Posner, Marshall R.] Dana Farber Canc Inst, Dept Med Oncol Solid Tumor Oncol, Boston, MA 02115 USA. [Clark, John R.] Massachusetts Gen Hosp, Dept Med Hematol Oncol, Boston, MA 02114 USA. [Nelson, Heather H.] Univ Minnesota, Mason Canc Ctr, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Poage, GM (reprint author), Brown Univ, Dept Mol Pharmacol, Providence, RI 02912 USA. EM Karl_Kelsey@Brown.edu RI Christensen, Brock/B-8460-2009; Kelsey, Karl/I-1252-2014; McClean, Michael/J-2934-2015 OI McClean, Michael/0000-0002-3902-8823; Houseman, Eugene Andres/0000-0003-0703-1830; Marsit, Carmen/0000-0003-4566-150X; FU Flight Attendant Medical Research Institute; National Institutes of Health [5R01CA078609-10, 2R01CA100679-06A1, 5RO1ES006717-13] FX This work was supported by Flight Attendant Medical Research Institute (C. M. and M. M.), and the National Institutes of Health (5R01CA078609-10, 2R01CA100679-06A1, 5RO1ES006717-13) (K.K. and J.W.). The funders had no role in study design, data collection, decision to publish, or preparation of the manuscript. NR 53 TC 20 Z9 20 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 11 PY 2010 VL 5 IS 3 AR e9651 DI 10.1371/journal.pone.0009651 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 569SJ UT WOS:000275620600007 PM 20300172 ER PT J AU Lee, BY Wiringa, AE Bailey, RR Lewis, GJ Feura, J Muder, RR AF Lee, Bruce Y. Wiringa, Ann E. Bailey, Rachel R. Lewis, G. Jonathan Feura, Jared Muder, Robert R. TI Staphylococcus aureus vaccine for orthopedic patients: An economic model and analysis SO VACCINE LA English DT Article DE Staphylococcus aureus; Vaccine; Orthopedic surgery; Economics; Computer simulation ID POLYSACCHARIDE CONJUGATE VACCINE; QUALITY-OF-LIFE; PASSIVE-IMMUNIZATION; TOTAL HIP; MRSA; INFECTIONS; SURGERY; UTILITY; IMMUNOTHERAPY; ARTHROPLASTY AB To evaluate the potential economic value of a Staphylococcus aureus vaccine for pre-operative orthopedic surgery patients, we developed an economic computer simulation model. At MRSA colonization rates as low as 1%, a $50 vaccine was cost-effective [<=$50,000 per quality-adjusted life year (QALY) saved] at vaccine efficacy >= 30%, and a $100 vaccine at vaccine efficacy >= 70%. High MASA prevalence (>= 25%) could justify a vaccine price as high as $1000. Our results suggest that a S. aureus vaccine for the pre-operative orthopedic population would be very cost-effective over a wide range of MASA prevalence and vaccine efficacies and costs. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Lee, Bruce Y.] Univ Pittsburgh, Publ Hlth Computat & Operat Res PHICOR, Sect Decis Sci & Clin Syst Modeling, Pittsburgh, PA 15213 USA. [Lee, Bruce Y.; Wiringa, Ann E.; Bailey, Rachel R.; Lewis, G. Jonathan; Feura, Jared] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [Lee, Bruce Y.; Wiringa, Ann E.; Bailey, Rachel R.; Lewis, G. Jonathan; Feura, Jared] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Muder, Robert R.] Univ Pittsburgh, Div Infect Dis, VA Pittsburgh Hlth Syst, Pittsburgh, PA 15213 USA. RP Lee, BY (reprint author), Univ Pittsburgh, Publ Hlth Computat & Operat Res PHICOR, Sect Decis Sci & Clin Syst Modeling, 200 Meyran Ave,Suite 200, Pittsburgh, PA 15213 USA. EM BYL1@pitt.edu OI Slayton, Rachel/0000-0003-4699-8040 FU National Institute of General Medical Sciences Models of Infectious Disease Agent Study (MIDAS) [1U54GM088491-0109] FX Supported by the National Institute of General Medical Sciences Models of Infectious Disease Agent Study (MIDAS) through grant 1U54GM088491-0109. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 15 Z9 15 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 11 PY 2010 VL 28 IS 12 BP 2465 EP 2471 DI 10.1016/j.vaccine.2009.12.075 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 576HN UT WOS:000276135200015 PM 20064479 ER PT J AU Burstein, HJ Sun, Y Dirix, LY Jiang, ZF Paridaens, R Tan, AR Awada, A Ranade, A Jiao, SC Schwartz, G Abbas, R Powell, C Turnbull, K Vermette, J Zacharchuk, C Badwe, R AF Burstein, Harold J. Sun, Yan Dirix, Luc Y. Jiang, Zefei Paridaens, Robert Tan, Antoinette R. Awada, Ahmad Ranade, Anantbhushan Jiao, Shunchang Schwartz, Gary Abbas, Richat Powell, Christine Turnbull, Kathleen Vermette, Jennifer Zacharchuk, Charles Badwe, Rajendra TI Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-II; ADJUVANT CHEMOTHERAPY; LAPATINIB MONOTHERAPY; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; SINGLE-AGENT; SOLID TUMORS; TRASTUZUMAB; EFFICACY; SAFETY AB Purpose Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial. Patients and Methods Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review. Results The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naive cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported. Conclusion Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naive patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification. C1 [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA 02115 USA. Oncol Ctr AZ St Augustinus, Antwerp, Belgium. Univ Hosp Gasthuisberg, Leuven, Belgium. Inst Jules Bordet, B-1000 Brussels, Belgium. Chinese Acad Med Sci, Canc Hosp, Beijing, Peoples R China. Hosp Affiliated Acad Mil Med Sci, Beijing, Peoples R China. Canc Inst New Jersey, New Brunswick, NJ USA. Deenanath Mangeshkar Hosp, Pune, Maharashtra, India. Tata Mem Hosp, Mumbai 400012, Maharashtra, India. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Wyeth Ayerst Res, Cambridge, MA USA. Wyeth Ayerst Res, Collegeville, PA USA. RP Burstein, HJ (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM hburstein@partners.org FU Wyeth Research, Cambridge FX Supported by research funding from Wyeth Research, Cambridge, MA. NR 21 TC 220 Z9 231 U1 2 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 MAR 10 PY 2010 VL 28 IS 8 BP 1301 EP 1307 DI 10.1200/JCO.2009.25.8707 PG 7 WC Oncology SC Oncology GA 565RP UT WOS:000275312300007 PM 20142587 ER PT J AU Rose, SL Krzyzanowska, MK Joffe, S AF Rose, Susannah L. Krzyzanowska, Monika K. Joffe, Steven TI Relationships Between Authorship Contributions and Authors' Industry Financial Ties Among Oncology Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CONFLICTS-OF-INTEREST; PHARMACEUTICAL-INDUSTRY; COMPETING INTERESTS; BIOMEDICAL-RESEARCH; SPONSORSHIP; ASSOCIATION; CONCLUSIONS; DISCLOSURE; DRUGS; METAANALYSES AB Purpose To test the hypothesis that authors who play key scientific roles in oncology clinical trials, and who therefore have increased influence over the design, analysis, interpretation or reporting of trials, are more likely than those who do not play such roles to have financial ties to industry. Methods Data were abstracted from all trials (n = 235) of drugs or biologic agents published in the Journal of Clinical Oncology between January 1, 2006 and June 30, 2007. Article-level data included sponsorship, age group (adult v pediatric), phase, single versus multicenter, country (United States v other), and number of authors. Author-level data (n = 2,927) included financial ties (eg, employment, consulting) and performance of key scientific roles (ie, conception/design, analysis/ interpretation, or manuscript writing). Associations between performance of key roles and financial ties, adjusting for article-level covariates, were examined using generalized linear mixed models. Results One thousand eight hundred eighty-one authors (64%) reported performing at least one key role, and 842 authors (29%) reported at least one financial tie. Authors who reported performing a key role were more likely than other authors to report financial ties to industry (adjusted odds ratio [OR], 4.3; 99% Cl, 3.0 to 6.0; P < .0001). The association was stronger among trials with, compared with those without, industry funding (OR, 5.0 [99% Cl, 3.4 to 7.5] v OR, 2.5 [99% Cl, 1.3 to 4.8]), but was present regardless of sponsorship. Conclusion Authors who perform key roles in the conception and design, analysis, and interpretation, or reporting of oncology clinical trials are more likely than authors who do not perform such roles to have financial ties to industry. C1 [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Dept Hlth Care Policy, Sch Med, Cambridge, MA 02138 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. RP Joffe, S (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM steven_joffe@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 FU National Cancer Institute [2R25CA092203-08] FX Supported by National Cancer Institute Grant No. 2R25CA092203-08 (S. L. R.). NR 46 TC 19 Z9 19 U1 1 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2010 VL 28 IS 8 BP 1316 EP 1321 DI 10.1200/JCO.2008.21.6606 PG 6 WC Oncology SC Oncology GA 565RP UT WOS:000275312300009 PM 20065190 ER PT J AU Manne, SL Meropol, NJ Weinberg, DS Vig, H Catts, ZAK Manning, C Ross, E Shannon, K Chung, DC AF Manne, Sharon L. Meropol, Neal J. Weinberg, David S. Vig, Hetal Catts, Zohra Ali-Khan Manning, Cheri Ross, Eric Shannon, Kristen Chung, Daniel C. TI Facilitating Informed Decisions Regarding Microsatellite Instability Testing Among High-Risk Individuals Diagnosed With Colorectal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LYNCH-SYNDROME; REDUCING MORBIDITY; COLON-CANCER; WOMEN; AID; STRATEGIES; MORTALITY; KNOWLEDGE; ATTITUDES; MUTATION AB Purpose To evaluate the impact of a CD-ROM intervention in the education of patients with suspected Lynch syndrome (LS) about microsatellite instability (MSI) and immunohisochemistry (IHC) testing. Patients and Methods Two hundred thirteen patients meeting Bethesda criteria were randomly assigned to receive either a brief educational session with a health educator (n = 105) or a brief educational session plus a CD-ROM (n = 108). Assessments were administered at baseline and 2 weeks post-treatment. Primary outcomes included MSI and IHC knowledge and level of satisfaction with and completeness of the preparation to make the decision for MSI testing. Secondary outcomes included decisional conflict, difficulty making the decision, cancer-specific and global anxiety, and level of discussion about MSI testing with family and friends. Results Participants in the education plus CD-ROM condition reported significant increases in knowledge about the MSI and IHC tests, greater satisfaction with the preparation to make a decision for testing, lower decisional conflict, and greater decisional self-efficacy. The effects of the education plus CD-ROM on most outcomes were not moderated by preintervention levels of exposure to MSI testing, family support for MSI testing, or the family history of cancer. Conclusion Incorporation of new media education strategies for individuals at risk for LS may be a valuable component of the informed consent process. As clinical criteria for MSI and IHC testing continue to expand, the need for alternative educational approaches to meet this increased demand could be met by the self-administered computer-based strategy that we described. C1 [Manne, Sharon L.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Helen F Graham Canc Ctr Christiana Care, Newark, DE USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Triad Interact Inc, Washington, DC USA. RP Manne, SL (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave,P1100, Philadelphia, PA 19111 USA. EM Sharon.Manne@fccc.edu FU National Cancer Institute [CA109332]; Fox Chase Cancer Center [P30 CA006927] FX Supported by Grant No. CA109332 from the National Cancer Institute and Grant No. P30 CA006927 to Fox Chase Cancer Center. NR 28 TC 22 Z9 22 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 MAR 10 PY 2010 VL 28 IS 8 BP 1366 EP 1372 DI 10.1200/JCO.2009.25.0399 PG 7 WC Oncology SC Oncology GA 565RP UT WOS:000275312300016 PM 20142594 ER PT J AU Ghobrial, IM Gertz, M LaPlant, B Camoriano, J Hayman, S Lacy, M Chuma, S Harris, B Leduc, R Rourke, M Ansell, SM DeAngelo, D Dispenzieri, A Bergsagel, L Reeder, C Anderson, KC Richardson, PG Treon, SP Witzig, TE AF Ghobrial, Irene M. Gertz, Morie LaPlant, Betsy Camoriano, John Hayman, Suzanne Lacy, Martha Chuma, Stacey Harris, Brianna Leduc, Renee Rourke, Meghan Ansell, Stephen M. DeAngelo, Daniel Dispenzieri, Angela Bergsagel, Leif Reeder, Craig Anderson, Kenneth C. Richardson, Paul G. Treon, Steven P. Witzig, Thomas E. TI Phase II Trial of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Relapsed or Refractory Waldenstrom Macroglobulinemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; SINGLE-AGENT TEMSIROLIMUS; RENAL-CELL CARCINOMA; RITUXIMAB THERAPY; MULTIPLE-MYELOMA; INTERFERON-ALPHA; CLINICAL-TRIALS; CANCER; PATHWAYS AB Purpose The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Patients and Methods Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10% marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 x 10(6)/L, a neutrophil count more than 1,000 x 10(6)/L, and a creatinine and bilirubin less than 2 x the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression. Results Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70% (95% Cl, 55% to 82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75% (95% Cl, 64% to 89%) and 62% (95% Cl, 48% to 80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. Conclusion Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group. C1 [Witzig, Thomas E.] Mayo Clin, Coll Med, Rochester, MN 55905 USA. Dana Farber Canc Ctr, Boston, MA USA. Mayo Fdn, Rochester, MN USA. Mayo Clin, Coll Med, Scottsdale, AZ USA. Mayo Fdn, Scottsdale, AZ USA. RP Witzig, TE (reprint author), Mayo Clin, Coll Med, Stabile 628,200 1st St SW, Rochester, MN 55905 USA. EM witzig@mayo.edu RI Bergsagel, Peter/A-7842-2011; OI Bergsagel, Peter/0000-0003-1523-7388; Harris, Brianna/0000-0001-6229-9907; Dispenzieri, Angela/0000-0001-8780-9512 FU Novartis Inc; International Waldenstrom's Macroglobulinemia Foundation; National Institutes of Health [R21CA126119] FX Supported in part by Novartis Inc, International Waldenstrom's Macroglobulinemia Foundation, and National Institutes of Health Grant No. R21CA126119. NR 48 TC 79 Z9 79 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2010 VL 28 IS 8 BP 1408 EP 1414 DI 10.1200/JCO.2009.24.0994 PG 7 WC Oncology SC Oncology GA 565RP UT WOS:000275312300022 PM 20142598 ER PT J AU Ghobrial, IM Hong, FX Padmanabhan, S Badros, A Rourke, M Leduc, R Chuma, S Kunsman, J Warren, D Harris, B Sam, A Anderson, KC Richardson, PG Treon, SP Weller, E Matous, J AF Ghobrial, Irene M. Hong, Fangxin Padmanabhan, Swaminathan Badros, Ashraf Rourke, Meghan Leduc, Renee Chuma, Stacey Kunsman, Janet Warren, Diane Harris, Brianna Sam, Amy Anderson, Kenneth C. Richardson, Paul G. Treon, Steven P. Weller, Edie Matous, Jeffrey TI Phase II Trial of Weekly Bortezomib in Combination With Rituximab in Relapsed or Relapsed and Refractory Waldenstrom Macroglobulinemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; COOPERATIVE-ONCOLOGY-GROUP; NF-KAPPA-B; CLINICAL-TRIAL; THERAPY; MANAGEMENT; SURVIVAL; MYELOMA; UPDATE AB Purpose This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Patients and Methods Patients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response. Results Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% Cl, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% Cl, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% Cl, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% Cl, 39% to 75%) and 45% (95% Cl, 27% to 63%), respectively. The median overall survival has not been reached. Conclusion The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM. C1 [Ghobrial, Irene M.] Dana Farber Canc Inst, Boston, MA 02115 USA. Roswell Pk Canc Ctr, Buffalo, NY USA. Univ Maryland, Baltimore, MD 21201 USA. Rocky Mt Canc Ctr, Denver, CO USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu OI Harris, Brianna/0000-0001-6229-9907 FU International Waldenstrom Macroglobulinemia Foundation (IWMF); Michelle and Steven Kirsch lab for Waldenstrom Macroglobulinemia FX Supported in part by the International Waldenstrom Macroglobulinemia Foundation (IWMF), and Michelle and Steven Kirsch lab for Waldenstrom Macroglobulinemia. NR 32 TC 63 Z9 64 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 MAR 10 PY 2010 VL 28 IS 8 BP 1422 EP 1428 DI 10.1200/JCO.2009.25.3237 PG 7 WC Oncology SC Oncology GA 565RP UT WOS:000275312300024 PM 20142586 ER PT J AU Heinlen, LD McClain, MT Ritterhouse, LL Bruner, BF Edgerton, CC Keith, MP James, JA Harley, JB AF Heinlen, Latisha D. McClain, Micah T. Ritterhouse, Lauren L. Bruner, Benjamin F. Edgerton, Colin C. Keith, Michael P. James, Judith A. Harley, John B. TI 60 kD Ro and nRNP A Frequently Initiate Human Lupus Autoimmunity SO PLOS ONE LA English DT Article ID ANTI-SM ANTIBODIES; CLINICAL-SIGNIFICANCE; PEPTIDE IMMUNIZATION; HUMORAL AUTOIMMUNITY; SURFACE-STRUCTURES; REVISED CRITERIA; ERYTHEMATOSUS; AUTOANTIBODIES; DIAGNOSIS; NEPHRITIS AB Systemic lupus erythematosus (SLE) is a clinically heterogeneous, humoral autoimmune disorder. The unifying feature among SLE patients is the production of large quantities of autoantibodies. Serum samples from 129 patients collected before the onset of SLE and while in the United States military were evaluated for early pre-clinical serologic events. The first available positive serum sample frequently already contained multiple autoantibody specificities (65%). However, in 34 SLE patients the earliest pre-clinical serum sample positive for any detectable common autoantibody bound only a single autoantigen, most commonly 60 kD Ro (29%), nRNP A (24%), anti-phospholipids (18%) or rheumatoid factor (15%). We identified several recurrent patterns of autoantibody onset using these pre-diagnostic samples. In the serum samples available, anti-nRNP A appeared before or simultaneously with anti-nRNP 70 K in 96% of the patients who had both autoantibodies at diagnosis. Anti-60 kD Ro antibodies appeared before or simultaneously with anti-La (98%) or anti-52 kD Ro (95%). The autoantibody response in SLE patients begins simply, often binding a single specific autoantigen years before disease onset, followed by epitope spreading to additional autoantigenic specificities that are accrued in recurring patterns. C1 [Heinlen, Latisha D.; McClain, Micah T.; Ritterhouse, Lauren L.; Bruner, Benjamin F.; James, Judith A.] Oklahoma Med Res Fdn, Dept Clin Immunol, Oklahoma City, OK 73104 USA. [Heinlen, Latisha D.; Ritterhouse, Lauren L.; James, Judith A.; Harley, John B.] Univ Oklahoma, Hlth Sci Ctr, Dept Internal Med, Oklahoma City, OK USA. [Heinlen, Latisha D.; Ritterhouse, Lauren L.; James, Judith A.; Harley, John B.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Edgerton, Colin C.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Keith, Michael P.] Natl Naval Med Ctr, Bethesda, MD USA. [Harley, John B.] US Dept Vet Affairs, Oklahoma City, OK USA. [Harley, John B.] Oklahoma Med Res Fdn, Dept Arthrit & Immunol, Oklahoma City, OK 73104 USA. RP Heinlen, LD (reprint author), Oklahoma Med Res Fdn, Dept Clin Immunol, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM harley@omrf.org FU National Institutes of Health [AI31584, AR48045, AR49084, AR45084, AR45451, RR15577, AR48940, RR20143, AI62629, AI50350]; Kirkland Scholar Awards; United States Department of Veterans Affairs; Lou Kerr Chair in Biomedical Research FX This work was supported in part by grants from the National Institutes of Health (AI31584, AR48045, AR49084, AR45084, AR45451, RR15577, AR48940, RR20143, AI62629, AI50350), Kirkland Scholar Awards (JBH and JAJ) and the United States Department of Veterans Affairs. This work was also supported in part by the Lou Kerr Chair in Biomedical Research to JAJ. Bio-Rad provided the ANA test kits and selected the laboratory as a beta-test site for their commercial bead based assay. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 22 Z9 22 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2010 VL 5 IS 3 AR e9599 DI 10.1371/journal.pone.0009599 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XE UT WOS:000275328800012 PM 20224770 ER PT J AU Miranda, KC Karet, FE Brown, D AF Miranda, Kevin C. Karet, Fiona E. Brown, Dennis TI An Extended Nomenclature for Mammalian V-ATPase Subunit Genes and Splice Variants SO PLOS ONE LA English DT Article ID VACUOLAR H+-ATPASE; PROTON-TRANSLOCATING ATPASE; RENAL TUBULAR-ACIDOSIS; TISSUE-SPECIFIC ISOFORMS; MOLECULAR-CLONING; CHROMAFFIN GRANULES; LUMINAL ACIDIFICATION; MESSENGER-RNA; CDNA CLONING; C-SUBUNIT AB The vacuolar-type H(+)-ATPase (V-ATPase) is a multisubunit proton pump that is involved in both intra-and extracellular acidification processes throughout the body. Multiple homologs and splice variants of V-ATPase subunits are thought to explain its varied spatial and temporal expression pattern in different cell types. Recently subunit nomenclature was standardized with a total of 22 subunit variants identified. However this standardization did not accommodate the existence of splice variants and is therefore incomplete. Thus, we propose here an extension of subunit nomenclature along with a literature and sequence database scan for additional V-ATPase subunits. An additional 17 variants were pulled from a literature search while 4 uncharacterized potential subunit variants were found in sequence databases. These findings have been integrated with the current V-ATPase knowledge base to create a new V-ATPase subunit catalogue. It is envisioned this catalogue will form a new platform on which future studies into tissue-and organelle-specific V-ATPase expression, localization and function can be based. C1 [Miranda, Kevin C.; Brown, Dennis] Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. [Miranda, Kevin C.; Brown, Dennis] Massachusetts Gen Hosp, Div Nephrol, Ctr Syst Biol, Boston, MA 02114 USA. [Miranda, Kevin C.; Brown, Dennis] Harvard Univ, Sch Med, Boston, MA USA. [Karet, Fiona E.] Univ Cambridge, Dept Med Genet, Cambridge, England. RP Miranda, KC (reprint author), Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. EM fek1000@cam.ac.uk; brown@receptor.mgh.harvard.edu OI Karet, Fiona/0000-0002-2457-2869 FU National Kidney Foundation; Wellcome Trust; National Institutes of Health [DK42956] FX KCM is funded through a National Kidney Foundation Research Fellowship. FEK is funded through the Wellcome Trust, while DB is funded by a National Institutes of Health grant DK42956 (DB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 20 Z9 21 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2010 VL 5 IS 3 AR e9531 DI 10.1371/journal.pone.0009531 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XE UT WOS:000275328800004 PM 20224822 ER PT J AU Xu, C Lo, A Yammanuru, A Tallarico, ASC Brady, K Murakami, A Barteneva, N Zhu, Q Marasco, WA AF Xu, Chen Lo, Agnes Yammanuru, Anuradha Tallarico, Aimee St. Clair Brady, Kristen Murakami, Akikazu Barteneva, Natasha Zhu, Quan Marasco, Wayne A. TI Unique Biological Properties of Catalytic Domain Directed Human Anti-CAIX Antibodies Discovered through Phage-Display Technology SO PLOS ONE LA English DT Article ID RENAL-CELL CARCINOMA; CARBONIC-ANHYDRASE-IX; DIAGNOSTIC BIOMARKER; IN-VITRO; CANCER; PROTEIN; THERAPY; IDENTIFICATION; EXPRESSION; KIDNEY AB Carbonic anhydrase IX (CAIX, gene G250/MN-encoded transmembrane protein) is highly expressed in various human epithelial tumors such as renal clear cell carcinoma (RCC), but absent from the corresponding normal tissues. Besides the CA signal transduction activity, CAIX may serve as a biomarker in early stages of oncogenesis and also as a reliable marker of hypoxia, which is associated with tumor resistance to chemotherapy and radiotherapy. Although results from preclinical and clinical studies have shown CAIX as a promising target for detection and therapy for RCC, only a limited number of murine monoclonal antibodies (mAbs) and one humanized mAb are available for clinical testing and development. In this study, paramagnetic proteoliposomes of CAIX (CAIX-PMPLs) were constructed and used for anti-CAIX antibody selection from our 27 billion human single-chain antibody (scFv) phage display libraries. A panel of thirteen human scFvs that specifically recognize CAIX expressed on cell surface was identified, epitope mapped primarily to the CA domain, and affinity-binding constants (KD) determined. These human anti-CAIX mAbs are diverse in their functions including induction of surface CAIX internalization into endosomes and inhibition of the carbonic anhydrase activity, the latter being a unique feature that has not been previously reported for anti-CAIX antibodies. These human anti-CAIX antibodies are important reagents for development of new immunotherapies and diagnostic tools for RCC treatment as well as extending our knowledge on the basic structure-function relationships of the CAIX molecule. C1 [Xu, Chen; Lo, Agnes; Yammanuru, Anuradha; Tallarico, Aimee St. Clair; Brady, Kristen; Murakami, Akikazu; Zhu, Quan; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Barteneva, Natasha] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Barteneva, Natasha] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Xu, Chen; Lo, Agnes; Zhu, Quan; Marasco, Wayne A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Barteneva, Natasha] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Xu, C (reprint author), Beijing Tri Prime Genet Engn Corp Ltd, Beijing, Peoples R China. EM quan_zhu@dfci.harvard.edu; wayne_marasco@dfci.harvard.edu FU National Institutes of Health (NIH) [R21DK072282, 1S10RR23459-01]; Kidney SPORE [5P50CA101942]; PI; National Foundation for Cancer Research; [R21AI058804] FX This study was supported by National Institutes of Health (NIH) grants R21DK072282 to WAM, in part by the Kidney SPORE grant 5P50CA101942 where WAM is a subcontract PI, and in part by R21AI058804 to QKZ. The Flow and Imaging Cytometry Resource (FICR) and Imagestream 100 instrument used in this study were funded, in part, under NIH grant 1S10RR23459-01. The FACS Calibur used for flow cytometric analysis performed in this study was funded through the National Foundation for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 21 Z9 22 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2010 VL 5 IS 3 AR e9625 DI 10.1371/journal.pone.0009625 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XE UT WOS:000275328800020 PM 20224781 ER PT J AU Nautiyal, A Chaukiyal, P AF Nautiyal, Amit Chaukiyal, Pooja TI Second neoplasm: 31-year latency after childhood leukemia SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID CANCER SURVIVOR C1 [Nautiyal, Amit] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Chaukiyal, Pooja] Vet Affairs Pittsburgh Hlth Care Syst, Dept Med, Pittsburgh, PA USA. RP Nautiyal, A (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD MAR 9 PY 2010 VL 182 IS 4 BP E185 EP E185 DI 10.1503/cmaj.090562 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 560RO UT WOS:000274920000022 PM 20026628 ER PT J AU Shin, SH Hung, CL Uno, H Hassanein, AH Verma, A Bourgoun, M Kober, L Ghali, JK Velazquez, EJ Califf, RM Pfeffer, MA Solomon, SD AF Shin, Sung-Hee Hung, Chung-Lieh Uno, Hajime Hassanein, Amira H. Verma, Anil Bourgoun, Mikhail Kober, Lars Ghali, Jalal K. Velazquez, Eric J. Califf, Robert M. Pfeffer, Marc A. Solomon, Scott D. CA Valsartan Acute Myocardial Infarct TI Mechanical Dyssynchrony After Myocardial Infarction in Patients With Left Ventricular Dysfunction, Heart Failure, or Both SO CIRCULATION LA English DT Article DE echocardiography; heart failure; myocardial infarction ID CARDIAC-RESYNCHRONIZATION THERAPY; ECHOCARDIOGRAPHIC METHOD; MITRAL REGURGITATION; PREDICT RESPONSE; QRS DURATION; STRAIN; TISSUE; VALIDATION; ASYNCHRONY; VALSARTAN AB Background-Mechanical dyssynchrony is considered an independent predictor for adverse cardiovascular outcomes in patients with heart failure. However, its importance as a risk factor after myocardial infarction is not well defined. Methods and Results-We examined the influence of mechanical dyssynchrony on outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echocardiography study. B-mode speckle tracking with velocity vector imaging was used to assess ventricular synchrony in 381 patients who had image quality sufficient for analysis. Time to regional peak velocity and time to strain rate were measured among 12 left ventricular segments from the apical 4- and 2- chamber views, and the SDs between all 12 segments were used as a measure of dyssynchrony. The relationships between the SD of time to regional peak velocity and strain rate and clinical outcome of death or heart failure were assessed. In a multivariate Cox model adjusted for clinical and echocardiographic variables, the SD of time to peak velocity (hazard ratio per 10 ms, 1.10; 95% confidence interval, 1.02 to 1.18; P=0.010) and the SD of time to strain rate (hazard ratio per 10 ms, 1.16; 95% confidence interval, 1.06 to 1.27; P=0.001) were independent predictors of death or heart failure. Conclusion-Left ventricular dyssynchrony is independently associated with increased risk of death or heart failure after myocardial infarction, suggesting that contractile pattern may play a role in post-myocardial infarction prognosis. (Circulation. 2010; 121: 1096-1103.) C1 [Shin, Sung-Hee; Hung, Chung-Lieh; Hassanein, Amira H.; Verma, Anil; Bourgoun, Mikhail; Pfeffer, Marc A.; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Uno, Hajime] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Uno, Hajime] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kober, Lars] Univ Copenhagen, Copenhagen, Denmark. [Ghali, Jalal K.] Wayne State Med Ctr, Detroit, MI USA. [Velazquez, Eric J.; Califf, Robert M.] Duke Univ, Med Ctr, Durham, NC USA. RP Solomon, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM ssolomon@rics.bwh.harvard.edu RI Max, Mad/E-5238-2010; Solomon, Scott/I-5789-2013 OI Max, Mad/0000-0001-6966-6829; FU Novartis Pharmaceuticals, East Hanover, NJ FX VALIANT was supported by a grant from Novartis Pharmaceuticals, East Hanover, NJ. NR 42 TC 54 Z9 58 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 MAR 9 PY 2010 VL 121 IS 9 BP 1096 EP 1103 DI 10.1161/CIRCULATIONAHA.109.863795 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 565XR UT WOS:000275331600006 PM 20176989 ER PT J AU Truong, QA Yared, K Maurovich-Horvat, P Siegel, E Cubeddu, RJ King, ME Heist, EK Mansour, M Holmvang, G AF Truong, Quynh A. Yared, Kibar Maurovich-Horvat, Pal Siegel, Emily Cubeddu, Roberto J. King, Mary Etta Heist, E. Kevin Mansour, Moussa Holmvang, Godtfred TI Double-Chambered Right Ventricle and Situs Inversus With Dextrocardia SO CIRCULATION LA English DT Editorial Material C1 [Truong, Quynh A.; Maurovich-Horvat, Pal; Siegel, Emily; Holmvang, Godtfred] Harvard Univ, Cardiac MR PET CT Program, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Truong, Quynh A.; Yared, Kibar; Cubeddu, Roberto J.; King, Mary Etta; Heist, E. Kevin; Mansour, Moussa; Holmvang, Godtfred] Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Truong, Quynh A.; Maurovich-Horvat, Pal; Siegel, Emily; Holmvang, Godtfred] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Holmvang, G (reprint author), Harvard Univ, Cardiac MR PET CT Program, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,BUL 161, Boston, MA 02114 USA. EM gholmvang@partners.org OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU NHLBI NIH HHS [K23 HL098370, L30 HL093806, L30 HL093806-01, T32 HL076136] NR 6 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 9 PY 2010 VL 121 IS 9 BP E229 EP E232 DI 10.1161/CIR.0b013e3181d56ebd PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 565XR UT WOS:000275331600014 PM 20212287 ER PT J AU Huang, HC Benoist, C Mathis, D AF Huang, Haochu Benoist, Christophe Mathis, Diane TI Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoimmunity; B cell depletion therapy; CD20; plasma cell; autoantibody ID MONOCLONAL-ANTIBODIES; DIRECTED THERAPIES; AUTOIMMUNE-DISEASE; B-CELLS; MICE; EXPRESSION; DIFFERENTIATION; IMMUNOTHERAPY; ACTIVATION; SURVIVAL AB There is increasing appreciation of the important role of B cells in many autoimmune diseases and consequently, increasing interest in treating these disorders through B cell-depletion therapy with rituximab, an anti-CD20 monoclonal antibody. Yet, precisely how this and related drugs exert their therapeutic effects remains controversial. In particular, it is unclear how, in a number of contexts, rituximab can greatly reduce the titer of serum autoantibodies without substantially altering the overall antibody titer. We have studied the action of this drug in the K/BxN mouse model of inflammatory arthritis after first crossing in a human CD20 transgene. Rituximab treatment of these mice led to a decrease in the titer of serum antibodies targeting glucose-6-phosphate isomerase, the relevant autoantigen, but not in the total antibody titer. Glucose-6-phosphate isomerase-specific plasma cells did not reside primarily in the bone marrow as expected but rather in the spleen and lymph nodes, where they had short lives, expressed CD20, and were rapidly depleted by rituximab. These data support a model whereby autoreactive plasma cells (at least certain specificities thereof) are intrinsically different from protective antimicrobial plasma cells in their differentiation, migration, and survival properties. Rituximab targets the former and spares the latter. C1 [Huang, Haochu; Benoist, Christophe; Mathis, Diane] Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. [Huang, Haochu] Univ Chicago, Dept Med, Rheumatol Sect, Chicago, IL 60637 USA. [Huang, Haochu] Univ Chicago, Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. [Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. RP Huang, HC (reprint author), Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. EM hhuang@bsd.uchicago.edu; cbdm@hms.harvard.edu FU National Institutes of Health [R01 AR046580]; Joslin's National Institute of Diabetes and Digestive and Kidney Diseases; Damon Runyon Cancer Research Foundation [DRG-1616] FX We thank Dr. Rudolf A. Manz for advice on plasma-cell detection, Vanesa Tran, Kimie Hattori, and Adriana Ortiz-Lopez for help with mice, Genentech for providing human CD20 transgenic mice and rituximab, Marilyn Kehry and Robert Dunn for anti-mouse CD20 mAb, and Dr. Martin Weigert for critical reading of the manuscript. This work was supported by Grant R01 AR046580 (to D. M. and C. B.) from the National Institutes of Health and by grants from Joslin's National Institute of Diabetes and Digestive and Kidney Diseases-supported Diabetes and Endocrinology Research Center cores. H. H. was supported by Grant DRG-1616 from the Damon Runyon Cancer Research Foundation. NR 24 TC 61 Z9 63 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 MAR 9 PY 2010 VL 107 IS 10 BP 4658 EP 4663 DI 10.1073/pnas.1001074107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566KF UT WOS:000275368400032 PM 20176942 ER PT J AU Horak, P Crawford, AR Vadysirisack, DD Nash, ZM DeYoung, MP Sgroi, D Ellisen, LW AF Horak, Peter Crawford, Andrew R. Vadysirisack, Douangsone D. Nash, Zachary M. DeYoung, M. Phillip Sgroi, Dennis Ellisen, Leif W. TI Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hypoxia; mTOR; mitochondria; breast cancer; tuberous sclerosis ID EXPRESSION PROFILES; HUMAN CANCER; CELL-GROWTH; HYPOXIA; MTOR; GENE; REDD1; APOPTOSIS; INHIBITION; ADAPTATION AB The HIF family of hypoxia-inducible transcription factors are key mediators of the physiologic response to hypoxia, whose dysregulation promotes tumorigenesis. One important HIF-1 effector is the REDD1 protein, which is induced by HIF-1 and which functions as an essential regulator of TOR complex 1 (TORC1) activity in Drosophila and mammalian cells. Here we demonstrate a negative feedback loop for regulation of HIF-1 by REDD1, which plays a key role in tumor suppression. Genetic loss of REDD1 dramatically increases HIF-1 levels and HIF-regulated target gene expression in vitro and confers tumorigenicity in vivo. Increased HIF-1 in REDD1(-/-) ells induces a shift to glycolytic metabolism and provides a growth advantage under hypoxic conditions, and HIF-1 knockdown abrogates this advantage and suppresses tumorigenesis. Surprisingly, however, HIF-1 up-regulation in REDD1(-/-) cells is largely independent of mTORC1 activity. Instead, loss of REDD1 induces HIF-1 stabilization and tumorigenesis through a reactive oxygen species (ROS) -dependent mechanism. REDD1(-/-) cells demonstrate a substantial elevation of mitochondrial ROS, and antioxidant treatment is sufficient to normalize HIF-1 levels and inhibit REDD1-dependent tumor formation. REDD1 likely functions as a direct regulator of mitochondrial metabolism, as endogenous REDD1 localizes to the mitochondria, and this localization is required for REDD1 to reduce ROS production. Finally, human primary breast cancers that have silenced REDD1 exhibit evidence of HIF activation. Together, these findings uncover a specific genetic mechanism for HIF induction through loss of REDD1. Furthermore, they de. ne REDD1 as a key metabolic regulator that suppresses tumorigenesis through distinct effects on mTORC1 activity and mitochondrial function. C1 [Horak, Peter; Crawford, Andrew R.; Vadysirisack, Douangsone D.; Nash, Zachary M.; DeYoung, M. Phillip; Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Horak, Peter; Crawford, Andrew R.; Vadysirisack, Douangsone D.; Nash, Zachary M.; DeYoung, M. Phillip; Ellisen, Leif W.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Sgroi, Dennis] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Ellisen, LW (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM ellisen@helix.mgh.harvard.edu FU Austrian Science Fund (FWF); [R01 CA122589] FX We thank Nabeel Bardeesy and Raul Mostaslavsky for critical review of the manuscript. This work was supported by R01 CA122589 to L. W. E. and by an Austrian Science Fund (FWF) award to P. H. NR 34 TC 73 Z9 74 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 9 PY 2010 VL 107 IS 10 BP 4675 EP 4680 DI 10.1073/pnas.0907705107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566KF UT WOS:000275368400035 PM 20176937 ER PT J AU Patel, GH Shulman, GL Baker, JT Akbudak, E Snyder, AZ Snyder, LH Corbetta, M AF Patel, Gaurav H. Shulman, Gordon L. Baker, Justin T. Akbudak, Erbil Snyder, Abraham Z. Snyder, Lawrence H. Corbetta, Maurizio TI Topographic organization of macaque area LIP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BOLD signal; functional MRI; retinotopy; parietal cortex; visual attention ID POSTERIOR PARIETAL CORTEX; LATERAL INTRAPARIETAL AREA; FRONTAL EYE FIELDS; FUNCTIONAL ARCHITECTURE; BEHAVING MONKEY; CORTICOCORTICAL CONNECTIONS; ASSOCIATION CORTEX; VISUAL TOPOGRAPHY; SPATIAL ATTENTION; CEREBRAL-CORTEX AB Despite several attempts to define retinotopic maps in the macaque lateral intraparietal area (LIP) using histological, electrophysiological, and neuroimaging methods, the degree to which this area is topographically organized remains controversial. We recorded blood oxygenation level-dependent signals with functional MRI from two macaques performing a difficult visual search task on stimuli presented at the fovea or in the periphery of the visual field. The results revealed the presence of a single topographic representation of the contralateral hemifield in the ventral subdivision of the LIP (LIPv) in both hemispheres of both monkeys. Also, a foveal representation was localized in rostral LIPv rather than in dorsal LIP (LIPd) as previous experiments had suggested. Finally, both LIPd and LIPv responded only to contralateral stimuli. In contrast, human studies have reported multiple topographic maps in intraparietal cortex and robust responses to ipsilateral stimuli. These blood oxygenation level-dependent functional MRI results provide clear evidence for the topographic organization of macaque LIP that complements the results of previous electrophysiology studies, and also reveal some unexpected characteristics of this organization that have eluded these previous studies. The results also delineate organizational differences between LIPv and LIPd, providing support for these two histologically defined areas may subserve different visuospatial functions. Finally, these findings point to potential evolutionary differences in functional organization with human posterior parietal cortex. C1 [Patel, Gaurav H.; Akbudak, Erbil; Snyder, Abraham Z.; Corbetta, Maurizio] Washington Univ, Dept Radiol, St Louis, MO 63110 USA. [Patel, Gaurav H.; Shulman, Gordon L.; Snyder, Abraham Z.; Corbetta, Maurizio] Washington Univ, Dept Neurol, St Louis, MO 63110 USA. [Patel, Gaurav H.; Baker, Justin T.; Snyder, Lawrence H.; Corbetta, Maurizio] Washington Univ, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Patel, Gaurav H.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Baker, Justin T.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Patel, GH (reprint author), Washington Univ, Dept Radiol, St Louis, MO 63110 USA. EM gauravpatel@gmail.com RI Snyder, Lawrence/A-4593-2017 FU McDonnell Center for Systems Neuroscience at Washington University; National Institute of Neurological Disease and Stroke [R01 NS48013, F31 NS051972]; National Institute of Mental Health (NIMH) [R01 MH71920-06]; European Union [MEXC-CT-2004-006783]; National Eye Institute [R01 EY012135]; Washington University Silvio Conte Center (NIMH) [MH-071616]; National Science Foundation [0548890] FX We thank Tom Malone, David Borton, Marcel Fremont, Jason Vytlacil, Matt Reiter, Erin Reid, Chad Sylvester, Anthony Jack, Giovanni D'Avossa, Carlo Sestieri, Mark McAvoy, Justin Vincent, John Harwell, Donna Dierker, David Van Essen, Marc Raichle, Steve Petersen, Leonardo Chelazzi, and Wim Vanduffel for aiding this study and for their comments on the manuscript. This study was supported by the McDonnell Center for Systems Neuroscience at Washington University, National Institute of Neurological Disease and Stroke Grants R01 NS48013 and F31 NS051972, National Institute of Mental Health (NIMH) Grant R01 MH71920-06, a European Union-funded Marie Curie Chair (MEXC-CT-2004-006783), National Eye Institute Grant R01 EY012135, the Washington University Silvio Conte Center (NIMH Grant MH-071616), and National Science Foundation (Integrative Graduate Education and Research Traineeship Program Grant 0548890). NR 50 TC 29 Z9 29 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 MAR 9 PY 2010 VL 107 IS 10 BP 4728 EP 4733 DI 10.1073/pnas.0908092107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566KF UT WOS:000275368400044 PM 20173093 ER PT J AU Bouche, C Lopez, X Fleischman, A Cypess, AM O'Shea, S Stefanovski, D Bergman, RN Rogatsky, E Stein, DT Kahn, CR Kulkarni, RN Goldfine, AB AF Bouche, Clara Lopez, Ximena Fleischman, Amy Cypess, Aaron M. O'Shea, Sheila Stefanovski, Darko Bergman, Richard N. Rogatsky, Eduard Stein, Daniel T. Kahn, C. Ronald Kulkarni, Rohit N. Goldfine, Allison B. TI Insulin enhances glucose-stimulated insulin secretion in healthy humans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE beta cell; type 2 diabetes mellitus; insulin resistance; insulin clearance; C-peptide ID PANCREATIC BETA-CELLS; DEPENDENT DIABETES-MELLITUS; C-PEPTIDE; GENE-EXPRESSION; HUMAN ISLETS; RECEPTOR SUBSTRATE-1; CONNECTING PEPTIDE; MICE; HYPERINSULINEMIA; HYPERGLYCEMIA AB Islet beta-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates beta-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) clamps using B28-Asp insulin that could be immunologically distinguished from endogenous insulin. Insulin and C-peptide clearance were evaluated to understand the impact of hyperinsulinemia on estimates of beta-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by approximate to 40%. C-peptide response also increased, although not to the level predicted by insulin. Insulin clearance was not saturated at hyperinsulinemia, but metabolic clearance of C-peptide, assessed by infusion of stable isotope-labeled C-peptide, increased modestly during hyperinsulinemic clamp. These studies demonstrate that insulin potentiates glucose-stimulated insulin secretion in vivo in healthy humans. In addition, hyperinsulinemia increases C-peptide clearance, which may lead to modest underestimation of beta-cell secretory response when using these methods during prolonged dynamic testing. C1 [Bouche, Clara; Lopez, Ximena; Fleischman, Amy; Cypess, Aaron M.; O'Shea, Sheila; Kahn, C. Ronald; Kulkarni, Rohit N.; Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Bouche, Clara; Lopez, Ximena; Fleischman, Amy; Cypess, Aaron M.; Kahn, C. Ronald; Kulkarni, Rohit N.; Goldfine, Allison B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Lopez, Ximena] Massachusettes Gen Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Fleischman, Amy] Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Stefanovski, Darko; Bergman, Richard N.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Rogatsky, Eduard; Stein, Daniel T.] Albert Einstein Coll Med, Div Endocrinol Diabet & Metab, Dept Med, Bronx, NY 10461 USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu; allison.goldfine@joslin.harvard.edu FU National Institutes of Health [K23-DK02795, R01 DK070648, DK67536, DK061644, DK33201, P30-DK36836, M01-RR001032, RR12248]; American Diabetes Association [06-CD-07]; Harvard 50th Anniversary Scholars in Medicine; Priscilla White Fellowship; Lilly Fellowship; Harvard Massachusetts Institute of Technology Health Sciences and Technology-Beth Israel Deaconess Medical Center FX Supported by National Institutes of Health Grants K23-DK02795, R01 DK070648, DK67536, DK061644, DK33201, P30-DK36836, M01-RR001032, and RR12248; American Diabetes Association 06-CD-07; the Harvard 50th Anniversary Scholars in Medicine: Priscilla White Fellowship; a Lilly Fellowship Grant; and the Clinical Investigator Training Program of Harvard Massachusetts Institute of Technology Health Sciences and Technology-Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. and Merck & Company, Inc. NR 46 TC 44 Z9 48 U1 2 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 9 PY 2010 VL 107 IS 10 BP 4770 EP 4775 DI 10.1073/pnas.1000002107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566KF UT WOS:000275368400051 PM 20176932 ER PT J AU Sykiotis, GP Bohmann, D AF Sykiotis, Gerasimos P. Bohmann, Dirk TI Stress-Activated Cap'n'collar Transcription Factors in Aging and Human Disease SO SCIENCE SIGNALING LA English DT Review ID ANTIOXIDANT-RESPONSE ELEMENT; AMYOTROPHIC-LATERAL-SCLEROSIS; SMALL MAF PROTEINS; OBSTRUCTIVE PULMONARY-DISEASE; HEME OXYGENASE-1 GENE; NAD(P)H-QUINONE OXIDOREDUCTASE1 GENE; AFLATOXIN-INDUCED TUMORIGENESIS; NRF2 ENHANCES SUSCEPTIBILITY; GLUTATHIONE S-TRANSFERASES; FACTOR E2-RELATED FACTOR-2 AB Cap'n'collar (Cnc) transcription factors are conserved in metazoans and have important developmental and homeostatic functions. The vertebrate Nrf1, Nrf2, and Nrf3; the Caenorhabditis elegans SKN-1; and the Drosophila CncC comprise a subgroup of Cnc factors that mediate adaptive responses to cellular stress. The most studied stress-activated Cnc factor is Nrf2, which orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In rodent models, signaling by Nrf2 defends against oxidative stress and aging-associated disorders, such as neurodegeneration, respiratory diseases, and cancer. In humans, polymorphisms that decrease Nrf2 abundance have been associated with various pathologies of the skin, respiratory system, and digestive tract. In addition to preventing disease in rodents and humans, Cnc factors have life-span-extending and anti-aging functions in invertebrates. However, despite the pro-longevity and antioxidant roles of stress-activated Cnc factors, their activity paradoxically declines in aging model organisms and in humans suffering from progressive respiratory disease or neurodegeneration. We review the roles and regulation of stress-activated Cnc factors across species, present all reported instances in which their activity is paradoxically decreased in aging and disease, and discuss the possibility that the pharmacological restoration of Nrf2 signaling may be useful in the prevention and treatment of age-related diseases. C1 [Sykiotis, Gerasimos P.; Bohmann, Dirk] Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA. [Sykiotis, Gerasimos P.] Massachusetts Gen Hosp, Dept Internal Med, Reprod Endocrine Unit, Boston, MA 02114 USA. [Sykiotis, Gerasimos P.] Massachusetts Gen Hosp, Dept Internal Med, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. RP Sykiotis, GP (reprint author), Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA. EM gerasimos_sykiotis@urmc.rochester.edu OI Sykiotis, Gerasimos/0000-0002-9565-4941 FU NIH [RO3 CA123591] FX Support was provided by JP Wilmot Cancer Research Fellowship (G. P. S.) and NIH grant RO3 CA123591 (D. B). NR 321 TC 224 Z9 230 U1 2 U2 26 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 9 PY 2010 VL 3 IS 112 AR re3 DI 10.1126/scisignal.3112re3 PG 22 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 570CF UT WOS:000275648500003 PM 20215646 ER PT J AU Chen, J Krumholz, HM Wang, Y Curtis, JP Rathore, SS Ross, JS Normand, SLT Schreiner, GC Mulvey, G Nallamothu, BK AF Chen, Jersey Krumholz, Harlan M. Wang, Yun Curtis, Jeptha P. Rathore, Saif S. Ross, Joseph S. Normand, Sharon-Lise T. Schreiner, Geoffrey C. Mulvey, Gregory Nallamothu, Brahmajee K. TI Differences in Patient Survival After Acute Myocardial Infarction by Hospital Capability of Performing Percutaneous Coronary Intervention SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SITE CARDIAC-CATHETERIZATION; PRIMARY ANGIOPLASTY; OUTCOMES; CARE; REGIONALIZATION; FACILITIES; THROMBOLYSIS; CENTERS; IMPACT; TRIAL AB Background: There are increasing calls for regionalization of acute myocardial infarction ( AMI) care in the United States to hospitals with the capacity to perform percutaneous coronary intervention (PCI). Whether regionalization will improve outcomes depends in part on the magnitude of existing differences in outcomes between PCI and non-PCI hospitals within the same health care region. Methods: A 100% sample of claims from Medicare fee-for-service beneficiaries 65 years or older hospitalized for AMI between January 1, 2004, and December 31, 2006, was used to calculate hospital-level, 30-day risk-standardized mortality rates (RSMRs). The RSMRs between PCI and local non-PCI hospitals were compared within local health care regions defined by hospital referral regions (HRRs). Results: A total of 523 119 AMI patients was admitted to 1382 PCI hospitals, and 194 909 AMI patients were admitted to 2491 non-PCI hospitals in 295 HRRs with at least 1 PCI and 1 non-PCI hospital. Although PCI hospitals had lower RSMRs than non-PCI hospitals ( mean, 16.1% vs 16.9%; P < .001), considerable overlap was seen in RSMRs between non-PCI and PCI hospitals within the same HRR. In 80 HRRs, the RSMRs at the best-performing PCI hospital were lower than those at local non-PCI hospitals by 3% or more. Among the remaining HRRs, the RSMRs at the best-performing PCI hospital were lower by 1.5% to 3.0% in 104 HRRs and by greater than 0 to 1.5% in 74 HRRs. In 37 HRRs, the RSMRs at the best-performing PCI hospital were no better or were higher than at local non-PCI hospitals. Conclusions: The magnitude of benefit from comprehensively regionalizing AMI care to PCI hospitals appears to vary greatly across HRRs. These findings support a tailored regionalization policy that targets areas with the greatest outcome differences between PCI and local non-PCI hospitals. C1 [Chen, Jersey] Yale Univ, Sch Med, Dept Internal Med, Cardiol Sect,Div Cardiol, New Haven, CT 06520 USA. [Chen, Jersey; Krumholz, Harlan M.; Wang, Yun; Curtis, Jeptha P.; Schreiner, Geoffrey C.; Mulvey, Gregory] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. [Ross, Joseph S.] Mt Sinai Sch Med, Div Geriatr & Palliat Med, New York, NY USA. [Ross, Joseph S.] James P Peters Vet Adm Med Ctr, Hlth Serv Res & Dev Res Enhancement Program, Bronx, NY USA. [Ross, Joseph S.] James P Peters Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Nallamothu, Brahmajee K.] Univ Michigan, Vet Affairs Ann Arbor Hlth Serv Res & Dev Ctr Exc, Ann Arbor, MI USA. [Nallamothu, Brahmajee K.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. RP Chen, J (reprint author), Yale Univ, Sch Med, Dept Internal Med, Cardiol Sect,Div Cardiol, 333 Cedar St,POB 208017, New Haven, CT 06520 USA. EM jersey.chen@yale.edu FU NIA NIH HHS [K08 AG032886-02, K08 AG032886] NR 20 TC 12 Z9 12 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 8 PY 2010 VL 170 IS 5 BP 433 EP 439 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 565PU UT WOS:000275307300007 PM 20212179 ER PT J AU Stevens, JC Chia, R Hendriks, WT Bros-Facer, V van Minnen, J Martin, JE Jackson, GS Greensmith, L Schiavo, G Fisher, EMC AF Stevens, James C. Chia, Ruth Hendriks, William T. Bros-Facer, Virginie van Minnen, Jan Martin, Joanne E. Jackson, Graham S. Greensmith, Linda Schiavo, Giampietro Fisher, Elizabeth M. C. TI Modification of Superoxide Dismutase 1 (SOD1) Properties by a GFP Tag - Implications for Research into Amyotrophic Lateral Sclerosis (ALS) SO PLOS ONE LA English DT Article ID FAMILIAL ALS; MUTANT SOD1; HUMAN-CELLS; MUTATIONS; PROTEIN; ULTRACENTRIFUGATION; DEATH; MODEL; GENE; MICE AB Background: Since the discovery that mutations in the enzyme SOD1 are causative in human amyotrophic lateral sclerosis (ALS), many strategies have been employed to elucidate the toxic properties of this ubiquitously expressed mutant protein, including the generation of GFP-SOD1 chimaeric proteins for studies in protein localization by direct visualization using fluorescence microscopy. However, little is known about the biochemical and physical properties of these chimaeric proteins, and whether they behave similarly to their untagged SOD1 counterparts. Methodology/Principal Findings: Here we compare the physicochemical properties of SOD1 and the effects of GFP-tagging on its intracellular behaviour. Immunostaining demonstrated that SOD1 alone and GFP-SOD1 have an indistinguishable intracellular distribution in PC12 cells. Cultured primary motor neurons expressing GFP or GFP-SOD1 showed identical patterns of cytoplasmic expression and of movement within the axon. However, GFP tagging of SOD1 was found to alter some of the intrinsic properties of SOD1, including stability and specific activity. Evaluation of wildtype and mutant SOD1, tagged at either the N- or C-terminus with GFP, in PC12 cells demonstrated that some chimaeric proteins were degraded to the individual proteins, SOD1 and GFP. Conclusions/Significance: Our findings indicate that most, but not all, properties of SOD1 remain the same with a GFP tag. C1 [Stevens, James C.; Chia, Ruth; Fisher, Elizabeth M. C.] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England. [Hendriks, William T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA USA. [Bros-Facer, Virginie; Greensmith, Linda] UCL Inst Neurol, Sobell Dept Motor Sci & Movement Disorders, London, England. [van Minnen, Jan] Univ Calgary, Hotchkiss Brain Inst, Dept Cell Biol & Anat, Calgary, AB, Canada. [Martin, Joanne E.] Queen Mary Univ London, ICMS Pathol Grp, London, England. [Jackson, Graham S.] UCL Inst Neurol, MRC Prion Unit, London, England. [Schiavo, Giampietro] Canc Res UK, Mol Neuropathobiol Lab, London, England. RP Stevens, JC (reprint author), UCL Inst Neurol, Dept Neurodegenerat Dis, London, England. EM e.fisher@prion.ucl.ac.uk OI Jackson, Graham/0000-0002-3125-2011; Schiavo, Giampietro/0000-0002-4319-8745 FU Ipsen Fund; UK Motor Neurone Disease Association; Research Advisory Board of St Bartholomew's and the Royal London Charitable Foundation [RAB04/F7]; Brain Research Trust; Biotechnology and Biological Sciences Research Council; Cancer Research UK; EU FP6 NEST [12702] FX This work was supported by research grants from The Ipsen Fund, the UK Motor Neurone Disease Association, the Research Advisory Board of St Bartholomew's and the Royal London Charitable Foundation (RAB04/F7), The Brain Research Trust, the Biotechnology and Biological Sciences Research Council, Cancer Research UK and EU FP6 NEST grant 12702. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 16 Z9 17 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 8 PY 2010 VL 5 IS 3 BP A8 EP A17 AR e9541 DI 10.1371/journal.pone.0009541 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565WZ UT WOS:000275328200001 PM 20221404 ER PT J AU Tucker, JD Yang, LG Zhu, ZJ Yang, B Yin, YP Cohen, MS Chen, XS AF Tucker, Joseph D. Yang, Li-Gang Zhu, Zheng-Jun Yang, Bin Yin, Yue-Pin Cohen, Myron S. Chen, Xiang-Sheng TI Integrated syphilis/HIV screening in China: a qualitative analysis SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID STD SERVICES; HEALTH; PRIVATIZATION; PHYSICIANS; PROVIDERS; SETTINGS; SYSTEM; HIV-1; INDIA AB Background: The last decade has seen enormous advances in HIV treatment and care, but how to implement scaled up HIV testing, prevention, and treatment in low-income areas still presents a formidable public health challenge. South China faces expanding syphilis and sexually transmitted HIV epidemics, but health systems characteristics important for scaling up syphilis and HIV testing have not been defined. Methods: A purposive sample to ensure public, private, and public-private hybrid STI clinic inclusion was selected in a South China city. Eight key informant interviews were conducted with the STI clinic manager, followed by eight focus group discussions with physicians. Data collection relied on a semi-structured format that included questions in each of the following domains: 1) clinical facilities; 2) laboratory capacity with a focus on syphilis/HIV diagnosis; 3) clinic personnel; 4) physical space with a focus on locations to disclose confidential results; 5) financial support. Results: Public STI clinics had free syphilis testing/treatment and laboratory facilities to perform essential syphilis and HIV tests. However, despite serving a large number of STI patients, private STI clinics lacked nontreponemal syphilis testing, HIV testing, and had fewer connections to the public health infrastructure. Formally trained assistant physicians were 2.5 times as common as physicians at STI clinics. Only one of the 8 sites had onsite voluntary counseling and testing (VCT) services available. Conclusion: These STI case studies reveal the potential for expanding integrated syphilis/HIV services at public STI clinics in China. More health services research is needed to guide scale-up of syphilis/HIV testing in China. C1 [Tucker, Joseph D.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Yang, Li-Gang; Yang, Bin] Guangdong Prov Ctr STI Control & Prevent, Guangzhou, Guangdong, Peoples R China. [Zhu, Zheng-Jun] Jiangmen Skin Hosp, Jiangmen, Peoples R China. [Yin, Yue-Pin; Chen, Xiang-Sheng] Natl Ctr STD Control, Nanjing, Peoples R China. [Cohen, Myron S.] UNC, Inst Global Hlth & Infect Dis, Chapel Hill Sch Med, Chapel Hill, NC USA. RP Tucker, JD (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM jtucker4@partners.org FU China Syphilis Working Group; UNC Fogarty AIDS International Research and Training Program (NIH FIC) [D43 TW01039]; UNC Social Science Research on HIV/AIDS in China (NIH NICHD) [R24 HD056670-01]; WHO Rapid Syphilis Test Project (WHO) [OD/TS-08-00088]; American Society for Tropical Medicine and Hygiene Postdoctoral Fellowship; Harvard Initiative for Global Health; US NIH Fogarty Institute FX We acknowledge the China Syphilis Working Group, the UNC Fogarty AIDS International Research and Training Program (NIH FIC D43 TW01039), the UNC Social Science Research on HIV/AIDS in China (NIH NICHD R24 HD056670-01), the WHO Rapid Syphilis Test Project (WHO OD/TS-08-00088), the American Society for Tropical Medicine and Hygiene Postdoctoral Fellowship, the Harvard Initiative for Global Health, and the US NIH Fogarty Institute. The authors would like to thank the assistance of Lu He-Kun, Zhang Bao-Yuan, Huang Shu-Jie, Deng Wei-Jun, Shen Song-Ying, and Wang Cheng. NR 31 TC 15 Z9 15 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD MAR 7 PY 2010 VL 10 AR 58 DI 10.1186/1472-6963-10-58 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 569TS UT WOS:000275625400001 PM 20205942 ER PT J AU McGurk, R Seco, J Riboldi, M Wolfgang, J Segars, P Paganetti, H AF McGurk, Ross Seco, Joao Riboldi, Marco Wolfgang, John Segars, Paul Paganetti, Harald TI Extension of the NCAT phantom for the investigation of intra-fraction respiratory motion in IMRT using 4D Monte Carlo SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID 4-DIMENSIONAL COMPUTED-TOMOGRAPHY; ORGAN MOTION; DOSE CALCULATIONS; TUMOR MOTION; LUNG IMRT; MULTILEAF COLLIMATOR; HUMAN ANATOMY; RADIOTHERAPY; SIMULATION; MODEL AB The purpose of this work was to create a computational platform for studying motion in intensity modulated radiotherapy (IMRT). Specifically, the non-uniform rational B-spline (NURB) cardiac and torso (NCAT) phantom was modified for use in a four-dimensional Monte Carlo (4D-MC) simulation system to investigate the effect of respiratory-induced intra-fraction organ motion on IMRT dose distributions as a function of diaphragm motion, lesion size and lung density. Treatment plans for four clinical scenarios were designed: diaphragm peak-to-peak amplitude of 1 cm and 3 cm, and two lesion sizes 2 cm and 4 cm diameter placed in the lower lobe of the right lung. Lung density was changed for each phase using a conservation of mass calculation. Further, a new heterogeneous lung model was implemented and tested. Each lesion had an internal target volume (ITV) subsequently expanded by 15 mm isotropically to give the planning target volume (PTV). The PTV was prescribed to receive 72 Gy in 40 fractions. The MLC leaf sequence defined by the planning system for each patient was exported and used as input into the MC system. MC simulations using the dose planning method (DPM) code together with deformable image registration based on the NCAT deformation field were used to find a composite dose distribution for each phantom. These composite distributions were subsequently analyzed using information from the dose volume histograms (DVH). Lesion motion amplitude has the largest effect on the dose distribution. Tumor size was found to have a smaller effect and can be mitigated by ensuring the planning constraints are optimized for the tumor size. The use of a dynamic or heterogeneous lung density model over a respiratory cycle does not appear to be an important factor with a <= 0.6% change in the mean dose received by the ITV, PTV and right lung. The heterogeneous model increases the realism of the NCAT phantom and may provide more accurate simulations in radiation therapy investigations that use the phantom. This work further evaluates the NCAT phantom for use as a tool in radiation therapy research in addition to its extensive use in diagnostic imaging and nuclear medicine research. Our results indicate that the NCAT phantom, combined with 4D-MC simulations, is a useful tool in radiation therapy investigations and may allow the study of relative effects in many clinically relevant situations. C1 [McGurk, Ross; Seco, Joao; Wolfgang, John; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Seco, Joao; Wolfgang, John; Paganetti, Harald] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Riboldi, Marco] Politecn Milano Univ, Dept Bioengn, TBMLab, I-20133 Milan, Italy. [Segars, Paul] Duke Univ, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA. RP McGurk, R (reprint author), Duke Univ, Med Phys Grad Program, Durham, NC 27705 USA. EM ross.mcgurk@duke.edu RI Seco, Joao/J-4451-2012; Riboldi, Marco/I-2980-2014 OI Riboldi, Marco/0000-0002-2431-4966 FU Fulbright New Zealand Science and Technology Scholarship; NIH [R01-CA 111590] FX This work was supported by a Fulbright New Zealand Science and Technology Scholarship and by the NIH under R01-CA 111590 'Four-dimensional Monte Carlo dose calculation'. NR 52 TC 11 Z9 12 U1 0 U2 3 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 MAR 7 PY 2010 VL 55 IS 5 BP 1475 EP 1490 DI 10.1088/0031-9155/55/5/014 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 555YY UT WOS:000274554100014 PM 20157230 ER PT J AU Ramanathan, L Hu, SX Frautschy, SA Siegel, JM AF Ramanathan, Lalini Hu, Shuxin Frautschy, Sally A. Siegel, Jerome M. TI Short-term total sleep deprivation in the rat increases antioxidant responses in multiple brain regions without impairing spontaneous alternation behavior SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Total sleep deprivation; Y maze; Metabolic activity; Antioxidant responses; Rat ID GLUTATHIONE DEPLETION; SUPEROXIDE-DISMUTASE; PARADOXICAL SLEEP; OXIDATIVE STRESS; SPATIAL MEMORY; HIPPOCAMPUS; DECREASES; ENZYMES; MICE; FRAGMENTATION AB Total sleep deprivation (TSD) induces a broad spectrum of cognitive, behavioral and cellular changes. We previously reported that long term (5-11 days) TSD in the rat, by the disk-over-water method, decreases the activity of the antioxidant enzyme superoxide dismutase (SOD) in the brainstem and hippocampus. To gain insight into the mechanisms causing cognitive impairment, here we explore the early associations between metabolic activity, antioxidant responses and working memory (one form of cognitive impairment). Specifically we investigated the impact of short-term (6h) TSD, by gentle handling, on the levels of the endogenous antioxidant, total glutathione (GSHt), and the activities of the antioxidative enzymes, SOD and glutathione peroxidase (GPx). Short-term TSD had no significant impact on SOD activity, but increased GSHt levels in the rat cortex, brainstem and basal forebrain, and GPx activity in the rat hippocampus and cerebellum. We also observed increased activity of hexokinase, (HK), the rate limiting enzyme of glucose metabolism, in the rat cortex and hypothalamus. We further showed that 6 h of TSD leads to increased exploratory behavior to a new environment, without impairing spontaneous alternation behavior (SAB) in the Y maze. We conclude that acute (6 h) sleep loss may trigger compensatory mechanisms (like increased antioxidant responses) that prevent initial deterioration in working memory. Published by Elsevier B.V. C1 [Ramanathan, Lalini; Siegel, Jerome M.] Greater Los Angeles Hlth Care Syst, Neurobiol Res 151A3, North Hills, CA USA. [Ramanathan, Lalini; Siegel, Jerome M.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Hu, Shuxin; Frautschy, Sally A.] Greater Los Angeles Hlth Care Syst, Geriatr Res & Educ Clin Ctr 151A3, North Hills, CA USA. [Hu, Shuxin; Frautschy, Sally A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Frautschy, Sally A.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. RP Siegel, JM (reprint author), VA GLAHS Sepulveda, Neurobiol Res 151A3,16111 Plummer St, North Hills, CA 91343 USA. EM jsiegel@ucla.edu RI Sanguansri, Luz/B-6630-2011 OI Sanguansri, Luz/0000-0003-1908-7604 FU Department of Veteran Affairs [HL-060296, HL-41370, MH-64109] FX This research was supported by grants HL-060296, HL-41370 and MH-64109 and by the Medical Research Services of the Department of Veteran Affairs. NR 31 TC 17 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 5 PY 2010 VL 207 IS 2 BP 305 EP 309 DI 10.1016/j.bbr.2009.10.014 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 558RC UT WOS:000274761800009 PM 19850085 ER PT J AU Heinrichs, SC Leite-Morris, KA Carey, RJ Kaplan, GB AF Heinrichs, S. C. Leite-Morris, K. A. Carey, R. J. Kaplan, G. B. TI Baclofen enhances extinction of opiate conditioned place preference SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Opiate; Baclofen; Conditioning; Extinction; Reconsolidation; Reward; Mouse ID VENTROMEDIAL PREFRONTAL CORTEX; STIMULUS-REWARD MEMORY; COCAINE-SEEKING; D-CYCLOSERINE; BASOLATERAL AMYGDALA; FEAR EXTINCTION; RATS; DRUG; REINSTATEMENT; AGONIST AB Conditioned opiate reward (COR) is rapidly acquired and slowly extinguished. The slow rate of extinction of the salience of drug-related cues contributes to drug craving and relapse. The gamma-aminobutyric acid receptor type B (GABA(B)) agonist, baclofen, attenuates the unconditioned rewarding actions of several drugs of abuse and was investigated for effects on the extinction of COR. C57BL/6 mice were utilized in an unbiased conditioned place preference (CPP) protocol using morphine (10 mg/kg, s.c.) and saline. CPP was measured by increases in time spent in the morphine-associated (CS+) vs. the saline-associated (CS-) chamber in a 15-min test after four morphine and four saline alternated conditioning sessions. CPP and locomotor sensitization were produced to the CS+ chamber. Subsequently, sixteen daily extinction sessions were conducted with eithervehicle or baclofen (1 or 2.5 mg/kg, s.c.) treatment given either before or after the sessions. This design was used to create the baclofen drug state before or after the activation of the CPP memory trace in the extinction protocol. After morphine CPP development, its extinction was significantly facilitated in a dose-dependent manner by post-session, but not by pre-session, baclofen treatments. No significant sedative effects of baclofen were detected during any extinction training or testing phase. Baclofen treatment facilitated the extinction of COR and reduced conditioned sensitization during extinction when given after, but not before, the activation of the CPP memory trace. Baclofen appears to have disrupted reconsolidation of conditioned reward memory during extinction training and might similarly facilitate extinction learning in human opiate addiction. (C) 2009 Elsevier B.V. All rights reserved. C1 [Leite-Morris, K. A.; Kaplan, G. B.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Leite-Morris, K. A.; Kaplan, G. B.] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA. [Leite-Morris, K. A.; Kaplan, G. B.] Boston Univ, Sch Med, Dept Expt Therapeut, Boston, MA 02118 USA. [Kaplan, G. B.] Mental Hlth Serv, Boston, MA USA. [Heinrichs, S. C.; Leite-Morris, K. A.] VA Boston Healthcare Syst, Res Serv, Boston, MA USA. [Carey, R. J.] VA Med Ctr, Res & Dev, Syracuse, NY USA. [Carey, R. J.] SUNY Hlth Sci Ctr, Syracuse, NY 13210 USA. RP Leite-Morris, KA (reprint author), VA Boston Healthcare Syst 116A, 150 S Huntington Ave, Boston, MA 02130 USA. EM Gary.Kaplan@va.gov OI Leite-Morris, Kimberly/0000-0003-3407-7375 FU Department of Veterans Affairs FX The authors gratefully acknowledge the technical assistance of Angela Pieroni and Cynthia Philip. This research was supported by a grant from the Department of Veterans Affairs. The funding agency had no involvement in study design, collection, analysis or interpretation of the data, writing of the report or decision to submit the paper for publication. Authors Heinrichs, Leite-Morris, Carey and Kaplan designed the study. Author Heinrichs collected the behavioral measures, undertook the statistical analysis, and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. NR 45 TC 26 Z9 30 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 5 PY 2010 VL 207 IS 2 BP 353 EP 359 DI 10.1016/j.bbr.2009.10.013 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 558RC UT WOS:000274761800014 PM 19840820 ER PT J AU Abraham, S Sheridan, SD Laurent, LC Albert, K Stubban, C Ulitsky, I Miller, B Loring, JF Rao, RR AF Abraham, Sheena Sheridan, Steven D. Laurent, Louise C. Albert, Kelsey Stubban, Christopher Ulitsky, Igor Miller, Bradley Loring, Jeanne F. Rao, Raj R. TI Propagation of human embryonic and induced pluripotent stem cells in an indirect co-culture system SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Human pluripotent stem cells; Microporous membranes; Indirect co-culture; Cell separation ID REAL-TIME PCR; HUMAN BLASTOCYSTS; LINES; CULTURE; DIFFERENTIATION AB We have developed and validated a microporous poly(ethylene terephthalate) membrane-based indirect co-culture system for human pluripotent stem cell (hPSC) propagation, which allows real-time conditioning of the culture medium with human fibroblasts while maintaining the complete separation of the two cell types. The propagation and pluripotent characteristics of a human embryonic stem cell (hESC) line and a human induced pluripotent stem cell (hiPSC) line were studied in prolonged culture in this system. We report that hPSCs cultured on membranes by indirect co-culture with fibroblasts were indistinguishable by multiple criteria from hPSCs cultured directly on a fibroblast feeder layer. Thus this co-culture system is a significant advance in hPSC culture methods, providing a facile stem cell expansion system with continuous medium conditioning while preventing mixing of hPSCs and feeder cells. This membrane culture method will enable testing of novel feeder cells and differentiation studies using co-culture with other cell types, and will simplify stepwise changes in culture conditions for staged differentiation protocols. (C) 2010 Elsevier Inc. All rights reserved. C1 [Sheridan, Steven D.; Loring, Jeanne F.] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Abraham, Sheena; Albert, Kelsey; Rao, Raj R.] Virginia Commonwealth Univ, Richmond, VA USA. [Sheridan, Steven D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Laurent, Louise C.] Scripps Res Inst, Ctr Regenerat Med, La Jolla, CA 92037 USA. [Laurent, Louise C.] Univ Calif San Diego, San Diego, CA 92103 USA. [Stubban, Christopher; Loring, Jeanne F.] Burnham Inst Med Res, La Jolla, CA USA. [Ulitsky, Igor] Tel Aviv Univ, Sch Comp Sci, Tel Aviv, Israel. [Miller, Bradley] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. RP Loring, JF (reprint author), MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, E25-618, Cambridge, MA 02139 USA. EM jloring@scripps.edu; rrrao@vcu.edu OI Ulitsky, Igor/0000-0003-0555-6561 FU NIH [5K12HD000849-20, T15 HL085028-01, T15-HL074303]; CIRM [RN2-00931]; Tel Aviv University; Israel Science Foundation [385/06]; Alzheimer's Association [IIRG-05-14975, CIRM RT1-01108]; NSF-CAREER [0744556] FX Funding in part was provided by NIH 5K12HD000849-20 (L.C.L.), CIRM RN2-00931 (L.C.L.), Tel Aviv University (IU), Israel Science Foundation 385/06 (R.S.), NIH T15 HL085028-01 (J.F.L.), Alzheimer's Association IIRG-05-14975 (J.F.L.), CIRM RT1-01108 (J.F.L.), NSF-CAREER 0744556 (R.R.R.), NIH T15-HL074303 (R.R.R.). NR 23 TC 8 Z9 8 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 5 PY 2010 VL 393 IS 2 BP 211 EP 216 DI 10.1016/j.bbrc.2010.01.101 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 573WT UT WOS:000275946700006 PM 20117095 ER PT J AU Eiring, AM Harb, JG Neviani, P Garton, C Oaks, JJ Spizzo, R Liu, SJ Schwind, S Santhanam, R Hickey, CJ Becker, H Chandler, JC Andino, R Cortes, J Hokland, P Huettner, CS Bhatia, R Roy, DC Liebhaber, SA Caligiuri, MA Marcucci, G Garzon, R Croce, CM Calin, GA Perrotti, D AF Eiring, Anna M. Harb, Jason G. Neviani, Paolo Garton, Christopher Oaks, Joshua J. Spizzo, Riccardo Liu, Shujun Schwind, Sebastian Santhanam, Ramasamy Hickey, Christopher J. Becker, Heiko Chandler, Jason C. Andino, Raul Cortes, Jorge Hokland, Peter Huettner, Claudia S. Bhatia, Ravi Roy, Denis C. Liebhaber, Stephen A. Caligiuri, Michael A. Marcucci, Guido Garzon, Ramiro Croce, Carlo M. Calin, George A. Perrotti, Danilo TI miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts SO CELL LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; FRAGILE-X-SYNDROME; C/EBP-ALPHA; CD34(+) CELLS; HUMAN CANCER; EXPRESSION; BCR/ABL; MICRORNAS; BINDING; DIFFERENTIATION AB MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins. C1 [Eiring, Anna M.; Harb, Jason G.; Neviani, Paolo; Garton, Christopher; Oaks, Joshua J.; Santhanam, Ramasamy; Caligiuri, Michael A.; Marcucci, Guido; Garzon, Ramiro; Croce, Carlo M.; Perrotti, Danilo] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, Columbus, OH 43210 USA. [Liu, Shujun; Schwind, Sebastian; Hickey, Christopher J.; Becker, Heiko; Chandler, Jason C.; Caligiuri, Michael A.; Marcucci, Guido; Garzon, Ramiro] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Schwind, Sebastian; Hickey, Christopher J.; Becker, Heiko; Caligiuri, Michael A.; Marcucci, Guido; Garzon, Ramiro; Croce, Carlo M.; Perrotti, Danilo] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Perrotti, Danilo] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. [Andino, Raul] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Spizzo, Riccardo; Cortes, Jorge; Calin, George A.] Univ Texas Houston, MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Dept Leukemia, Houston, TX 77030 USA. [Spizzo, Riccardo; Cortes, Jorge; Calin, George A.] Univ Texas Houston, MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Dept Expt Therapeut, Houston, TX 77030 USA. [Hokland, Peter] Aarhus Univ, Dept Hematol, DK-8000 Aarhus C, Denmark. [Huettner, Claudia S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Bhatia, Ravi] City Hope Natl Med Ctr, Dept Hematopoiet Stem Cell & Leukemia Res, Duarte, CA 91010 USA. [Roy, Denis C.] Hop Maison Neuve Rosemont, Dept Hematol Oncol, Montreal, PQ H3T 1J4, Canada. [Roy, Denis C.] Univ Montreal, Montreal, PQ H3T 1J4, Canada. [Liebhaber, Stephen A.] Univ Penn, Sch Med, Dept Genet & Med, Philadelphia, PA 19104 USA. RP Perrotti, D (reprint author), Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, Columbus, OH 43210 USA. EM danilo.perrotti@osumc.edu RI Garzon, Ramiro/E-3104-2011; Perrotti, Danilo/E-3852-2011; OI Spizzo, Riccardo/0000-0001-7772-0960; Hokland, Peter/0000-0002-1177-9756 FU National Cancer Institute [CA095512, CA16058]; NIH, Bethesda, MD, USA; US Army [W81XWH-07-1-0270]; American-Italian Cancer Foundation; Fonds de la Recherche en Sante du Quebec; OSU Graduate School; Leukemia and Lymphoma Society; M.D. Anderson Research Trust; University of Texas System Regents FX This work was supported in part by grants from the National Cancer Institute CA095512 (D.P.), CA16058 (OSU-CCC), NIH, Bethesda, MD, USA; the US Army, CML Research Program, W81XWH-07-1-0270 (D. P.); the American-Italian Cancer Foundation (P.N.); Fonds de la Recherche en Sante du Quebec (D.C.R.); and AGGRS from The OSU Graduate School (A.M.E.). D.P. is a Scholar of The Leukemia and Lymphoma Society. G.A.C. is a Fellow of the M.D. Anderson Research Trust and Scholar of the University of Texas System Regents. We thank J.-S. Chang, M. Odeh, and A. Martin for technical assistance and S. Lee for editorial assistance; T. Skorski (Temple University, Philadelphia, PA, USA) for providing PIM1 cDNAs; F. Racke ( OSU, Columbus OH, USA) for histopathology analysis; B. Calabretta (TJU, Philadelphia, PA, USA), R. Arlinghaus ( MDACC, Houston, TX, USA), and K. Huebner (OSU) for critical reading of the manuscript. NR 45 TC 256 Z9 278 U1 5 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 5 PY 2010 VL 140 IS 5 BP 652 EP 665 DI 10.1016/j.cell.2010.01.007 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 564EZ UT WOS:000275197400015 PM 20211135 ER PT J AU North, TE Goessling, W AF North, Trista E. Goessling, Wolfram TI NOTCHing an Arrow at Cord Blood: Translating Stem Cell Knowledge into Clinical Practice SO CELL STEM CELL LA English DT Editorial Material ID TRANSPLANTATION; EXPANSION AB Umbilical cord transplants have emerged as an important therapeutic option for patients with leukemia and lymphoma. A recent study in Nature Medicine highlights the potential and challenges of translating cell-based therapies to the clinic. C1 [North, Trista E.] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [North, Trista E.; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Genet,Med Sch, Boston, MA 02115 USA. [North, Trista E.; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Gastroenterol,Med Sch, Boston, MA 02115 USA. [Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP North, TE (reprint author), Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. EM tnorth@bidmc.harvard.edu; wgoessling@partners.org NR 10 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD MAR 5 PY 2010 VL 6 IS 3 BP 186 EP 187 DI 10.1016/j.stem.2010.02.009 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 577WL UT WOS:000276254600003 PM 20207217 ER PT J AU Sanda, T Li, X Gutierrez, A Ahn, Y Neuberg, DS O'Neil, J Strack, PR Winter, CG Winter, SS Larson, RS von Boehmer, H Look, AT AF Sanda, Takaomi Li, Xiaoyu Gutierrez, Alejandro Ahn, Yebin Neuberg, Donna S. O'Neil, Jennifer Strack, Peter R. Winter, Christopher G. Winter, Stuart S. Larson, Richard S. von Boehmer, Harald Look, A. Thomas TI Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia SO BLOOD LA English DT Article ID NF-KAPPA-B; HISTONE DEACETYLASE INHIBITOR; GENE-EXPRESSION SIGNATURES; TUMOR-SUPPRESSOR; C-MYC; HOMOZYGOUS DELETIONS; SIGNALING PATHWAY; MTS1 P16(INK4A); NOTCH1; CHILDHOOD AB To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for gamma-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-kappa B and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells. (Blood. 2010;115:1735-1745) C1 [Li, Xiaoyu; von Boehmer, Harald] Harvard Univ, Dept Canc Immunol & AIDS, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Sanda, Takaomi; Gutierrez, Alejandro; Ahn, Yebin; O'Neil, Jennifer; Look, A. Thomas] Harvard Univ, Sch Med, Dept Pediat Oncol, Boston, MA 02115 USA. [Gutierrez, Alejandro] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Neuberg, Donna S.] Harvard Univ, Dept Biostat & Computat Biol, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Strack, Peter R.; Winter, Christopher G.] Merck Res Labs, Boston, MA USA. [Winter, Stuart S.] Univ New Mexico, Hlth Sci Ctr, Dept Pediat, Albuquerque, NM 87131 USA. [Larson, Richard S.] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. RP von Boehmer, H (reprint author), Harvard Univ, Dept Canc Immunol & AIDS, Sch Med, Dana Farber Canc Inst, 44 Binney St,Smith 736, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu; thomas_look@dfci.harvard.edu OI Gutierrez, Alejandro/0000-0002-0249-9007 FU National Cancer Institute [5P01CA109901-040001]; Lymphoma Research Foundation; Claudia Adams Barr; [COG 9900]; [CA98543]; [CA114766] FX This work was supported by the National Cancer Institute (grant 5P01CA109901-040001; A. T. L. and H. v. B) and by the Lymphoma Research Foundation fellowship and the Claudia Adams Barr grant (X. L.). COG cell banking and sample distribution were supported by the COG 9900 cell biology study and grants CA98543 and CA114766. NR 46 TC 30 Z9 30 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 4 PY 2010 VL 115 IS 9 BP 1735 EP 1745 DI 10.1182/blood-2009-07-235143 PG 11 WC Hematology SC Hematology GA 571KR UT WOS:000275751200014 PM 20007543 ER PT J AU Robledo, RF Lambert, AJ Birkenmeier, CS Cirlan, MV Cirlan, AFM Campagna, DR Lux, SE Peters, LL AF Robledo, Raymond F. Lambert, Amy J. Birkenmeier, Connie S. Cirlan, Marius V. Cirlan, Andreea Flavia M. Campagna, Dean R. Lux, Samuel E. Peters, Luanne L. TI Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in alpha-spectrin-deficient red cells SO BLOOD LA English DT Article ID HEMATOLOGICALLY IMPORTANT MUTATIONS; HERMANSKY-PUDLAK-SYNDROME; MESSENGER-RNA DECAY; MEMBRANE SKELETON; HEREDITARY ELLIPTOCYTOSIS; ERYTHROCYTE-MEMBRANE; MOUSE MODEL; ANKYRIN VARIANTS; HEMOLYTIC-ANEMIA; ALTERED LEVELS AB Five spontaneous, allelic mutations in the alpha-spectrin gene, Spna1, have been identified in mice (spherocytosis [sph], sph(1J), sph(2J), sph(2BC), sph(Dem)). All cause severe hemolytic anemia. Here, analysis of 3 new alleles reveals previously unknown consequences of red blood cell (RBC) spectrin deficiency. In sph(3J), a missense mutation (H2012Y) in repeat 19 introduces a cryptic splice site resulting in premature termination of translation. In sph(Ihj), a premature stop codon occurs (Q1853Stop) in repeat 18. Both mutations result in markedly reduced RBC membrane spectrin content, decreased band 3, and absent beta-adducin. Reevaluation of available, previously described sph alleles reveals band 3 and adducin deficiency as well. In sph(4J), a missense mutation occurs in the C-terminal EF hand domain (C2384Y). Notably, an equally severe hemolytic anemia occurs despite minimally decreased membrane spectrin with normal band 3 levels and present, although reduced, beta-adducin. The severity of anemia in sph(4J) indicates that the highly conserved cysteine residue at the C-terminus of alpha-spectrin participates in interactions critical to membrane stability. The data reinforce the notion that a membrane bridge in addition to the classic protein 4.1-p55-glycophorin C linkage exists at the RBC junctional complex that involves interactions between spectrin, adducin, and band 3. (Blood. 2010;115:1804-1814) C1 [Robledo, Raymond F.; Lambert, Amy J.; Birkenmeier, Connie S.; Peters, Luanne L.] Jackson Lab, Bar Harbor, ME 04609 USA. [Cirlan, Marius V.] Petre Andrei Univ, Fac Med Dent, Iasi, Romania. [Cirlan, Andreea Flavia M.] Univ Agr Sci & Vet Med, Fac Vet Med, Iasi, Romania. [Campagna, Dean R.] Childrens Hosp Boston, Div Pathol, Boston, MA USA. [Lux, Samuel E.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, Boston, MA USA. [Lux, Samuel E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Peters, LL (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM luanne.peters@jax.org FU National Institutes of Health [HL088468, HL075714, HL081608]; Jackson Laboratory Mouse Mutant Resource [RR01183]; National Cancer Institute [CA34196] FX This work was supported by National Institutes of Health grants HL088468 and HL075714 (to L. L. P.), HL081608 (to S. E. L.); RR01183 (The Jackson Laboratory Mouse Mutant Resource); and The National Cancer Institute (CA34196, The Jackson Laboratory). NR 53 TC 7 Z9 7 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 MAR 4 PY 2010 VL 115 IS 9 BP 1804 EP 1814 DI 10.1182/blood-2009-07-232199 PG 11 WC Hematology SC Hematology GA 571KR UT WOS:000275751200022 PM 20056793 ER PT J AU Canault, M Duerschmied, D Brill, A Stefanini, L Schatzberg, D Cifuni, SM Bergmeier, W Wagner, DD AF Canault, Matthias Duerschmied, Daniel Brill, Alexander Stefanini, Lucia Schatzberg, Daphne Cifuni, Stephen M. Bergmeier, Wolfgang Wagner, Denisa D. TI p38 mitogen-activated protein kinase activation during platelet storage: consequences for platelet recovery and hemostatic function in vivo SO BLOOD LA English DT Article ID ALPHA-CONVERTING-ENZYME; CYTOSOLIC PHOSPHOLIPASE A(2); MAP KINASE; ARACHIDONIC-ACID; GLYCOPROTEIN-IB; MOUSE MODEL; PHOSPHORYLATION; INHIBITION; ADAM17; VITRO AB Platelets undergo several modifications during storage that reduce their post-transfusion survival and functionality. One important feature of these changes, which are known as platelet storage lesion, is the shedding of the surface glycoproteins GPIb-alpha and GPV. We recently demonstrated that tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) mediates mitochondrial injury-induced shedding of adhesion receptors and that TACE activity correlates with reduced posttransfusion survival of these cells. We now confirm that TACE mediates receptor shedding and clearance of platelets stored for 16 hours at 37 degrees C or 22 degrees C. We further demonstrate that both storage and mitochondrial injury lead to the phosphorylation of p38 mitogen-activated kinase (MAPK) in platelets and that TACE-mediated receptor shedding from mouse and human platelets requires p38 MAP kinase signaling. Protein kinase C, extracellular regulated-signal kinase MAPK, and caspases were not involved in TACE activation. Both inhibition of p38 MAPK and inactivation of TACE during platelet storage led to a markedly improved posttransfusion recovery and hemostatic function of platelets in mice. p38 MAPK inhibitors had only minor effects on the aggregation of fresh platelets under static or flow conditions in vitro. In summary, our data suggest that inhibition of p38 MAPK or TACE during storage may significantly improve the quality of stored platelets. (Blood. 2010;115:1835-1842) C1 [Canault, Matthias; Duerschmied, Daniel; Brill, Alexander; Schatzberg, Daphne; Cifuni, Stephen M.; Wagner, Denisa D.] Immune Dis Inst, Boston, MA 02115 USA. [Canault, Matthias; Duerschmied, Daniel; Brill, Alexander; Schatzberg, Daphne; Cifuni, Stephen M.; Wagner, Denisa D.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Canault, Matthias; Duerschmied, Daniel; Brill, Alexander; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Stefanini, Lucia; Bergmeier, Wolfgang] Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA. [Stefanini, Lucia; Bergmeier, Wolfgang] Thomas Jefferson Univ, Cardeza Fdn, Philadelphia, PA 19107 USA. RP Wagner, DD (reprint author), Immune Dis Inst, 3 Blackfan Cir, Boston, MA 02115 USA. EM wolfgang.bergmeier@jefferson.edu; wagner@idi.harvard.edu RI Silva, Mariana/B-9530-2012; stefanini, lucia/K-3992-2016; Canault, Matthias/H-5128-2013 OI stefanini, lucia/0000-0001-7420-301X; Canault, Matthias/0000-0002-7880-5250 FU National Heart, Lung, and Blood Institute of the National Institutes of Health [P01 HL056949]; American Heart Association [0630044N] FX This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grant P01 HL056949; D. D. W.) and the American Heart Association (Scientist Development grant 0630044N; W. B.). NR 36 TC 39 Z9 42 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 4 PY 2010 VL 115 IS 9 BP 1835 EP 1842 DI 10.1182/blood-2009-03-211706 PG 8 WC Hematology SC Hematology GA 571KR UT WOS:000275751200025 PM 19965619 ER PT J AU Litzow, MR Tarima, S Perez, WS Bolwell, BJ Cairo, MS Camitta, BM Cutler, CS de Lima, M DiPersio, JF Gale, RP Keating, A Lazarus, HM Luger, S Marks, DI Maziarz, RT McCarthy, PL Pasquini, MC Phillips, GL Rizzo, JD Sierra, J Tallman, MS Weisdorf, DJ AF Litzow, Mark R. Tarima, Sergey Perez, Waleska S. Bolwell, Brian J. Cairo, Mitchell S. Camitta, Bruce M. Cutler, Corey S. de Lima, Marcos DiPersio, John F. Gale, Robert Peter Keating, Armand Lazarus, Hillard M. Luger, Selina Marks, David I. Maziarz, Richard T. McCarthy, Philip L. Pasquini, Marcelo C. Phillips, Gordon L. Rizzo, J. Douglas Sierra, Jorge Tallman, Martin S. Weisdorf, Daniel J. TI Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; ACUTE NONLYMPHOCYTIC LEUKEMIA; DOSE CYTOSINE-ARABINOSIDE; LATE COMPLICATION; HOST DISEASE; RISK-FACTORS; LYMPHOMA; CHEMOTHERAPY; CYTOGENETICS AB Therapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P < .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation. (Blood. 2010; 115: 1850-1857) C1 [Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Adult Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Perez, Waleska S.; Pasquini, Marcelo C.; Rizzo, J. Douglas] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Bolwell, Brian J.] Cleveland Clin Fdn, Cleveland, OH USA. [Cairo, Mitchell S.] Morgan Stanley Childrens Hosp NY Presbyterian, New York, NY USA. [Camitta, Bruce M.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [de Lima, Marcos] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [DiPersio, John F.] St Louis Childrens Hosp, St Louis, MO USA. [Gale, Robert Peter] Celgene Corp, Summit, NJ USA. [Keating, Armand] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Luger, Selina] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Marks, David I.] United Bristol Healthcare, Bristol, Avon, England. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [McCarthy, Philip L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Phillips, Gordon L.] Univ Rochester, Med Ctr, Rochester, NY 14627 USA. [Sierra, Jorge] Hosp Santa Cruz & Sant Pau, Barcelona, Spain. [Tallman, Martin S.] NW Mem Hosp, Chicago, IL 60611 USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Med Ctr, Adult Blood & Marrow Transplant Program, MMC 480,516 Delaware St SE, Minneapolis, MN 55455 USA. EM weisd001@umn.edu RI Lopez, Dulce/A-7700-2013 FU National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI) [5U01HL069294]; National Institute of Allergy and Infectious Diseases (NIAID); Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); 2 grants, N00014-06-1-0704 and N00014-08-1-0058, from the Office of Naval Research; and grants from AABB, Aetna, American Society for Blood and Marrow Transplantation, Amgen Inc, anonymous donation to the Medical College of Wisconsin, Astellas Pharma US Inc, Baxter International Inc, Bayer HealthCare Pharmaceuticals, Be the Match Foundation, Biogen IDEC, Bio Marin Pharmaceutical Inc, Biovitrum AB, BloodCenter of Wisconsin, Blue Cross and Blue Shield Association, Bone Marrow Foundation, Canadian Blood and Marrow Transplant Group, CaridianBCT, Celgene Corporation, CellGenix GmbH, Centers for Disease Control and Prevention, Children's Leukemia Research Association, ClinImmune Labs, CTI Clinical Trial and Consulting Services, Cubist Pharmaceuticals, Cylex Inc, CytoTherm, DOR BioPharma Inc, Dynal Biotech (an Invitrogen Company), Eisai Inc, Enzon Pharmaceuticals Inc, European Group for Blood and Marrow Transplantation, Gamida Cell Ltd, GE Healthcare, Genen-tech Inc, Genzyme Corporation, Histogenetics Inc, HKS Medical Information Systems, Hospira Inc, Infectious Diseases Society of America, Kiadis Pharma, Kirin Brewery Co Ltd, The Leukemia & Lymphoma Society, Merck & Company, The Medical College of Wisconsin, MGI Pharma Inc, Michigan Community Blood Centers, Millennium Pharmaceuticals Inc, Miller Pharmacal Group, Milliman USA Inc, Miltenyi Biotec Inc, National Marrow Donor Program, Nature Publishing Group, New York Blood Center, Novartis Oncology, Oncology Nursing Society, Osiris Therapeutics Inc, Otsuka America Pharmaceutical Inc, Pall Life Sciences, Pfizer Inc, Saladax Biomedical Inc, Schering Corporation, Society for Healthcare Epidemiology of America, StemCyte Inc, StemSoft Software Inc, Sysmex America Inc, Teva Pharmaceutical Industries, THERAKOS Inc, Thermogenesis Corporation, Vidacare Corporation, Vion Pharmaceuticals Inc, ViraCor Laboratories, ViroPharma Inc, and Wellpoint Inc. NR 30 TC 82 Z9 89 U1 3 U2 5 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 MAR 4 PY 2010 VL 115 IS 9 BP 1850 EP 1857 DI 10.1182/blood-2009-10-249128 PG 8 WC Hematology SC Hematology GA 571KR UT WOS:000275751200027 PM 20032503 ER PT J AU Hirschey, MD Shimazu, T Goetzman, E Jing, E Schwer, B Lombard, DB Grueter, CA Harris, C Biddinger, S Ilkayeva, OR Stevens, RD Li, Y Saha, AK Ruderman, NB Bain, JR Newgard, CB Farese, RV Alt, F Kahn, CR Verdin, E AF Hirschey, Matthew D. Shimazu, Tadahiro Goetzman, Eric Jing, Enxuan Schwer, Bjoern Lombard, David B. Grueter, Carrie A. Harris, Charles Biddinger, Sudha Ilkayeva, Olga R. Stevens, Robert D. Li, Yu Saha, Asish K. Ruderman, Neil B. Bain, James R. Newgard, Christopher B. Farese, Robert V., Jr. Alt, FrederickW. Kahn, C. Ronald Verdin, Eric TI SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation SO NATURE LA English DT Article ID COA DEHYDROGENASE-DEFICIENCY; GENE-EXPRESSION PROFILES; LYSINE ACETYLATION; METABOLIC SYNDROME; INSULIN-RESISTANCE; HEPATIC STEATOSIS; BETA-OXIDATION; LIVER-DISEASE; IN-VIVO; MICE AB Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins(3). Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting. C1 [Hirschey, Matthew D.; Shimazu, Tadahiro; Schwer, Bjoern; Verdin, Eric] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Hirschey, Matthew D.; Shimazu, Tadahiro; Schwer, Bjoern; Verdin, Eric] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Goetzman, Eric] Univ Pittsburgh, Sch Med, Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15201 USA. [Jing, Enxuan; Biddinger, Sudha; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Schwer, Bjoern; Lombard, David B.; Alt, FrederickW.] Harvard Univ, Sch Med, Childrens Hosp,Immune Dis Inst,Dept Genet, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA. [Grueter, Carrie A.; Harris, Charles; Farese, Robert V., Jr.] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. [Ilkayeva, Olga R.; Stevens, Robert D.; Bain, James R.; Newgard, Christopher B.] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27704 USA. [Li, Yu] Cell Signaling Technol, Danvers, MA 01923 USA. [Saha, Asish K.; Ruderman, Neil B.] Boston Univ, Med Ctr, Diabet Unit, Boston, MA 02118 USA. [Saha, Asish K.; Ruderman, Neil B.] Boston Univ, Med Ctr, Dept Physiol & Med Biophys, Boston, MA 02118 USA. RP Verdin, E (reprint author), Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. EM everdin@gladstone.ucsf.edu OI Grueter, Carrie/0000-0002-1913-2527; Saha, Asish/0000-0003-1001-5110; Ruderman, Neil/0000-0002-6589-6587; Verdin, Eric/0000-0003-3703-3183; Bain, James/0000-0002-8917-9187; Hirschey, Matthew/0000-0003-4541-5376 FU Elison Medical Foundation; National Institute on Aging; National Institutes of Health (NIH) [PO1 HL068758-06A1, DK019514-29, R01 DK067509-04] FX We thank T. Canavan and J. J. Maher for primary hepatocyte preparation (P30 DK026743); C. Harris, L. Swift and the Mouse Metabolic Phenotyping Center (DK59637) for analysis of plasma and tissue lipid analysis; J. Wong for electron microscopy studies, S. Mihalik and D. Cuebas for synthesis of the 2,6-dimethylheptanoyl-CoA; A.-W. Mohsen for purification of recombinant pig ETF; Y.-C. Si for assistance with adenoviral studies; A. Wilson and J. Carroll for preparation of figures; and G. Howard and S. Ordway for editorial review. This work was supported in part by a Senior Scholarship in Aging from the Elison Medical Foundation to E. V. and by institutional support from the J. David Gladstone Institutes. F. W. A. is an Investigator of the Howard Hughes Medical Institute and recipient of an Ellison Medical Foundation Senior Scholar Award. D. B. L. is supported by a K08 award from the National Institute on Aging and the National Institutes of Health. B. S. is supported by an Ellison Medical Foundation/AFAR Senior Postdoctoral Research Grant. N.B.R. and A. K. S. are supported by National Institutes of Health (NIH) grants PO1 HL068758-06A1, DK019514-29 and R01 DK067509-04. NR 43 TC 550 Z9 573 U1 13 U2 135 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 4 PY 2010 VL 464 IS 7285 BP 121 EP U137 DI 10.1038/nature08778 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563GZ UT WOS:000275117500046 PM 20203611 ER PT J AU Hancock, EW Desai, AS Chutkow, WA Dec, GW AF Hancock, E. William Desai, Akshay S. Chutkow, William A. Dec, G. William, Jr. TI A Crisis in Late Pregnancy. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hancock, E. William] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. [Desai, Akshay S.; Chutkow, William A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Dec, G. William, Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hancock, EW (reprint author), Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. EM whancock@cvmed.stanford.edu NR 1 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 MAR 4 PY 2010 VL 362 IS 9 BP 857 EP 858 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 563DQ UT WOS:000275108300029 PM 20200395 ER PT J AU Losina, E Bassett, IV Giddy, J Chetty, S Regan, S Walensky, RP Ross, D Scott, CA Uhler, LM Katz, JN Holst, H Freedberg, KA AF Losina, Elena Bassett, Ingrid V. Giddy, Janet Chetty, Senica Regan, Susan Walensky, Rochelle P. Ross, Douglas Scott, Callie A. Uhler, Lauren M. Katz, Jeffrey N. Holst, Helga Freedberg, Kenneth A. TI The "ART" of Linkage: Pre-Treatment Loss to Care after HIV Diagnosis at Two PEPFAR Sites in Durban, South Africa SO PLOS ONE LA English DT Article ID ANTIRETROVIRAL THERAPY; FOLLOW-UP; OUTCOMES; MORTALITY; PROGRAM; DISTRICT; SERVICE; MALAWI; KENYA AB Background: Although loss to follow-up after antiretroviral therapy (ART) initiation is increasingly recognized, little is known about pre-treatment losses to care (PTLC) after an initial positive HIV test. Our objective was to determine PTLC in newly identified HIV-infected individuals in South Africa. Methodology/Principal Findings: We assembled the South African Test, Identify and Link (STIAL) Cohort of persons presenting for HIV testing at two sites offering HIV and CD4 count testing and HIV care in Durban, South Africa. We defined PTLC as failure to have a CD4 count within 8 weeks of HIV diagnosis. We performed multivariate analysis to identify factors associated with PTLC. From November 2006 to May 2007, of 712 persons who underwent HIV testing and received their test result, 454 (64%) were HIV-positive. Of those, 206 (45%) had PTLC. Infected patients were significantly more likely to have PTLC if they lived >= 10 kilometers from the testing center (RR = 1.37; 95% CI: 1.11-1.71), had a history of tuberculosis treatment (RR = 1.26; 95% CI: 1.00-1.58), or were referred for testing by a health care provider rather than self-referred (RR = 1.61; 95% CI: 1.22-2.13). Patients with one, two or three of these risks for PTLC were 1.88, 2.50 and 3.84 times more likely to have PTLC compared to those with no risk factors. Conclusions/Significance: Nearly half of HIV-infected persons at two high prevalence sites in Durban, South Africa, failed to have CD4 counts following HIV diagnosis. These high rates of pre-treatment loss to care highlight the urgent need to improve rates of linkage to HIV care after an initial positive HIV test. C1 [Losina, Elena; Bassett, Ingrid V.; Regan, Susan; Walensky, Rochelle P.; Scott, Callie A.; Uhler, Lauren M.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Bassett, Ingrid V.; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Losina, Elena; Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Orthoped, Boston, MA 02115 USA. [Losina, Elena; Katz, Jeffrey N.] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. [Losina, Elena; Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, Elena; Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. [Losina, Elena; Bassett, Ingrid V.; Regan, Susan; Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Walensky, Rochelle P.; Katz, Jeffrey N.; Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Walensky, Rochelle P.; Katz, Jeffrey N.; Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Giddy, Janet; Chetty, Senica; Holst, Helga] McCord Hosp, Dept Med, Durban, South Africa. [Ross, Douglas] St Marys Hosp, Dept Med, Durban, South Africa. RP Losina, E (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. EM elosina@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X; Regan, Susan/0000-0003-0940-2017 FU US National Institute of Allergy and Infectious Diseases [R01 AI058736, K24 AI062476, K23 AI068458]; Harvard University Center for AIDS Research [P30 AI42851]; National Institutes of Health [K24 AR 02123]; Doris Duke Charitable Foundation; Harvard University FX This work was supported by the US National Institute of Allergy and Infectious Diseases (R01 AI058736, K24 AI062476, K23 AI068458), the Harvard University Center for AIDS Research P30 AI42851, National Institutes of Health K24 AR 02123, the Doris Duke Charitable Foundation (Clinical Scientist Development Award), and the Harvard University Program on AIDS (HUPA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 106 Z9 109 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 MAR 4 PY 2010 VL 5 IS 3 AR e9538 DI 10.1371/journal.pone.0009538 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 564EW UT WOS:000275197100018 PM 20209059 ER PT J AU Mengshol, JA Golden-Mason, L Arikawa, T Smith, M Niki, T McWilliams, R Randall, JA McMahan, R Zimmerman, MA Rangachari, M Dobrinskikh, E Busson, P Polyak, SJ Hirashima, M Rosen, HR AF Mengshol, John A. Golden-Mason, Lucy Arikawa, Tomohiro Smith, Maxwell Niki, Toshiro McWilliams, Ryan Randall, Jessica A. McMahan, Rachel Zimmerman, Michael A. Rangachari, Manu Dobrinskikh, Evgenia Busson, Pierre Polyak, Stephen J. Hirashima, Mitsuomi Rosen, Hugo R. TI A Crucial Role for Kupffer Cell-Derived Galectin-9 in Regulation of T Cell Immunity in Hepatitis C Infection SO PLOS ONE LA English DT Article ID VIRUS-INFECTION; LIVER-INJURY; HEPATOCELLULAR-CARCINOMA; GLYCAN INTERACTIONS; CD127 EXPRESSION; HCV INFECTION; LYMPHOCYTES; TOLERANCE; TIM-3; APOPTOSIS AB Approximately 200 million people throughout the world are infected with hepatitis C virus (HCV). One of the most striking features of HCV infection is its high propensity to establish persistence (similar to 70-80%) and progressive liver injury. Galectins are evolutionarily conserved glycan-binding proteins with diverse roles in innate and adaptive immune responses. Here, we demonstrate that galectin-9, the natural ligand for the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), circulates at very high levels in the serum and its hepatic expression (particularly on Kupffer cells) is significantly increased in patients with chronic HCV as compared to normal controls. Galectin-9 production from monocytes and macrophages is induced by IFN-gamma, which has been shown to be elevated in chronic HCV infection. In turn, galectin-9 induces proinflammatory cytokines in liver-derived and peripheral mononuclear cells; galectin-9 also induces anti-inflammatory cytokines from peripheral but not hepatic mononuclear cells. Galectin-9 results in expansion of CD4(+) CD25(+) FoxP3(+) CD127(low) regulatory T cells, contraction of CD4+ effector T cells, and apoptosis of HCV-specific CTLs. In conclusion, galectin-9 production by Kupffer cells links the innate and adaptive immune response, providing a potential novel immunotherapeutic target in this common viral infection. C1 [Mengshol, John A.; Golden-Mason, Lucy; McWilliams, Ryan; Randall, Jessica A.; McMahan, Rachel; Dobrinskikh, Evgenia; Rosen, Hugo R.] Univ Colorado, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Aurora, CO USA. [Mengshol, John A.; Rosen, Hugo R.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Golden-Mason, Lucy; Rosen, Hugo R.] Univ Colorado, Sch Med, Div Clin Immunol, Denver, CO USA. [Golden-Mason, Lucy; Rosen, Hugo R.] Natl Jewish Hosp, Denver, CO USA. [Smith, Maxwell] Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA. [Arikawa, Tomohiro; Hirashima, Mitsuomi] Kagawa Med Univ, Dept Immunol & Immunopathol, Kagawa, Japan. [Niki, Toshiro] GalPharma, Kagawa, Japan. [Zimmerman, Michael A.] Univ Colorado, Sch Med, Div Transplant Surg, Aurora, CO USA. [Rangachari, Manu] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Busson, Pierre] Inst Cancerol Gustave Roussy, Villejuif, France. [Polyak, Stephen J.] Univ Washington, Div Lab Med, Seattle, WA 98195 USA. RP Mengshol, JA (reprint author), Univ Colorado, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Aurora, CO USA. EM Hugo.Rosen@ucdenver.edu RI Polyak, Stephen/B-5743-2011 FU National Institutes of Health (NIH) [RO1 DK060590, U19 A 1066328-01] FX This research is supported by National Institutes of Health (NIH) grants RO1 DK060590 and U19 A 1066328-01 (HCV center grant) to HRR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr Niki from Galpharma provided antibodies. NR 52 TC 88 Z9 95 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 MAR 4 PY 2010 VL 5 IS 3 AR e9504 DI 10.1371/journal.pone.0009504 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 564EW UT WOS:000275197100005 PM 20209097 ER PT J AU Sopasakis, VR Liu, PX Suzuki, R Kondo, T Winnay, J Tran, TT Asano, T Smyth, G Sajan, MP Farese, RV Kahn, CR Zhao, JJ AF Sopasakis, Victoria Rotter Liu, Pixu Suzuki, Ryo Kondo, Tatsuya Winnay, Jonathon Tran, Thien T. Asano, Tomoichiro Smyth, Graham Sajan, Mini P. Farese, Robert V. Kahn, C. Ronald Zhao, Jean J. TI Specific Roles of the p110 alpha Isoform of Phosphatidylinsositol 3-Kinase in Hepatic Insulin Signaling and Metabolic Regulation SO CELL METABOLISM LA English DT Article ID PROTEIN-KINASE-C; IA PHOSPHOINOSITIDE 3-KINASES; GLUCOSE-PRODUCTION; CATALYTIC SUBUNIT; EMBRYONIC LETHALITY; DIABETES-MELLITUS; METFORMIN; LIVER; MICE; RESISTANCE AB The class I(A) phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110 alpha catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110 alpha in liver results in markedly blunted insulin signaling with decreased generation Of PIP(3) and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110 beta. As a result, mice with hepatic knockout of p110 alpha display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110 alpha in liver did not respond to metformin treatment. Together, these data indicate that the p11 alpha isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism. C1 [Sopasakis, Victoria Rotter; Suzuki, Ryo; Winnay, Jonathon; Tran, Thien T.; Smyth, Graham; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Liu, Pixu; Zhao, Jean J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Kondo, Tatsuya] Kumamoto Univ, Fac Life Sci, Dept Metab Med, Kumamoto 8608556, Japan. [Asano, Tomoichiro] Hiroshima Univ, Grad Sch Biomed Sci, Hiroshima 7398551, Japan. [Sajan, Mini P.; Farese, Robert V.] James A Haley Vet Adm Med Ctr, Res Serv, Tampa, FL 33612 USA. [Sajan, Mini P.] Univ S Florida, Dept Internal Med, Tampa, FL 33612 USA. [Farese, Robert V.] Roskamp Inst, Sarasota, FL 34243 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI Farese, Robert/B-3605-2015 FU NIH [DK33201, DK55545, CA134502, CA089393-08S1, DK34834]; V Foundation; Claudia Barr Program; Swedish Research Council FX This work was Supported by NIH R01 grants DK33201 and DK55545 to C.R.K. and CA134502 and CA089393-08S1 to J.J.Z. Additional support came from the V Foundation (J.J.Z.), the Claudia Barr Program (J.J.Z.), the Swedish Research Council (V.R.S.), the NIH-funded Joslin Diabetes and Endocrinology Center (grant DK34834), and the Mary K. Iacocca Professorship fund. In compliance with Harvard Medical School guidelines, we disclose the consulting relationships: Novartis Pharmaceuticals, Inc. (J.J.Z.) and Sirtns/GSK Pharmaceuticals (C.R.K.). NR 44 TC 51 Z9 56 U1 1 U2 2 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 MAR 3 PY 2010 VL 11 IS 3 BP 220 EP 230 DI 10.1016/j.cmet.2010.02.002 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 565WE UT WOS:000275325400009 PM 20197055 ER PT J AU Liu, F Kozanek, M Hosseini, A Van de Velde, SK Gill, TJ Rubash, HE Li, GA AF Liu, Fang Kozanek, Michal Hosseini, Ali Van de Velde, Samuel K. Gill, Thomas J. Rubash, Harry E. Li, Guoan TI In vivo tibiofemoral cartilage deformation during the stance phase of gait SO JOURNAL OF BIOMECHANICS LA English DT Article DE Gait; Stance phase; Cartilage; Deformation; Treadmill ID LIGAMENT-DEFICIENT KNEE; JOINT CARTILAGE; KINEMATICS; CONTACT; THICKNESS; WALKING; MRI; TOPOGRAPHY; MOVEMENT; HEALTHY AB The knowledge of articular cartilage contact biomechanics in the knee joint is important for understanding the joint function and cartilage pathology. However, the in vivo tibiofemoral articular cartilage contact biomechanics during gait remains unknown. The objective of this study was to determine the in vivo tibiofemoral cartilage contact biomechanics during the stance phase of treadmill gait. Eight healthy knees were magnetic resonance (MR) scanned and imaged with a dual fluoroscopic system during gait on a treadmill. The tibia, femur and associated cartilage were constructed from the MR images and combined with the dual fluoroscopic images to determine in vivo cartilage contact deformation during the stance phase of gait. Throughout the stance phase of gait, the magnitude of peak compartmental contact deformation ranged between 7% and 23% of the resting cartilage thickness and occurred at regions with thicker cartilage. Its excursions in the anteroposterior direction were greater in the medial tibiofemoral compartment as compared to those in the lateral compartment. The contact areas throughout the stance phase were greater in the medial compartment than in the lateral compartment. The information on in vivo tibiofemoral cartilage contact biomechanics during gait could be used to provide physiological boundaries for in vitro testing of cartilage. Also, the data on location and magnitude of deformation among non-diseased knees during gait could identify where loading and later injury might occur in diseased knees. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Liu, Fang; Kozanek, Michal; Hosseini, Ali; Van de Velde, Samuel K.; Gill, Thomas J.; Rubash, Harry E.; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Liu, Fang; Kozanek, Michal; Hosseini, Ali; Van de Velde, Samuel K.; Gill, Thomas J.; Rubash, Harry E.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Hosseini, Ali] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU National Institute of Health [R01 AR052408, R21 AR051078]; Department of Orthopaedic Surgery at Massachusetts General Hospital FX We would like to gratefully acknowledge the financial support of the National Institute of Health (R01 AR052408, R21 AR051078) and the Department of Orthopaedic Surgery at Massachusetts General Hospital. We would also like to thank the volunteers who participated in this study and Bijoy Thomas for technical assistance. NR 24 TC 56 Z9 56 U1 1 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD MAR 3 PY 2010 VL 43 IS 4 BP 658 EP 665 DI 10.1016/j.jbiomech.2009.10.028 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 574QW UT WOS:000276008500009 PM 19896131 ER PT J AU Tsika, E Moysidou, M Guo, J Cushman, M Gannon, P Sandaltzopoulos, R Giasson, BI Krainc, D Ischiropoulos, H Mazzulli, JR AF Tsika, Elpida Moysidou, Maria Guo, Jing Cushman, Mimi Gannon, Patrick Sandaltzopoulos, Raphael Giasson, Benoit I. Krainc, Dimitri Ischiropoulos, Harry Mazzulli, Joseph R. TI Distinct Region-Specific alpha-Synuclein Oligomers in A53T Transgenic Mice: Implications for Neurodegeneration SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SPORADIC PARKINSONS-DISEASE; SOLUBLE AMYLOID OLIGOMERS; MULTIPLE SYSTEM ATROPHY; ALZHEIMERS-DISEASE; FIBRIL FORMATION; LEWY BODIES; IN-VITRO; TYROSINE-HYDROXYLASE; SECONDARY STRUCTURE; DOPAMINE AB Aggregation of alpha-synuclein (alpha-syn), a process that generates oligomeric intermediates, is a common pathological feature of several neurodegenerative disorders. Despite the potential importance of the oligomeric alpha-syn intermediates in neuron function, their biochemical properties and pathobiological functions in vivo remain vastly unknown. Here we used two-dimensional analytical separation and an array of biochemical and cell-based assays to characterize alpha-syn oligomers that are present in the nervous system of A53T alpha-syn transgenic mice. The most prominent species identified were 53 angstrom detergent-soluble oligomers, which preceded neurological symptom onset, and were found at equivalent amounts in regions containing alpha-syn inclusions as well as histologically unaffected regions. These oligomers were resistant to SDS, heat, and urea but were sensitive to proteinase-K digestion. Although the oligomers shared similar basic biochemical properties, those obtained from inclusion-bearing regions were prominently reactive to antibodies that recognize oxidized alpha-syn oligomers, significantly accelerated aggregation of alpha-syn in vitro, and caused primary cortical neuron degeneration. In contrast, oligomers obtained from non-inclusion-bearing regions were not toxic and delayed the in vitro formation of alpha-syn fibrils. These data indicate that specific conformations of alpha-syn oligomers are present in distinct brain regions of A53T alpha-syn transgenic mice. The contribution of these oligomers to the development of neuron dysfunction appears to be independent of their absolute quantities and basic biochemical properties but is dictated by the composition and conformation of the intermediates as well as unrecognized brain-region-specific intrinsic factors. C1 [Krainc, Dimitri; Mazzulli, Joseph R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Tsika, Elpida; Moysidou, Maria; Guo, Jing; Cushman, Mimi; Ischiropoulos, Harry; Mazzulli, Joseph R.] Childrens Hosp Philadelphia, Res Inst, Philadelphia, PA 19104 USA. [Ischiropoulos, Harry] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Gannon, Patrick; Giasson, Benoit I.; Ischiropoulos, Harry] Univ Penn, Childrens Hosp Philadelphia, Dept Pharmacol, Philadelphia, PA 19104 USA. [Tsika, Elpida; Moysidou, Maria; Sandaltzopoulos, Raphael] Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandroupolis, Greece. RP Mazzulli, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,MassGen Inst Neurodegenerat Dis, CNY Bldg,114 16th St,Neurol 114-2001, Charlestown, MA 02129 USA. EM ischirop@mail.med.upenn.edu; jmazzulli@partners.org FU National Institutes of Health [AG09215, NS053488, R01NS051303]; United States Public Health Service [AG13966]; National Institute of Environmental Health Sciences Center of Excellence in Environmental Toxicology [ES013508]; National Institute of Neurological Disorders and Stroke [F32NS066730] FX This work was supported by the National Institutes of Health Grants AG09215 (B. I. G), NS053488 (B. I. G.), and R01NS051303 (D. K.), United States Public Health Service Grant AG13966 (H. I.), National Institute of Environmental Health Sciences Center of Excellence in Environmental Toxicology Grant ES013508 (H. I), and National Institute of Neurological Disorders and Stroke Award F32NS066730 (J.R.M.). H. I. is the Gisela and Dennis Alter Research Professor of Pediatrics. NR 55 TC 43 Z9 44 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 3 PY 2010 VL 30 IS 9 BP 3409 EP 3418 DI 10.1523/JNEUROSCI.4977-09.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 564CS UT WOS:000275191000026 PM 20203200 ER PT J AU Soscia, SJ Kirby, JE Washicosky, KJ Tucker, SM Ingelsson, M Hyman, B Burton, MA Goldstein, LE Duong, S Tanzi, RE Moir, RD AF Soscia, Stephanie J. Kirby, James E. Washicosky, Kevin J. Tucker, Stephanie M. Ingelsson, Martin Hyman, Bradley Burton, Mark A. Goldstein, Lee E. Duong, Scott Tanzi, Rudolph E. Moir, Robert D. TI The Alzheimer's Disease-Associated Amyloid beta-Protein Is an Antimicrobial Peptide SO PLOS ONE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PRECURSOR-LIKE PROTEIN; A-BETA; INNATE IMMUNITY; CELL-DEATH; APOLIPOPROTEIN-E; FAMILY-MEMBERS; ALAMAR-BLUE; BRAIN; LL-37 AB Background: The amyloid beta-protein (A beta) is believed to be the key mediator of Alzheimer's disease (AD) pathology. A beta is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, A beta has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings: Here, we provide data supporting an in vivo function for A beta as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of A beta and LL-37, an archetypical human AMP. Findings reveal that A beta exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue A beta levels. Consistent with A beta-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-A beta antibodies. Conclusions/Significance: Our findings suggest A beta is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of A beta-mediated pathology and has important implications for ongoing and future AD treatment strategies. C1 [Soscia, Stephanie J.; Washicosky, Kevin J.; Tucker, Stephanie M.; Hyman, Bradley; Tanzi, Rudolph E.; Moir, Robert D.] Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat Dis, Genet & Aging Res Unit, Charlestown, MA USA. [Soscia, Stephanie J.; Washicosky, Kevin J.; Tucker, Stephanie M.; Hyman, Bradley; Tanzi, Rudolph E.; Moir, Robert D.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Soscia, Stephanie J.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Kirby, James E.; Duong, Scott] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Ingelsson, Martin] Uppsala Univ, Dept Publ Hlth Geriatr, Uppsala, Sweden. [Hyman, Bradley; Tanzi, Rudolph E.; Moir, Robert D.] Harvard Univ, Sch Med, Boston, MA USA. [Burton, Mark A.; Goldstein, Lee E.] Boston Univ, Sch Med, Coll Engn, Mol Aging & Dev Lab,Photon Ctr, Boston, MA 02118 USA. [Burton, Mark A.; Goldstein, Lee E.] Boston Univ, Alzheimers Dis Ctr, Boston, MA 02118 USA. RP Soscia, SJ (reprint author), Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat Dis, Genet & Aging Res Unit, Charlestown, MA USA. EM tanzi@helix.mgh.harvard.edu OI Goldstein, Lee/0000-0001-8419-9800 FU Cure Alzheimer's Disease Fund FX This work was supported by grants from the Cure Alzheimer's Disease Fund (http://www.curealzfund.org/). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 85 TC 234 Z9 239 U1 10 U2 54 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 MAR 3 PY 2010 VL 5 IS 3 AR e9505 DI 10.1371/journal.pone.0009505 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562OZ UT WOS:000275063400012 PM 20209079 ER PT J AU Yao, JK Dougherty, GG Reddy, RD Keshavan, MS Montrose, DM Matson, WR McEvoy, J Kaddurah-Daouk, R AF Yao, Jeffrey K. Dougherty, George G., Jr. Reddy, Ravinder D. Keshavan, Matcheri S. Montrose, Debra M. Matson, Wayne R. McEvoy, Joseph Kaddurah-Daouk, Rima TI Homeostatic Imbalance of Purine Catabolism in First-Episode Neuroleptic-Naive Patients with Schizophrenia SO PLOS ONE LA English DT Article ID SERUM URIC-ACID; PERFORMANCE LIQUID-CHROMATOGRAPHY; IMPAIRED GLUTATHIONE SYNTHESIS; MULTIPLE-SCLEROSIS PATIENTS; PLASMA ANTIOXIDANTS; PARKINSONS-DISEASE; OXIDATIVE STRESS; RISK-FACTOR; SYSTEM; BRAIN AB Background: Purine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology. Methodology/Principal Findings: Using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. Significantly higher levels of xanthosine (Xant) and lower levels of guanine (G) were seen in both patient groups compared to HC subjects. Moreover, the ratios of G/guanosine (Gr), uric acid (UA)/Gr, and UA/Xant were significantly lower, whereas the ratio of Xant/G was significantly higher in FENNS-BL than in HC. Such changes remained in FENNS-4w with exception that the ratio of UA/Gr was normalized. All 3 groups had significant correlations between G and UA, and Xan and hypoxanthine (Hx). By contrast, correlations of UA with each of Xan and Hx, and the correlation of Xan with Gr were all quite significant for the HC but not for the FENNS. Finally, correlations of Gr with each of UA and G were significant for both HC and FENNS-BL but not for the FENNS-4w. Conclusions/Significance: During purine catabolism, both conversions of Gr to G and of Xant to Xan are reversible. Decreased ratios of product to precursor suggested a shift favorable to Xant production from Xan, resulting in decreased UA levels in the FENNS. Specifically, the reduced UA/Gr ratio was nearly normalized after 4 weeks of antipsychotic treatment. In addition, there are tightly correlated precursor and product relationships within purine pathways; although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. Taken together, these results suggest that the potential for steady formation of antioxidant UA from purine catabolism is altered early in the course of illness. C1 [Yao, Jeffrey K.; Dougherty, George G., Jr.; Reddy, Ravinder D.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Yao, Jeffrey K.; Dougherty, George G., Jr.; Reddy, Ravinder D.; Keshavan, Matcheri S.; Montrose, Debra M.] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Dept Psychiat, Pittsburgh, PA 15213 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. [Keshavan, Matcheri S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Keshavan, Matcheri S.] Harvard Univ, Boston, MA 02115 USA. [Matson, Wayne R.] Bedford VA Med Ctr, Bedford, MA USA. [McEvoy, Joseph; Kaddurah-Daouk, Rima] Duke Univ, Med Ctr, Durham, NC USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. EM jkyao@pitt.edu FU Department of Veterans Affairs (VA); Veterans Health Administration; Office of Research and Development; Biomedical Laboratory Research Development; VA Pittsburgh Healthcare System; National Institute of Health [MH58141, MH64118, MH45203, R24 GM078233, c UL1 RR024153]; NIH/NCRR/GCRC [M01 RR00056]; Metabolomics Research Network (RKD); Stanley Medical Research Institute (RKD); National Alliance for Research on Schizophrenia and Affective Disorders (RKD) FX This material is based upon work supported in part by the grants from the Department of Veterans Affairs (VA), Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research & Development [Merit Reviews (JKY) and Senior Research Career Scientist Award (JKY)], VA Pittsburgh Healthcare System (JKY, GGD, RDR), National Institute of Health [MH58141 (JKY), MH64118 (RDR), MH45203 (MSK), R24 GM078233 (RKD), c UL1 RR024153 and NIH/NCRR/GCRC Grant M01 RR00056], Metabolomics Research Network (RKD); Stanley Medical Research Institute (RKD), and National Alliance for Research on Schizophrenia and Affective Disorders (RKD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 31 Z9 31 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 MAR 3 PY 2010 VL 5 IS 3 AR e9508 DI 10.1371/journal.pone.0009508 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562OZ UT WOS:000275063400014 PM 20209081 ER PT J AU Villar, J Cabrera, NE Casula, M Flores, C Valladares, F Diaz-Flores, L Muros, M Slutsky, AS Kacmarek, RM AF Villar, Jesus Cabrera, Nuria E. Casula, Milena Flores, Carlos Valladares, Francisco Diaz-Flores, Lucio Muros, Mercedes Slutsky, Arthur S. Kacmarek, Robert M. TI Mechanical ventilation modulates TLR4 and IRAK-3 in a non-infectious, ventilator-induced lung injury model SO RESPIRATORY RESEARCH LA English DT Article ID END-EXPIRATORY PRESSURE; TOLL-LIKE RECEPTORS; RESPIRATORY-DISTRESS-SYNDROME; INFLAMMATORY RESPONSE; TIDAL-VOLUME; KAPPA-B; NEGATIVE REGULATOR; CYTOKINE RELEASE; EPITHELIAL-CELLS; IN-VITRO AB Background: Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury. Methods: Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (V(T)) ( 20 ml/kg) and low VT (6 ml/kg). Histological evaluation, TLR2, TLR4, IRAK3 gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (I kappa B alpha), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL6) gene expression in the lungs and TNF-alpha and IL-6 protein serum concentrations were analyzed. Results: High VT mechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of IRAK3 lung gene expression and protein levels, a significant decrease of I kappa Ba, and a higher lung expression and serum concentrations of pro-inflammatory cytokines. Conclusions: The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the overexpression and release of pro-inflammatory cytokines during ventilator-induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections. C1 [Villar, Jesus; Cabrera, Nuria E.; Casula, Milena; Flores, Carlos; Valladares, Francisco; Muros, Mercedes] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus; Cabrera, Nuria E.; Casula, Milena] Hosp Univ Dr Negrin, Res Unit, MODERN, Las Palmas Gran Canaria, Spain. [Villar, Jesus; Slutsky, Arthur S.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Flores, Carlos] Hosp Univ NS de Candelaria, Res Unit, Tenerife, Spain. [Valladares, Francisco; Diaz-Flores, Lucio] Univ La Laguna, Dept Anat Pathol & Histol, Tenerife, Spain. [Muros, Mercedes] Hosp Univ NS de Candelaria, Dept Clin Biochem, Tenerife, Spain. [Slutsky, Arthur S.] Univ Toronto, Interdepartmental Div Crit Care Med, Toronto, ON, Canada. [Slutsky, Arthur S.] King Saud Univ, Riyadh, Saudi Arabia. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. RP Villar, J (reprint author), Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. EM jesus.villar54@gmail.com FU Ministerio de Ciencia of Spain [SAF 2004-06833]; FUNCIS [53/04]; Instituto de Salud Carlos III and FUNCIS [EMER07/001]; ENCYT FX The study has been supported by grants from Ministerio de Ciencia of Spain (SAF 2004-06833), FUNCIS (53/04), and by a specific agreement between Instituto de Salud Carlos III and FUNCIS (EMER07/001) under the ENCYT 2015 framework. NR 44 TC 26 Z9 30 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD MAR 3 PY 2010 VL 11 AR 27 DI 10.1186/1465-9921-11-27 PG 11 WC Respiratory System SC Respiratory System GA 571RK UT WOS:000275772200001 PM 20199666 ER PT J AU Baggish, AL Hutter, AM Wang, F Yared, K Weiner, RB Kupperman, E Picard, MH Wood, MJ AF Baggish, Aaron L. Hutter, Adolph M., Jr. Wang, Francis Yared, Kibar Weiner, Rory B. Kupperman, Eli Picard, Michael H. Wood, Malissa J. TI Cardiovascular Screening in College Athletes With and Without Electrocardiography A Cross-sectional Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SUDDEN CARDIAC DEATH; EUROPEAN-SOCIETY; CLINICAL-SIGNIFICANCE; OF-CARDIOLOGY; RECOMMENDATIONS; DISEASE; ABNORMALITIES; HEART AB Background: Although cardiovascular screening is recommended for athletes before participating in sports, the role of 12-lead electrocardiography (ECG) remains uncertain. To date, no prospective data that compare screening with and without ECG have been available. Objective: To compare the performance of preparticipation screening limited to medical history and physical examination with a strategy that integrates these with ECG. Design: Cross-sectional comparison of screening strategies. Setting: University Health Services, Harvard University, Cambridge, Massachusetts. Participants: 510 collegiate athletes who received cardiovascular screening before athletic participation. Measurements: Each participant had routine history and examination limited screening and ECG. They received transthoracic echocardiography (TTE) to detect or exclude cardiac findings with relevance to sports participation. The performance of screening with history and examination only was compared with that of screening that integrated history, examination, and ECG. Results: Cardiac abnormalities with relevance to sports participation risk were observed on TTE in 11 of 510 participants (prevalence, 2.2%). Screening with history and examination alone detected abnormalities in 5 of these 11 athletes (sensitivity, 45.5% [95% CI, 16.8% to 76.2%]; specificity, 94.4% [CI, 92.0% to 96.2%]). Electrocardiography detected 5 additional participants with cardiac abnormalities (for a total of 10 of 11 participants), thereby improving the overall sensitivity of screening to 90.9% (CI, 58.7% to 99.8%). However, including ECG reduced the specificity of screening to 82.7% (CI, 79.1% to 86.0%) and was associated with a false-positive rate of 16.9% (vs. 5.5% for screening with history and examination only). Limitation: Definitive conclusions regarding the effect of ECG inclusion on sudden death rates cannot be made. Conclusion: Adding ECG to medical history and physical examination improves the overall sensitivity of preparticipation cardiovascular screening in athletes. However, this strategy is associated with an increased rate of false-positive results when current ECG interpretation criteria are used. C1 [Baggish, Aaron L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Cambridge, MA 02138 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 24 TC 152 Z9 154 U1 0 U2 16 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 MAR 2 PY 2010 VL 152 IS 5 BP 269 EP W79 DI 10.7326/0003-4819-152-5-201003020-00004 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 565XJ UT WOS:000275329600001 PM 20194232 ER PT J AU Goldstein, N Carlson, M Livote, E Kutner, JS AF Goldstein, Nathan Carlson, Melissa Livote, Elayne Kutner, Jean S. TI Brief Communication: Management of Implantable Cardioverter-Defibrillators in Hospice: A Nationwide Survey SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID OF-LIFE; CARE; END AB Background: Communication about the deactivation of implantable cardioverter-defibrillators (ICDs) in patients near the end of life is rare. Objective: To determine whether hospices are admitting patients with ICDs, whether such patients are receiving shocks, and how hospices manage ICDs. Design: Cross-sectional survey. Setting: Randomly selected hospice facilities. Participants: 900 hospices, 414 of which responded fully. Measurements: Frequency of admission of patients with ICDs, frequency with which patients received shocks, existence of ICD deactivation policies, and frequency of deactivation. Results: 97% of hospices admitted patients with ICDs, and 58% reported that in the past year, a patient had been shocked. Only 10% of hospices had a policy that addressed deactivation. On average, 42% (95% CI, 37% to 48%) of patients with ICDs had the shocking function deactivated. Limitation: The study relied on the knowledge of hospice administrators. Conclusion: Hospices are admitting patients with ICDs, and patients are being shocked at the end of life. Ensuring that hospices have policies in place to address deactivation may improve the care for patients with these devices. The authors provide a sample deactivation policy (available at www.annals.org). C1 [Goldstein, Nathan] Mt Sinai Sch Med, Dept Geriatr, New York, NY 10029 USA. James J Peters Vet Affairs Med Ctr, Bronx, NY USA. Univ Colorado, Denver Sch Med, Aurora, CO USA. RP Goldstein, N (reprint author), Mt Sinai Sch Med, Dept Geriatr, Box 1070,1 Gustave Levy Pl, New York, NY 10029 USA. EM Nathan.Goldstein@mssm.edu FU National Institute of Aging [K23 AG025933K07AG030337-01A2]; National Institute of Nursing Research [1K99NR010495-01] FX By the National Institute of Aging, grants K23 AG025933 (Dr. Goldstein) and K07AG030337-01A2 (Dr. Kutner), and the National Institute of Nursing Research, grant 1K99NR010495-01 (Dr. Carlson). NR 14 TC 56 Z9 56 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAR 2 PY 2010 VL 152 IS 5 BP 296 EP W94 DI 10.7326/0003-4819-152-5-201003020-00007 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 565XJ UT WOS:000275329600004 PM 20194235 ER PT J AU Vetter, ML Iqbal, N Dalton-Bakes, C Volger, S Wadden, TA AF Vetter, Marion L. Iqbal, Nayyar Dalton-Bakes, Cornelia Volger, Sheri Wadden, Thomas A. TI Long-Term Effects of Low-Carbohydrate Versus Low-Fat Diets in Obese Persons SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID WEIGHT-LOSS DIETS C1 [Vetter, Marion L.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Iqbal, Nayyar; Dalton-Bakes, Cornelia] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Volger, Sheri; Wadden, Thomas A.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Vetter, ML (reprint author), Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. OI volger, sheri/0000-0002-1689-1173 NR 3 TC 6 Z9 6 U1 0 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 MAR 2 PY 2010 VL 152 IS 5 BP 334 EP 335 DI 10.7326/0003-4819-152-5-201003020-00020 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 565XJ UT WOS:000275329600016 PM 20194246 ER PT J AU Punglia, RS Saito, AM Neville, BA Earle, CC Weeks, JC AF Punglia, Rinaa S. Saito, Akiko M. Neville, Bridget A. Earle, Craig C. Weeks, Jane C. TI Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis SO BRITISH MEDICAL JOURNAL LA English DT Article ID RADIATION-THERAPY; CONSERVATIVE SURGERY; RANDOMIZED-TRIALS; COMORBIDITY INDEX; 15-YEAR SURVIVAL; CHEMOTHERAPY; POPULATION; CARCINOMA; OUTCOMES; TIME AB Objectives To determine if the length of interval between breast conserving surgery and start of radiotherapy affects local recurrence and to identify factors that might be associated with delay in older women with breast cancer. Design Retrospective cohort analysis with Cox proportional hazards models to study the association between time to radiotherapy and local recurrence, and propensity score and instrumental variable analyses to confirm findings. Logistic regression investigated factors associated with later start of radiotherapy. Setting Linked database ( Surveillance, Epidemiology, and End Results Program-Medicare) in the United States Participants 18 050 women aged over 65 with stage 0-II breast cancer diagnosed in 1991-2002 who received breast conserving surgery and radiotherapy but not chemotherapy. Main outcome measure Local recurrence. Results Median time from surgery to start of radiotherapy was 34 days, with 29.9% (n=5389) of women starting radiotherapy after six weeks. Just over 4% (n=734) of the cohort experienced a local recurrence. After adjustment for clinical and sociodemographic factors, intervals over six weeks were associated with increased likelihood of local recurrence (hazard ratio 1.19, 95% confidence interval 1.01 to 1.39, P=0.033). When the interval was modelled continuously ( assessing accumulation of risk by day), the effect was statistically stronger ( hazard ratio 1.005 per day, 1.002 to 1.008, P=0.004). Propensity score and instrumental variable analysis confirmed these findings. Instrumental variable analysis showed that intervals over six weeks were associated with a 0.96% increase in recurrence at five years (P=0.026). In multivariable analysis, starting radiotherapy after six weeks was significantly associated with positive nodes, comorbidity, history of low income, Hispanic ethnicity, non-white race, later year of diagnosis, and residence outside the southern states of the US. Conclusions There is a continuous relation between the interval from breast conserving surgery to radiotherapy and local recurrence in older women with breast cancer, suggesting that starting radiotherapy as soon as possible could minimise the risk of local recurrence. There are considerable disparities in time to starting radiotherapy after breast conserving surgery. Regions of the US known to have increased rates of breast conserving surgery had longer intervals before radiotherapy, suggesting limitations in capacity. Given the known negative impact of local recurrence on survival, mechanisms to ameliorate disparities and policies regarding waiting times for treatment might be warranted. C1 [Punglia, Rinaa S.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Neville, Bridget A.; Earle, Craig C.; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Saito, Akiko M.] Natl Hosp Org Nagoya Med Ctr, Clin Res Ctr, Lab Clin Epidemiol & Hlth Serv Res, Aichi, Japan. [Earle, Craig C.] Inst Clin Evaluat Sci, Toronto, ON, Canada. RP Punglia, RS (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM rpunglia@lroc.harvard.edu FU National Institutes of Health [1K07 CA118629]; American Society of Clinical Oncology FX This study was supported in part by a grant from the National Institutes of Health (1K07 CA118629 to RSP) and from the American Society of Clinical Oncology (Career Development Award to RSP). It was first presented in part at the annual meeting of the American Society of Clinical Oncology, June 2008. NR 35 TC 32 Z9 34 U1 0 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD MAR 2 PY 2010 VL 340 AR c845 DI 10.1136/bmj.c845 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 565FI UT WOS:000275274300024 PM 20197326 ER PT J AU Vandebroek, I Balick, MJ Ososki, A Kronenberg, F Yukes, J Wade, C Jimenez, F Peguero, B Castillo, D AF Vandebroek, Ina Balick, Michael J. Ososki, Andreana Kronenberg, Fredi Yukes, Jolene Wade, Christine Jimenez, Francisco Peguero, Brigido Castillo, Daisy TI The importance of botellas and other plant mixtures in Dominican traditional medicine SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Ethnobotany; Ethnomedicine; Plant mixtures; Herbal remedies; Dominican Republic; Migrants; New York City; Caribbean; Botella; Cultural keystone practice ID NEW-YORK-CITY; WOMENS HEALTH CONDITIONS; LATINO HEALERS; BOTANICAS; ETHNOBOTANY AB Ethnopharmacological relevance: Plant mixtures are understudied in ethnobotanical research. Aim of the study: To investigate the importance of plant mixtures (remedies consisting of at least two plants) in Dominican traditional medicine. Materials and methods: A Spanish language questionnaire was administered to 174 Dominicans living in New York City (NYC) and 145 Dominicans living in the Dominican Republic (DR), including lay persons (who self-medicate with plants) and specialists (traditional healers). Plants were identified through specimens purchased in NYC botanica shops and Latino grocery shops, and from voucher collections. Results: The percentage of mixtures as compared to single plants in plant use reports varied between 32 and 41%, depending on the geographic location (NYC or DR) and participant status (lay person or specialist). Respiratory conditions, reproductive health and genitourinary conditions were the main categories for which Dominicans use plant mixtures. Lay persons reported significantly more mixtures prepared as teas, mainly used in NYC to treat respiratory conditions. Specialists mentioned significantly more botellas (bottled herbal mixtures), used most frequently in the DR to treat reproductive health and genitourinary conditions. Cluster analysis demonstrated that different plant species are used to treat respiratory conditions as compared to reproductive health and genitourinary conditions. Interview participants believed that combining plants in mixtures increases their potency and versatility as medicines. Conclusions: The present study demonstrates the importance and complexity of plant mixtures in Dominican traditional medicine and the variation in its practices influenced by migration from the DR to NYC, shedding new lighten the foundations of a particular ethnomedical system. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Vandebroek, Ina; Balick, Michael J.; Kronenberg, Fredi; Yukes, Jolene] New York Bot Garden, Inst Econ Bot, Bronx, NY 10458 USA. [Ososki, Andreana] San Francisco VA Med Ctr, San Francisco, CA USA. [Wade, Christine] CUNY, Off Inst Res & Assessment, New York, NY 10021 USA. [Jimenez, Francisco; Peguero, Brigido; Castillo, Daisy] Jardin Bot Nacl Dr Rafael Ma Moscoso, Dept Bot, Santo Domingo, Dominican Rep. RP Vandebroek, I (reprint author), New York Bot Garden, Inst Econ Bot, 2900 So Blvd, Bronx, NY 10458 USA. EM ivandebroek@nybg.org FU National Institutes of Health/National Center for Complementary and Alternative Medicine [5 R21 AT 001889-02] FX The authors wish to thank Dominican interview participants in New York City and the Dominican Republic for generously sharing their knowledge about traditional medicine. This project was supported by a grant from the National Institutes of Health/National Center for Complementary and Alternative Medicine (PI: Dr. Michael J. Balick, Grant # 5 R21 AT 001889-02). Hannah Stevens, MA., Manager of the NYBG GIS laboratory is kindly thanked for elaborating maps of the study sites. Irina Adam took the picture of the Dominican botella. We are indebted to interns and research assistants at the Institute of Economic Botany of The New York Botanical Garden who collaborated in this project (Gabriela Alvarez, Frans Beltran, Levenia Duran, Daniel Kulakowski, Greta Meyers, Saneddy Quezada, Sam Stein, Margaret Terrero) and volunteers (Yadira Arias, Tomas Diaz, Ashley Duval, Claudia Remes). We would also like to thank Dr. Linda Cushman, Ms. Iris De Castro, Dr. Flor Henderson, Rafael Lantigua MD, Dr. Milciades Mejia, Ms. Miriam Mejia, and Lionel Robineau MD for their help with the project. NR 33 TC 25 Z9 25 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD MAR 2 PY 2010 VL 128 IS 1 BP 20 EP 41 DI 10.1016/j.jep.2009.12.013 PG 22 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 574RI UT WOS:000276010000003 PM 20006697 ER PT J AU Maloney, JD Maloney, JD AF Maloney, James D. Maloney, James D., III TI Vegetation Size Marker for Extraction Technique? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE lead extraction; percutaneous endocarditis; intracardiac vegetations ID INFECTIVE ENDOCARDITIS; PACEMAKER ENDOCARDITIS; SURGICAL EXTRACTION; LEAD EXTRACTION; MANAGEMENT; DIAGNOSIS; RISK C1 [Maloney, James D.] Heartland Spine & Specialty Hosp, Cardiovasc Serv, Overland Pk, KS USA. [Maloney, James D., III] Univ Wisconsin, Dept Cardiothorac Surg, Madison, WI USA. [Maloney, James D., III] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Thorac Surg Sect, Madison, WI 53792 USA. RP Maloney, JD (reprint author), Carondelet Heart Inst, 1000 Carondelet Dr, Kansas City, MO 64114 USA. EM jdmepmd@aol.com; jdmepmd@aol.com NR 20 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 2 PY 2010 VL 55 IS 9 BP 895 EP 897 DI 10.1016/j.jacc.2009.11.035 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 559XS UT WOS:000274865100008 PM 20185040 ER PT J AU Shi, JR Guan, J Jiang, BB Brenner, DA del Monte, F Ward, JE Connors, LH Sawyer, DB Semigran, MJ Macgillivray, TE Seldin, DC Falk, R Liao, R AF Shi, Jianru Guan, Jian Jiang, Bingbing Brenner, Daniel A. del Monte, Federica Ward, Jennifer E. Connors, Lawreen H. Sawyer, Douglas B. Semigran, Marc J. Macgillivray, Thomas E. Seldin, David C. Falk, Rodney Liao, Ronglih TI Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38 alpha MAPK pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amyloid; cell death; heart failure; TAB1; reactive oxygen species ID ACTIVATED PROTEIN-KINASE; ALZHEIMERS-DISEASE; INDEPENDENT ACTIVATION; P38 KINASE; STRESS; HEART; TAB1; MECHANISMS; RECEPTOR AB Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC-induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-beta-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38 alpha MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC-induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38 alpha MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure. C1 [Shi, Jianru; Guan, Jian; Jiang, Bingbing; Brenner, Daniel A.; Liao, Ronglih] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiac Muscle Res Lab,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Guan, Jian; Seldin, David C.; Liao, Ronglih] Boston Univ, Sch Med, Mol Med Grad Program, Boston, MA 02118 USA. [Ward, Jennifer E.; Connors, Lawreen H.; Seldin, David C.] Boston Univ, Sch Med, Amyloid Treatment & Res Program, Boston, MA 02118 USA. [del Monte, Federica] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [del Monte, Federica] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Sawyer, Douglas B.] Vanderbilt Univ, Dept Med, Sch Med, Div Cardiovasc Med, Nashville, TN 37232 USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. [Macgillivray, Thomas E.] Massachusetts Gen Hosp, Cardiac Surg Div, Boston, MA 02114 USA. [Falk, Rodney] Harvard Vanguard Med Associates, Boston, MA 02116 USA. RP Liao, R (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiac Muscle Res Lab,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. EM rliao@rics.bwh.harvard.edu OI Ward, Jennifer/0000-0003-0158-9091; Connors, Lawreen/0000-0002-4672-4296 FU National Institutes of Health [HL088533, HL071775, HL093148, HL086967, HL68705]; Gerry Amyloid Foundation; Amyloid Research Fund; American Heart Association FX We thank Dr. Yibin Wang for his generosity in providing reagents, DNp38 alpha TG mice, and critical scientific discussion. The authors thank Drs. Judith Gwathmey and William Dec for their generosity in providing human heart samples and helpful discussions. We thank Dr. Bo Wang and Mr. Soeun Ngoy for excellent technical support in adult cardiomyocyte isolation and osmotic pump implantation, respectively. This work was supported in part by funding from National Institutes of Health Grants HL088533, HL071775, HL093148 ( to R. L.), HL086967, and HL68705 ( to D. C. S.), as well as the Gerry Amyloid Foundation and Amyloid Research Fund at Boston University ( L. H. C. and D. C. S.). J.S. was supported by American Heart Association NE affiliate postdoctoral fellowship award. NR 27 TC 92 Z9 100 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 MAR 2 PY 2010 VL 107 IS 9 BP 4188 EP 4193 DI 10.1073/pnas.0912263107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KP UT WOS:000275131100045 PM 20150510 ER PT J AU Gethin-Jones, TL Evans, NR Morse, CR AF Gethin-Jones, Thomas L. Evans, Nathaniel R., III Morse, Christopher R. TI Surgical management of mediastinal liposarcoma extending from hypopharynx to carina: Case report SO WORLD JOURNAL OF SURGICAL ONCOLOGY LA English DT Article AB We describe the complete resection of a giant, well-differentiated mediastinal liposarcoma extending retropharynx to envelop the aortic arch, trachea and esophagus following preoperative radiotherapy. C1 [Gethin-Jones, Thomas L.; Evans, Nathaniel R., III; Morse, Christopher R.] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Morse, CR (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. EM crmorse@partners.org RI Evans, Nathaniel/I-2255-2013 OI Evans, Nathaniel/0000-0001-5767-6907 NR 5 TC 3 Z9 3 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7819 J9 WORLD J SURG ONCOL JI World J. Surg. Oncol. PD MAR 2 PY 2010 VL 8 AR 13 DI 10.1186/1477-7819-8-13 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 571TP UT WOS:000275779000001 PM 20196857 ER PT J AU Azar, AR Chopra, MP Cho, LY Coakley, EH Rudolph, JL AF Azar, Armin R. Chopra, Mohit P. Cho, Lydia Y. Coakley, Eugenie H. Rudolph, James L. TI Remission in Major Depression: Results from a Geriatric Primary Care Population SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 05-08, 2010 CL Savannah, GA SP Amer Assoc Geriat Psychiat C1 [Azar, Armin R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chopra, Mohit P.; Cho, Lydia Y.; Rudolph, James L.] VA Boston Healthcare Syst, Boston, MA USA. [Coakley, Eugenie H.] John Snow Inc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 SU 1 BP S59 EP S60 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PB UT WOS:000289790800061 ER PT J AU Cohen, CI Kasckow, J Jeste, DV Vahia, I AF Cohen, Carl I. Kasckow, John Jeste, Dilip V. Vahia, Ipsit TI SUICIDAL BEHAVIOR IN THE OLDER PATIENT WITH SCHIZOPHRENIA SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 05-08, 2010 CL Savannah, GA SP Amer Assoc Geriat Psychiat C1 [Kasckow, John] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Jeste, Dilip V.; Vahia, Ipsit] Univ Calif San Diego, San Diego, CA 92103 USA. [Cohen, Carl I.] Suny Downstate Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 SU 1 BP S42 EP S43 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PB UT WOS:000289790800051 ER PT J AU Mavandadi, S Sayers, SL Oslin, DW AF Mavandadi, Shahrzad Sayers, Steven L. Oslin, David W. TI Social Exchanges and Suicide Ideation among Older Veterans with Behavioral Health Issues SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 05-08, 2010 CL Savannah, GA SP Amer Assoc Geriat Psychiat C1 [Mavandadi, Shahrzad; Sayers, Steven L.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Oslin, David W.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 SU 1 BP S56 EP S56 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PB UT WOS:000289790800055 ER PT J AU Peskind, ER Li, G Millard, S Chi, PB Sokal, I Yu, CE Bekris, LM Raskind, M Galasko, D Montine, TJ AF Peskind, Elaine R. Li, Gail Millard, Steven Chi, Peter B. Sokal, Izabela Yu, Chang-En Bekris, Lynn M. Raskind, Murray Galasko, Douglas Montine, Thomas J. TI Age-related Decline in Cognitive Function is Associated with Cerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 05-08, 2010 CL Savannah, GA SP Amer Assoc Geriat Psychiat C1 [Peskind, Elaine R.; Li, Gail; Millard, Steven; Raskind, Murray] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Chi, Peter B.; Sokal, Izabela; Yu, Chang-En; Bekris, Lynn M.; Montine, Thomas J.] Univ Washington, Seattle, WA 98195 USA. [Galasko, Douglas] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 SU 1 BP S70 EP S71 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PB UT WOS:000289790800078 ER PT J AU Raskind, M Wang, LY Wilkinson, CW Li, G Sikkema, CL Millard, S Hanscom, B Galasko, D Peskind, ER AF Raskind, Murray Wang, Lucy Y. Wilkinson, Charles W. Li, Gail Sikkema, Carl L. Millard, Steven Hanscom, Brett Galasko, Douglas Peskind, Elaine R. TI Cerebrospinal Fluid Norepinephrine is Inversely Related to Aspects of Cognition in Brain Aging SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 05-08, 2010 CL Savannah, GA SP Amer Assoc Geriat Psychiat C1 [Raskind, Murray; Wang, Lucy Y.; Wilkinson, Charles W.; Li, Gail; Sikkema, Carl L.; Millard, Steven; Peskind, Elaine R.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Hanscom, Brett] Univ Washington, Seattle, WA 98195 USA. [Galasko, Douglas] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 SU 1 BP S70 EP S70 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PB UT WOS:000289790800077 ER PT J AU Sultzer, D Melrose, R Campa, OM Achamallah, N Harwood, D Brody, A Walston, A Mandelkern, M AF Sultzer, David Melrose, Rebecca Campa, Olivia M. Achamallah, Natalie Harwood, Dylan Brody, Arthur Walston, Amy Mandelkern, Mark TI Cholinergic Receptor Imaging in Alzheimer's Disease: Method and Early Results SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 05-08, 2010 CL Savannah, GA SP Amer Assoc Geriat Psychiat C1 [Melrose, Rebecca; Campa, Olivia M.; Achamallah, Natalie; Harwood, Dylan; Brody, Arthur; Walston, Amy] VA Greater Los Angeles Healthcare Syst, Psychiat Serv, Los Angeles, CA USA. [Mandelkern, Mark] VA Greater Los Angeles Healthcare Syst, Nucl Med Serv, Los Angeles, CA USA. [Sultzer, David] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 SU 1 BP S71 EP S72 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PB UT WOS:000289790800079 ER PT J AU Marill, KA deSouza, IS Nishijima, DK Senecal, EL Setnik, GS Stair, TO Ruskin, JN Ellinor, PT AF Marill, Keith A. deSouza, Ian S. Nishijima, Daniel K. Senecal, Emily L. Setnik, Gary S. Stair, Thomas O. Ruskin, Jeremy N. Ellinor, Patrick T. TI Amiodarone or Procainamide for the Termination of Sustained Stable Ventricular Tachycardia: An Historical Multicenter Comparison SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE tachycardia; ventricular; amiodarone; procainamide ID WIDE QRS COMPLEX; INTRAVENOUS AMIODARONE; INTRAVENTRICULAR-CONDUCTION; DIFFERENTIAL-DIAGNOSIS; REFRACTORINESS; INDUCTION; LIDOCAINE; EFFICACY; SAFETY AB Objectives: The objective was to compare the effectiveness of intravenous (IV) procainamide and amiodarone for the termination of spontaneous stable sustained ventricular tachycardia (VT). Methods: A historical cohort study of consecutive adult patients with stable sustained VT treated with IV amiodarone or procainamide was performed at four urban hospitals. Patients were identified for enrollment by admissions for VT and treatment with the study agents in the emergency department (ED) from 1993 to 2008. The primary measured outcome was VT termination within 20 minutes of onset of study medicine infusion. A secondary effectiveness outcome was the ultimate need for electrical therapy to terminate the VT episode. Major adverse effects were tabulated, and blood pressure responses to medication infusions were compared. Results: There were 97 infusions of amiodarone or procainamide in 90 patients with VT, but the primary outcome was unknown after 14 infusions due to administration of another antidysrhythmic during the 20-minute observation period. The rates of VT termination were 25% (13/53) and 30% (9/30) for amiodarone and procainamide, respectively. The adjusted odds of termination with procainamide compared to amiodarone was 1.2 (95% confidence interval [CI] = 0.4 to 3.9). Ultimately, 35/66 amiodarone patients (53%, 95% CI = 40 to 65%) and 13/31 procainamide patients (42%, 95% CI = 25 to 61%) required electrical therapy for VT termination. Hypotension led to cessation of medicine infusion or immediate direct current cardioversion (DCCV) in 4/66 (6%, 95% CI = 2 to 15%) and 6/31 (19%, 95% CI = 7 to 37%) patients who received amiodarone and procainamide, respectively. Conclusions: Procainamide was not more effective than amiodarone for the termination of sustained VT, but the ability to detect a significant difference was limited by the study design and potential confounding. As used in practice, both agents were relatively ineffective and associated with clinically important proportions of patients with decreased blood pressure. ACADEMIC EMERGENCY MEDICINE 2010; 17:297-306 (C) 2010 by the Society for Academic Emergency Medicine. C1 [Marill, Keith A.; Senecal, Emily L.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Ruskin, Jeremy N.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [deSouza, Ian S.; Nishijima, Daniel K.] Suny Downstate Med Ctr, Dept Emergency Med, Brooklyn, NY 11203 USA. [Setnik, Gary S.] Mt Auburn Hosp, Dept Emergency Med, Cambridge, MA USA. [Stair, Thomas O.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. RP Marill, KA (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM kmarill@partners.org FU Eleanor and Miles Shore Scholars in Medicine Fellowship, Harvard Medical School, Boston, MA FX This work was presented at the Society for Academic Emergency Medicine annual meeting, Chicago, IL, May 2007.; This work was supported by the Eleanor and Miles Shore Scholars in Medicine Fellowship, Harvard Medical School, Boston, MA. NR 22 TC 12 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD MAR PY 2010 VL 17 IS 3 BP 297 EP 306 DI 10.1111/j.1553-2712.2010.00680.x PG 10 WC Emergency Medicine SC Emergency Medicine GA 562YR UT WOS:000275092500010 PM 20370763 ER PT J AU Ginde, AA Camargo, CA AF Ginde, Adit A. Camargo, Carlos A., Jr. TI Trends in Midlevel Provider Utilization SO ACADEMIC EMERGENCY MEDICINE LA English DT Letter C1 [Ginde, Adit A.] Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Ginde, AA (reprint author), Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO USA. EM adit.ginde@ucdenver.edu NR 5 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD MAR PY 2010 VL 17 IS 3 BP 344 EP 344 DI 10.1111/j.1553-2712.2010.00686.x PG 1 WC Emergency Medicine SC Emergency Medicine GA 562YR UT WOS:000275092500019 PM 20148763 ER PT J AU Li, STT Tancredi, DJ Co, JPT West, DC AF Li, Su-Ting T. Tancredi, Daniel J. Co, John Patrick T. West, Daniel C. TI Factors Associated with Successful Self-Directed Learning Using Individualized Learning Plans During Pediatric Residency SO ACADEMIC PEDIATRICS LA English DT Article DE individualized learning plan; medical education; self-directed learning; survey ID MEDICAL PROFESSIONALISM; HEALTH-PROFESSIONS; LIFELONG; MILLENNIUM; EDUCATION; ACCURACY; VALIDITY; CHARTER AB Objective.-The aim of this study was to determine whether resident or program characteristics are associated with effective self-directed learning of residents. Methods.-A cross-sectional survey of pediatric and medicine/pediatric residents and program directors from a nationally representative sample of residency programs was conducted. Self-directed learning efficacy was measured by resident-reported progress on learning goals from their most recent individualized learning plan (ILP). Multilevel linear regression models were used to analyze the relationship between learner and program characteristics and self-directed learning efficacy of residents. Results.-All program directors of participating programs (N = 46) completed the survey; the response rate from residents was 57% (992/1739). At the time of the survey, 78% of residents had previously written an ILP. Most residents achieved moderate self-directed learning efficacy. The most important factors associated with greater self-directed learning efficacy included using a system to track one's own progress in achieving learning goals, higher score on a propensity toward lifelong learning scale, and reporting greater confidence in self-directed learning abilities. Program characteristics, including program-level support for ILPs, had little or mixed association with resident self-directed learning efficacy. Conclusions.-The most important factors associated with effective self-directed learning were resident characteristics. Our findings imply that residency programs should invest their limited resources in curricula that help residents develop measurable goals and systems for tracking progress toward goal attainment. Since propensity toward lifelong learning was an important factor, medical schools and residency training programs should enhance their efforts to develop this characteristic in learners. C1 [Li, Su-Ting T.; Tancredi, Daniel J.] Univ Calif Davis, Dept Pediat, Sacramento, CA 95817 USA. [Co, John Patrick T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Massachusetts Gen Hosp,Off Grad Med Educ, Boston, MA 02115 USA. [West, Daniel C.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Li, STT (reprint author), Univ Calif Davis, Dept Pediat, 2516 Stockton Blvd, Sacramento, CA 95817 USA. EM su-ting.li@ucdmc.ucdavis.edu RI Tancredi, Daniel/O-3381-2013 OI Tancredi, Daniel/0000-0002-3884-7907 FU Association of Pediatric; Bronx-Lebanon; Upstate New York; University of California Los Angeles; Lutheran General; University of Connecticut; New York Presbyterian Hospital Cornell; St Vincent; Texas Tech; Carolinas Medical; Blank Children's; Louisiana State University New Orleans; Driscoll Children's; University of Missouri; St Baniabas; University of Nebraska Medical Center/Creighton; University of Kansas; New York Methodist Hospital; Coopers; University of Vermont; University of Utah; University of New Mexico; Medical College of Georgia; Naval Medical Center; Marshfield Clinic; Orlando Health; Goryeb; Marshall University; Medical College of Wisconsin; St Joseph's Hospital and Medical Center, Phoenix; University of California, Davis; Tripler Army; West Virginia University Morgantown; East Tennessee State University; Elmhurst; University of Colorado; St Louis University; Medical University of South Carolina; University of Washington; Harbor-University of California Los Angeles; Jersey Shore University; A.I. du Pont/Jefferson; University of South Alabama; University of California, San Francisco; Morehouse School of Medicine; Kaiser Los Angeles; Maine Medical Center FX Funding for this study was provided in part by a Special (Principal Investigator was Dr Su-Ting Li) Projects grant from the Association of Pediatric Program Directors. We thank the following program directors and residency training programs for participating in our study: Ayoade Adeniyi, MD (Bronx-Lebanon); John Andrake, MD (Upstate New York); Virginia Barrow, MD (University of California Los Angeles); Frank Belmonte, DO (Lutheran General); Priti Bhansali, MD (University of Connecticut); Susan Bostwick, MD (New York Presbyterian Hospital Cornell); Niceta C. Bradburn, MD (St Vincent); Tammy Camp, MD (Texas Tech); Suzette Caudle, MD (Carolinas Medical); Ken Cheyne, MD (Blank Children's); Bonnie Desselle, MD (Louisiana State University New Orleans); William Dirksen, MD (Driscoll Children's); Joy Drass, MD (University of Missouri); David Fagan, MD (St Baniabas); Cristina Fernandez, MD (University of Nebraska Medical Center/Creighton); Lisa Gilmer, MD (University of Kansas); Susan Gottlieb, MD (New York Methodist Hospital); Bill Graessle, MD (Coopers); Ann Guillot, MD (University of Vermont); Wendy Hobson, MD (University of Utah); Ben Hoffman, MD (University of New Mexico); Valera Hudson, MD (Medical College of Georgia); Christine Johnson, MD (Naval Medical Center); Divya Joshi, MD (Marshfield Clinic); Joan Meek, MD (Orlando Health); Alan Meltzer, MD (Goryeb); Bob Miller, MD (Marshall University); Jay Nocton, MD (Medical College of Wisconsin); Lilia Parra-Roide, MD (St Joseph's Hospital and Medical Center, Phoenix); Richard Pan, MD, MPH (University of California, Davis); Robert Pedersen, MD (Tripler Army); John Phillips, MD (West Virginia University Morgantown); Rebecca Powers, MD (East Tennessee State University); Gwen Raphan, MD (Elmhurst); Adam Rosenberg, MD (University of Colorado); Heidi Sallee, MD (St Louis University); Cassandra Salgado, MD (Medical University of South Carolina); Richard Shugerman, MD (University of Washington); Monica Sifuentes, MD (Harbor-University of California Los Angeles); Paul Schwartzberg, MD (Jersey Shore University); Glenn Stryjewski, MD (A.I. du Pont/Jefferson); Franklin Trimm, MD (University of South Alabama); Daniel West, MD (University of California, San Francisco); Yolanda Wimberly, MD (Morehouse School of Medicine); Steven Woods, MD (Kaiser Los Angeles); and Brian Youth, MD (Maine Medical Center). We also thank Mohammadreza Hojat, PhD, for permission to use the Jefferson Physician Lifelong Learning Scale in our study, and HayGroup for permission to use the Kolb Learning Style Inventory in our study. NR 29 TC 23 Z9 23 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 J9 ACAD PEDIATR JI Acad. Pediatr. PD MAR-APR PY 2010 VL 10 IS 2 BP 124 EP 130 PG 7 WC Pediatrics SC Pediatrics GA 616DI UT WOS:000279188300008 PM 20206911 ER PT J AU Goisman, RM Levin, RM Krupat, E Pelletier, SR Alpert, JE AF Goisman, Robert M. Levin, Robert M. Krupat, Edward Pelletier, Stephen R. Alpert, Jonathan E. TI Psychiatric OSCE Performance of Students With and Without a Previous Core Psychiatry Clerkship SO ACADEMIC PSYCHIATRY LA English DT Article ID STRUCTURED CLINICAL EXAMINATION AB Objective: The OSCE has been demonstrated to be a reliable and valid method by which to assess students' clinical skills. An OSCE station was used to determine whether or not students who had completed a core psychiatry clerkship demonstrated skills that were superior to those who had not taken the clerkship and which areas discriminated between clerkship completers and noncompleters. Methods: One hundred thirty-six students took a 48-item, fourth-year OSCE with one psychiatry station. Sixty-three (46%) had already completed psychiatry, and 70 (51%) had not, with three unknown. Students were to take histories, perform mental status examinations, assess dangerousness, and propose the differential diagnosis and treatment plans. Results: Nine items differed significantly between completers and noncompleters, six concerning phenomenology and mental status and three concerning differential diagnosis. There were no differences regarding history, communication skills, or recommended interventions. Conclusion: Students may learn history taking, communication, and treatment planning in many settings. However, for the mental status examination, phenomenology, and differential diagnosis, completing a psychiatry clerkship was associated with better OSCE performance. C1 [Goisman, Robert M.] Massachusetts Mental Hlth Ctr, Boston, MA 02130 USA. [Goisman, Robert M.; Krupat, Edward] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA USA. [Goisman, Robert M.; Levin, Robert M.; Krupat, Edward; Pelletier, Stephen R.; Alpert, Jonathan E.] Harvard Univ, Sch Med, Boston, MA USA. [Levin, Robert M.] Mt Auburn Hosp, Dept Psychiat, Cambridge, MA USA. [Levin, Robert M.] Cambridge Hlth Alliance, Dept Psychiat, Cambridge, MA USA. [Alpert, Jonathan E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Goisman, RM (reprint author), Massachusetts Mental Hlth Ctr, 180 Morton St, Boston, MA 02130 USA. EM robert_goisman@hms.harvard.edu OI Alpert, Jonathan/0000-0002-4332-908X NR 11 TC 4 Z9 4 U1 0 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 J9 ACAD PSYCHIATR JI Acad. Psych. PD MAR-APR PY 2010 VL 34 IS 2 BP 141 EP 144 PG 4 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 567GX UT WOS:000275434500015 PM 20224028 ER PT J AU Ozsunar, Y Mullins, ME Kwong, K Hochberg, FH Ament, C Schaefer, PW Gonzalez, RG Lev, MH AF Ozsunar, Yelda Mullins, Mark E. Kwong, Kenneth Hochberg, Fred H. Ament, Christine Schaefer, Pamela W. Gonzalez, R. Gilberto Lev, Michael H. TI Glioma Recurrence Versus Radiation Necrosis? A Pilot Comparison of Arterial Spin-Labeled, Dynamic Susceptibility Contrast Enhanced MRI, and FDG-PET Imaging SO ACADEMIC RADIOLOGY LA English DT Article DE Arterial spin labeling; perfusion MRI; brain tumors; glioma; perfusion; radiation necrosis ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN BRAIN-TUMORS; BLOOD-VOLUME MAPS; HISTOLOGIC GRADE; MICROVASCULAR PERMEABILITY; PROTON/PHOTON IRRADIATION; GLIOBLASTOMA-MULTIFORME; MALIGNANT GLIOMAS; PERFUSION MRI; FLOW AB Rationale and objectives: Distinguishing recurrent glial tumor from radiation necrosis can be challenging. The purpose of this pilot study was to preliminarily compare unenhanced arterial spin-labeled (ASL) imaging, dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) magnetic resonance imaging, and positron emission tomographic (PET) imaging in distinguishing predominant glioma recurrence or progression from predominant radiation necrosis in postoperative patients treated with proton-beam therapy. Methods: Patients with grade 11 to IV glioma previously treated with surgery and proton-beam therapy were enrolled on the basis of new enhancing nodules or masses with primary differential diagnoses of predominant tumor recurrence or progression versus radiation necrosis. ASL, DSCE-CBV, and PET examinations were assessed by visual qualitative and quantitative analysis for the detection of predominant tumor recurrence. Imaging results were correlated with a clinical-pathologic reference standard. Results: Thirty patients were studied, resulting in 33 ASL, 32 DSCE-CBV, and 26 PET examinations. On the basis of visual inspection, the sensitivities of PET, ASL, and DSCE-CBV examinations for detecting high-grade tumor foci were 81%, 88%, and 86%, respectively. The highest sensitivity values for quantitative ASL imaging were obtained using a normalized cutoff ratio of 1.3, resulting in sensitivity of 94% for ASL imaging and 71% for DSCE-CBV imaging. When predominant high-grade tumors with superimposed regions of predominant mixed radiation necrosis were excluded, DSCE-CBV sensitivity improved to 90%, but ASL sensitivity remained unchanged. Conclusions: Compared with DSCE-CBV imaging, ASL imaging may more accurately distinguish predominant recurrent high-grade glioma from radiation necrosis, especially in regions with mixed radiation necrosis, for which DSCE-CBV imaging may underestimate true blood volume because of leakage artifacts. C1 [Ozsunar, Yelda] Adrian Menderes Univ, Sch Med, Dept Radiol, Aydin, Turkey. [Mullins, Mark E.] Emory Univ, Dept Radiol, Atlanta, GA 30322 USA. [Kwong, Kenneth; Schaefer, Pamela W.; Gonzalez, R. Gilberto; Lev, Michael H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kwong, Kenneth; Schaefer, Pamela W.; Gonzalez, R. Gilberto; Lev, Michael H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hochberg, Fred H.] Massachusetts Gen Hosp, Brain Tumor Ctr, Boston, MA 02114 USA. [Kwong, Kenneth; Hochberg, Fred H.; Schaefer, Pamela W.; Gonzalez, R. Gilberto; Lev, Michael H.] Harvard Univ, Sch Med, Boston, MA USA. [Ament, Christine] Boston Univ Eye Associates, Trygve Gunderson Eye Ctr, Boston, MA 02215 USA. RP Ozsunar, Y (reprint author), Adrian Menderes Univ, Sch Med, Dept Radiol, Hastane Caddesi, Aydin, Turkey. EM yeldaozsunar@gmail.com NR 50 TC 43 Z9 50 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD MAR PY 2010 VL 17 IS 3 BP 282 EP 290 DI 10.1016/j.acra.2009.10.024 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 564RX UT WOS:000275235500004 PM 20060750 ER PT J AU Coleman, JJ Okoli, I Tegos, GP Holson, EB Wagner, FF Hamblin, MR Mylonakis, E AF Coleman, Jeffrey J. Okoli, Ikechukwu Tegos, George P. Holson, Edward B. Wagner, Florence F. Hamblin, Michael R. Mylonakis, Eleftherios TI Characterization of Plant-Derived Saponin Natural Products against Candida albicans SO ACS CHEMICAL BIOLOGY LA English DT Article ID VULVO-VAGINAL CANDIDIASIS; TRITERPENOID SAPONINS; PHOTODYNAMIC THERAPY; EPIDEMIOLOGIC SURVEY; ANTIFUNGAL COMPOUNDS; IN-VITRO; INFECTIONS; RESISTANCE; BIOFILMS; IDENTIFICATION AB Candida albicans is an opportunistic fungal pathogen capable of life threatening disseminated infections particularly in immunocompromised patients. Resistance to many clinically used antifungal agents has created a need to identify and develop a new generation of compounds for therapeutic use. A compound screen to identify potential antifungal natural products was undertaken, identifying 12 saponins, some of which have not been previously described. In the Caenorhabditis elegans model, some saponins conferred nematode survival comparable to that of amphotericin B. Of the 12 antifungal saponins identified, two were selected for further analysis. C albicans isolates were inhibited by these compounds at relatively low concentrations (16 and 32 mu g mL(-1)) including isolates resistant to clinically used antifungal agents. C albicans hyphae and biofilm formation were also disrupted in the presence of these natural products, and studies demonstrate that fungal cells in the presence of saponins are more susceptible to salt-induced osmotic stress. Although saponins are known for their hemolytic activity, no hemolysis of erythrocytes was observed at three times the minimal inhibitory concentration for C. albicans, suggesting the saponins may have a preference for binding to fungal ergosterol when compared to cholesterol. Importantly, when used in combination with photosensitizer compounds, the fungus displayed increased susceptibility to photodynamic inactivation due to the ability of the saponins to increase cell permeability, thereby facilitating penetration of the photosensitizers. The large proportion of compounds identified as antifungal agents containing saponin structural features suggests it may be a suitable chemical scaffold for a new generation of antifungal compounds. C1 [Coleman, Jeffrey J.; Okoli, Ikechukwu; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Tegos, George P.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tegos, George P.; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Holson, Edward B.; Wagner, Florence F.] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Mylonakis, E (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM emylonakis@partners.org RI Tegos, George/C-8830-2011; Coleman, Jeffrey/E-2981-2015; OI Hamblin, Michael/0000-0001-6431-4605; Coleman, Jeffrey/0000-0001-8579-1996 FU NIH [Al075286, Al050875]; Broad Institute of MIT and Harvard; National Cancer Institute's Initiative for Chemical Genetics [N01-CO-12400] FX The authors thank B. Burgwyn Fuchs for her assistance with microscopy Support was provided by NIH R01 awards Al075286 (E M), and Al050875 (G P T and M R H) and by the Broad Institute of MIT and Harvard This project has also been funded in part by the National Cancer Institute's Initiative for Chemical Genetics under contract N01-CO-12400 and has been performed with the assistance of the Chemical Biology Platform of the Broad Institute NR 44 TC 58 Z9 60 U1 3 U2 18 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 MAR PY 2010 VL 5 IS 3 BP 321 EP 332 DI 10.1021/cb900243b PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 569VA UT WOS:000275629200008 PM 20099897 ER PT J AU Semenas, E Nozari, A Sharma, HS Basu, S Rubertsson, S Wiklund, L AF Semenas, E. Nozari, A. Sharma, H. S. Basu, S. Rubertsson, S. Wiklund, L. TI Sex differences in cerebral injury after severe haemorrhage and ventricular fibrillation in pigs SO ACTA ANAESTHESIOLOGICA SCANDINAVICA LA English DT Article ID CATALYZED LIPID-PEROXIDATION; TRAUMATIC CARDIAC-ARREST; PERINATAL BRAIN-INJURY; NITRIC-OXIDE; BLOOD-FLOW; CARDIOPULMONARY-RESUSCITATION; GENDER-DIFFERENCES; HYPERTONIC SALINE; OXIDATIVE INJURY; METHYLENE-BLUE AB Background Experimental studies of haemorrhagic shock have documented a superior haemodynamic response and a better outcome in female animals as compared with male controls. Such sexual dimorphism has, nevertheless, not been reported after circulatory arrest that follows exsanguination and shock. We aimed to study differences in cerebral injury markers after exsanguination cardiac arrest in pre-pubertal piglets. The hypothesis was that cerebral injury is less extensive in female animals, and that this difference is independent of sexual hormones or choice of resuscitative fluid. Methods Thirty-two sexually immature piglets (14 males and 18 females) were subjected to 5 min of haemorrhagic shock followed by 2 min of ventricular fibrillation and 8 min of cardiopulmonary resuscitation, using three resuscitation fluid regimens (whole blood, hypertonic saline and dextran, or acetated Ringers' solution plus whole blood and methylene blue). Haemodynamic values, cellular markers of brain injury and brain histology were studied. Results After successful resuscitation, female piglets had significantly greater cerebral cortical blood flow, tended to have lower S-100 beta values and a lower cerebral oxygen extraction ratio. Besides, in female animals, systemic and cerebral venous acidosis were mitigated. Female piglets exhibited a significantly smaller increase in neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) expression in their cerebral cortex, smaller blood-brain-barrier (BBB) disruption and significantly smaller neuronal injury. Conclusion After resuscitation from haemorrhagic circulatory arrest, cerebral reperfusion is greater, and BBB permeability and neuronal injury is smaller in female piglets. An increased cerebral cortical iNOS and nNOS expression in males implies a mechanistic relationship with post-resuscitation neuronal injury and warrants further investigation. C1 [Semenas, E.; Sharma, H. S.; Rubertsson, S.; Wiklund, L.] Univ Uppsala Hosp, Dept Surg Sci Anesthesiol & Intens Care, Fac Med, S-75185 Uppsala, Sweden. [Nozari, A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. [Basu, S.] Univ Uppsala Hosp, Dept Publ Hlth & Caring Sci Clin Nutr & Metab, Fac Med, S-75185 Uppsala, Sweden. RP Semenas, E (reprint author), Univ Uppsala Hosp, Dept Surg Sci Anesthesiol & Intens Care, Fac Med, S-75185 Uppsala, Sweden. EM egidijus.semenas@gmail.com RI Sharma, Aruna/D-4430-2011; Sharma, Hari/G-4508-2016 FU Laerdal Foundation for Acute Medicine, Stavanger, Norway FX The research was supported, in part, by the Laerdal Foundation for Acute Medicine, Stavanger, Norway. NR 41 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-5172 J9 ACTA ANAESTH SCAND JI Acta Anaesthesiol. Scand. PD MAR PY 2010 VL 54 IS 3 BP 343 EP 353 DI 10.1111/j.1399-6576.2009.02125.x PG 11 WC Anesthesiology SC Anesthesiology GA 552SF UT WOS:000274313000012 PM 19764903 ER PT J AU Pakhomova, ON Taylor, AB Becker, A Holloway, SP Kannan, TR Baseman, JB Hart, PJ AF Pakhomova, Olga N. Taylor, Alexander B. Becker, Argentina Holloway, Stephen P. Kannan, T. R. Baseman, Joel B. Hart, P. John TI Crystallization of community-acquired respiratory distress syndrome toxin from Mycoplasma pneumoniae SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID CHRONIC ASTHMA; IDENTIFICATION; PERTUSSIS; PROTEIN AB Community-acquired respiratory distress syndrome toxin (CARDS TX) is a 591-amino-acid protein with ADP-ribosyltransferase and vacuolating activities that damages the cells lining the respiratory tracts of patients infected with the bacterial pathogen Mycoplasma pneumoniae. Crystals of CARDS TX were grown in space group C2, with unit-cell parameters a = 191.4, b = 107.4, c = 222.1 angstrom, beta = 90.6 degrees. A complete 2.2 angstrom data set was obtained from a single CARDS TX crystal. C1 [Pakhomova, Olga N.; Taylor, Alexander B.; Becker, Argentina; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Pakhomova, Olga N.; Taylor, Alexander B.; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Kannan, T. R.; Baseman, Joel B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Hart, PJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM pjhart@biochem.uthscsa.edu FU Robert A. Welch Foundation [AQ-1399]; IH [U19 AI070412]; Kleberg Foundation FX This work was supported by the Robert A. Welch Foundation Grant AQ-1399 (to PJH), by IH grant U19 AI070412 (to JBB) and by the Kleberg Foundation (to JBB). NR 20 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD MAR PY 2010 VL 66 BP 294 EP 296 DI 10.1107/S1744309110000114 PN 3 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 562ND UT WOS:000275057700019 PM 20208164 ER PT J AU Papadaki, T Iaccheri, B Fiore, T Zacharopoulos, I Thadani, S Christen, W Androudi, S Foster, CS AF Papadaki, Thekla Iaccheri, Barbara Fiore, Tito Zacharopoulos, Ioannis Thadani, Sunil Christen, William Androudi, Sofia Foster, C. Stephen TI Serum soluble interleukin-2 receptor levels do not correlate with an associated systemic disease in patients with uveitis SO ACTA OPHTHALMOLOGICA LA English DT Letter ID CYTOKINES C1 [Foster, C. Stephen] Ocular Immunol & Uveitis Fdn, Massachusetts Eye Res & Surg Inst, Cambridge, MA 02142 USA. [Papadaki, Thekla; Iaccheri, Barbara; Fiore, Tito; Zacharopoulos, Ioannis; Thadani, Sunil; Androudi, Sofia; Foster, C. Stephen] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Christen, William] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. RP Foster, CS (reprint author), Ocular Immunol & Uveitis Fdn, Massachusetts Eye Res & Surg Inst, 5 Cambridge Ctr,8th Floor, Cambridge, MA 02142 USA. EM fosters@uveitis.org NR 5 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-375X J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD MAR PY 2010 VL 88 IS 2 BP e28 EP e29 DI 10.1111/j.1755-3768.2008.01422.x PG 2 WC Ophthalmology SC Ophthalmology GA 560WB UT WOS:000274933700016 PM 19493254 ER PT J AU Barnhill, RL Cerroni, L Cook, M Elder, DE Kerl, H LeBoit, PE McCarthy, SW Mihm, MC Mooi, WJ Piepkorn, MW Prieto, VG Scolyer, RA AF Barnhill, Raymond L. Cerroni, Lorenzo Cook, Martin Elder, David E. Kerl, Helmut LeBoit, Philip E. McCarthy, Stanley W. Mihm, Martin C. Mooi, Wolter J. Piepkorn, Michael W. Prieto, Victor G. Scolyer, Richard A. TI State of the Art, Nomenclature, and Points of Consensus and Controversy Concerning Benign Melanocytic Lesions: Outcome of an International Workshop SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE melanocytic nevus; spitz nevus; melanoma; blue nevus; congenital nevus; nevocellular nevi; nevi; spindle cell nevus; dysplastic nevus; atypical nevus; benign melanocytic tumors; benign melanocytic neoplasms; workshop; consensus conference ID SPINDLE CELL NEVUS; DEEP PENETRATING NEVUS; PIGMENTED-EPITHELIOID-MELANOCYTOMA; GERMAN-DERMATOLOGICAL-SOCIETY; MALIGNANT-MELANOMA REGISTRY; MULTICENTER CASE-CONTROL; COMPONENTS CLONAL NEVUS; DYSPLASTIC NEVI; BLUE NEVUS; SPITZ NEVI AB The following communication summarizes the proceedings of a one-day International Workshop focusing on the histology of benign melanocytic nevi. Areas of controversy identified in 6 focus sessions were the nomenclature and relationships among common nevi including nevi with halo reactions, traumatized nevi, "dysplastic'' nevi, and nevi from particular anatomic sites; developmental biology and frequency of malignant transformation associated with congenital nevi; the characterization and biologic nature of atypical spitzoid neoplasms; the basic definition of particular melanocytic cellular phenotypes, and the nomenclature and biologic nature of many candidate blue nevi, combined nevi, and other controversial lesions such as deep penetrating nevus and pigmented epithelioid melanocytoma. Concentrated data collection and follow-up, molecular characterization, and future consensus Workshops may facilitate the resolution of some of these problems. The Group recommended the description of ambiguous or 'borderline'' lesions as tumors with indeterminate or uncertain biologic/malignant potential. The participants also advised that such lesions at a minimum should be managed by complete excision with clear surgical margins. C1 [Barnhill, Raymond L.] Hop St Louis, Dept Dermatol, Paris, France. [Barnhill, Raymond L.] Hop St Louis, Dept Pathol, Paris, France. [Cerroni, Lorenzo; Kerl, Helmut] Med Univ Graz, Dept Dermatol, Graz, Austria. [Cook, Martin] Royal Surrey Cty Hosp, Dept Pathol, Guildford, Surrey, England. [Elder, David E.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [LeBoit, Philip E.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [LeBoit, Philip E.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [McCarthy, Stanley W.; Scolyer, Richard A.] Royal Prince Alfred Hosp, Melanoma Inst Australia, Sydney, NSW, Australia. [McCarthy, Stanley W.; Scolyer, Richard A.] Univ Sydney, Sydney, NSW 2006, Australia. [Mihm, Martin C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mooi, Wolter J.] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Pathol, Amsterdam, Netherlands. [Piepkorn, Michael W.] Univ Washington, Div Dermatol, Seattle, WA 98195 USA. [Prieto, Victor G.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Barnhill, RL (reprint author), Hop St Louis, Dept Dermatol, Paris, France. EM raymond.barnhill@sls.aphp.fr OI Scolyer, Richard/0000-0002-8991-0013 NR 104 TC 34 Z9 34 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-4109 J9 ADV ANAT PATHOL JI Adv. Anat. Pathol. PD MAR PY 2010 VL 17 IS 2 BP 73 EP 90 DI 10.1097/PAP.0b013e3181cfe758 PG 18 WC Pathology SC Pathology GA 564XB UT WOS:000275250600001 PM 20179431 ER PT J AU Chew, I Oliva, E AF Chew, Ivy Oliva, Esther TI Endometrial Stromal Sarcomas A Review of Potential Prognostic Factors SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE endometrial stromal nodule; endometrial stromal sarcoma; undifferentiated endometrial sarcoma; prognostic factors ID SMOOTH-MUSCLE TUMORS; FLOW CYTOMETRIC ANALYSIS; NUCLEAR BETA-CATENIN; HIGH-GRADE SARCOMA; SEX-CORD TUMORS; UTERINE SARCOMAS; MESENCHYMAL TUMORS; CLINICOPATHOLOGIC ANALYSIS; GLANDULAR DIFFERENTIATION; PROGESTERONE-RECEPTORS AB Endometrial stromal tumors are uncommon mesenchymal tumors of the uterus. The classification of these tumors has evolved and the most current World Health Organization classification (2003) divides these neoplasms into: endometrial stromal nodule, low-grade endometrial stromal sarcoma, and undifferentiated endometrial sarcoma. The salient clinicopathologic features of these tumors are described, and a comprehensive review of literature pertaining to potential prognostic factors in endometrial stromal sarcomas is provided. Clinical factors, including age, race, parity and menopausal status, and pathologic factors, including tumor size, tumor stage, nuclear atypia, mitotic activity, tumor necrosis, lymphovascular space invasion, DNA ploidy and proliferative activity, and expression of hormone receptors, have been explored with varying outcomes. Surgicopathologic stage seems to be the most important prognostic factor in low-grade endometrial stromal sarcomas. The impact of other prognostic factors on survival is unclear or controversial, especially in patients with stage I tumors. C1 [Chew, Ivy; Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 251A, Boston, MA 02114 USA. EM eoliva@partners.org NR 103 TC 25 Z9 29 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-4109 J9 ADV ANAT PATHOL JI Adv. Anat. Pathol. PD MAR PY 2010 VL 17 IS 2 BP 113 EP 121 DI 10.1097/PAP.0b013e3181cfb7c2 PG 9 WC Pathology SC Pathology GA 564XB UT WOS:000275250600003 PM 20179433 ER PT J AU Blagosklonny, MV Campisi, J Sinclair, DA Bartke, A Blasco, MA Bonner, WM Bohr, VA Brosh, RM Brunet, A DePinho, RA Donehower, LA Finch, CE Finkel, T Gorospe, M Gudkov, AV Hall, MN Hekimi, S Helfand, SL Karlseder, J Kenyon, C Kroemer, G Longo, V Nussenzweig, A Osiewacz, HD Peeper, DS Rando, TA Rudolph, KL Sassone-Corsi, P Serrano, M Sharpless, NE Skulachev, VP Tilly, JL Tower, J Verdin, E Vijg, J AF Blagosklonny, Mikhail V. Campisi, Judy Sinclair, David A. Bartke, Andrzej Blasco, Maria A. Bonner, William M. Bohr, Vilhelm A. Brosh, Robert M., Jr. Brunet, Anne DePinho, Ronald A. Donehower, Lawrence A. Finch, Caleb E. Finkel, Toren Gorospe, Myriam Gudkov, Andrei V. Hall, Michael N. Hekimi, Siegfried Helfand, Stephen L. Karlseder, Jan Kenyon, Cynthia Kroemer, Guido Longo, Valter Nussenzweig, Andre Osiewacz, Heinz D. Peeper, Daniel S. Rando, Thomas A. Rudolph, K. Lenhard Sassone-Corsi, Paolo Serrano, Manuel Sharpless, Norman E. Skulachev, Vladimir P. Tilly, Jonathan L. Tower, John Verdin, Eric Vijg, Jan TI Impact papers on aging in 2009 SO AGING-US LA English DT Review DE aging; senescence; signal transduction; genes for longevity ID LIFE-SPAN EXTENSION; SINGLE-NUCLEOTIDE POLYMORPHISMS; TELOMERE-DYSFUNCTIONAL MICE; STEM-CELL HOMEOSTASIS; DNA-DAMAGE RESPONSE; DROSOPHILA-MELANOGASTER; DIETARY RESTRICTION; PROTEIN-KINASE; GENETICALLY INTERACTS; CALORIE RESTRICTION AB The editorial board of Aging reviews research papers published in 2009, which they believe have or will have a significant impact on aging research. Among many others, the topics include genes that accelerate aging or in contrast promote longevity in model organisms, DNA damage responses and telomeres, molecular mechanisms of life span extension by calorie restriction and pharmacologic interventions into aging. The emerging message in 2009 is that aging is not random but determined by a genetically-regulated longevity network and can be decelerated both genetically and pharmacologically. C1 [Blagosklonny, Mikhail V.] Roswell Pk Canc Inst, Dept Cell Stress Biol, BLSC, Buffalo, NY 14263 USA. [Campisi, Judy] Buck Inst Age Res, Novato, CA USA. [Sinclair, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Bartke, Andrzej] So Illinois Univ, Springfield, IL USA. [Blasco, Maria A.; Serrano, Manuel] Spanish Natl Canc Ctr, Madrid, Spain. [Bonner, William M.; Nussenzweig, Andre] NCI, NIH, Bethesda, MD 20892 USA. [Bohr, Vilhelm A.; Brosh, Robert M., Jr.; Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. [Brunet, Anne; Rando, Thomas A.] Stanford Univ, Stanford, CA 94305 USA. [DePinho, Ronald A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Donehower, Lawrence A.] Baylor Coll Med, Houston, TX 77030 USA. [Finch, Caleb E.; Longo, Valter; Tower, John] Univ So Calif, Los Angeles, CA USA. [Finkel, Toren] NHLBI, NIH, Bethesda, MD 20892 USA. [Hall, Michael N.] Univ Basel, Basel, Switzerland. [Hekimi, Siegfried] McGill Univ, Montreal, PQ, Canada. [Helfand, Stephen L.] Brown Univ, Providence, RI 02912 USA. [Karlseder, Jan] Salk Inst Biol Studies, La Jolla, CA USA. [Kenyon, Cynthia; Verdin, Eric] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kroemer, Guido] INSERM, U848, Villejuif, France. [Osiewacz, Heinz D.] Goethe Univ Frankfurt, Frankfurt, Germany. [Peeper, Daniel S.] Netherlands Canc Inst, Amsterdam, Netherlands. [Rudolph, K. Lenhard] Hannover Med Sch, D-3000 Hannover, Germany. [Sassone-Corsi, Paolo] Univ Calif Irvine, Irvine, CA USA. [Sharpless, Norman E.] Univ N Carolina, Chapel Hill, NC USA. [Skulachev, Vladimir P.] Moscow MV Lomonosov State Univ, Moscow, Russia. [Tilly, Jonathan L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vijg, Jan] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Blagosklonny, MV (reprint author), Roswell Pk Canc Inst, Dept Cell Stress Biol, BLSC, L3-312,Elm & Carlton St, Buffalo, NY 14263 USA. EM Blagosklonny@oncotarget.com RI Osiewacz, Heinz/D-3454-2011; Sassone-Corsi, Paolo/H-6182-2011; Skulachev, Vladimir/J-4164-2012; Kroemer, Guido/B-4263-2013; Serrano, Manuel/H-2634-2015; Blasco , Maria A./M-1694-2014; Bartke, Andzej/D-6640-2017; OI Skulachev, Vladimir/0000-0003-4886-2243; Serrano, Manuel/0000-0001-7177-9312; Blasco , Maria A./0000-0002-4211-233X; Bartke, Andzej/0000-0002-2569-557X; Verdin, Eric/0000-0003-3703-3183; Sinclair, David/0000-0002-9936-436X FU NCI NIH HHS [R01 CA084628]; NIA NIH HHS [R01 AG011833, R01 AG024353, R01 AG028730] NR 115 TC 19 Z9 20 U1 0 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD MAR PY 2010 VL 2 IS 3 BP 111 EP 121 PG 11 WC Cell Biology SC Cell Biology GA 589AE UT WOS:000277115300001 PM 20351400 ER PT J AU Elrefaei, M Burke, CM Baker, CAR Jones, NG Bousheri, S Bangsberg, DR Cao, HY AF Elrefaei, Mohamed Burke, Candace M. Baker, Chris A. R. Jones, Norman G. Bousheri, Stephanie Bangsberg, David R. Cao, Huyen TI HIV-Specific TGF-beta-Positive CD4(+) T Cells Do Not Express Regulatory Surface Markers and Are Regulated by CTLA-4 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID GROWTH-FACTOR-BETA; ACTIVE ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; INFECTED INDIVIDUALS; CYTOKINE PRODUCTION; PERIPHERAL-BLOOD; IMMUNE-RESPONSES; UP-REGULATION; IN-VIVO; INTERLEUKIN-10 AB CD4(+) T cell dysfunction in HIV-1 infection is associated with increased CTLA-4 and TGF-beta expression. In this study we described a population of TGF-beta-positive CD4(+) T cells with multiple HIV specificities. These HIV-specific TGF-beta-positive CD4(+) T cells did not display the immunophenotypic patterns traditionally attributed to regulatory CD4(+) T cells. TGF-beta-positive CD4(+) T cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. We also examined one potential mechanism for regulating TGF-beta expression by HIV-specific CD4(+) T cells. Blocking of the TGF-beta receptor II led to increased HIV-specific IFN-gamma-positive CD4(+) and CD8(+) T cell responses. Interestingly, HIV-specific TGF-beta-positive CD4(+) T cells did not substantially express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-beta-positive CD4(+) T cell responses, and a concomitant increase in HIV-specific IFN-gamma-positive CD4(+) T cell responses. Our study proposes a mechanism by which HIV-specific TGF-beta production may be regulated by CTLA-4 engagement. C1 [Elrefaei, Mohamed; Burke, Candace M.; Baker, Chris A. R.; Jones, Norman G.; Bousheri, Stephanie; Cao, Huyen] Calif Dept Publ Hlth, Richmond, CA 94804 USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Harvard Initiat Global Hlth, Cambridge, MA 02138 USA. RP Elrefaei, M (reprint author), Calif Dept Publ Hlth, 850 Marina Bay Pkwy VRDL, Richmond, CA 94804 USA. EM melrefae@unch.unc.edu FU NIH [AI43885, MM54907, AI71772]; California Research Center for the Biology of HIV in Minorities FX This work was supported by NIH Grants AI43885, MM54907, and AI71772, and California Research Center for the Biology of HIV in Minorities grant, UC Davis. NR 50 TC 7 Z9 9 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2010 VL 26 IS 3 BP 329 EP 337 DI 10.1089/aid.2009.0149 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 574IT UT WOS:000275983300010 PM 20433405 ER PT J AU Long, AD AF Long, Aidan TI Aeroallergen sensitization in asthma: Genetics, environment, and pathophysiology SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article; Proceedings Paper CT Eastern Allergy Conference CY MAY 02, 2009 CL Palm Beach, FL DE Airway; allergen; anti-IgE; asthma; dendritic; epithelium; IgE; inflammation; remodeling ID ANTI-IGE ANTIBODY; HOUSE-DUST MITE; EPSILON-F-RI; DENDRITIC CELLS; ALLERGIC-ASTHMA; AIRWAY INFLAMMATION; IMMUNE-RESPONSES; OMALIZUMAB; INNATE; EXPRESSION AB A complex interplay of genetic predisposition and environmental influences results in the clinical picture of allergic asthma. This article addresses recently identified genetic markers and environmental factors that contribute to disease development in asthma. Focus is placed on aspects of the innate immune system, including inherent properties of allergens, the active role of airway epithelium, and the central importance of dendritic cells together with the pathophysiological processes in which these factors interact. Implications of these processes for asthma therapy, with a focus on anti-IgE treatment are also discussed. (Allergy Asthma Proc 31:89-95, 2010; doi: 10.2500/aap.2010.31.3328) C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, DRAI, Boston, MA 02114 USA. RP Long, AD (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, DRAI, COX 201,55 Fruit St, Boston, MA 02114 USA. EM aalong@partners.org NR 42 TC 6 Z9 6 U1 0 U2 0 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 MAR-APR PY 2010 VL 31 IS 2 BP 89 EP 95 DI 10.2500/aap.2010.31.3328 PG 7 WC Allergy SC Allergy GA 589OU UT WOS:000277162300001 PM 20406590 ER PT J AU Barnes, DE Covinsky, KE Whitmer, RA Kuller, LH Lopez, OL Yaffe, K AF Barnes, Deborah E. Covinsky, Kenneth E. Whitmer, Rachel A. Kuller, Lewis H. Lopez, Oscar L. Yaffe, Kristine TI Commentary on "Developing a national strategy to prevent dementia: Leon Thal Symposium 2009." Dementia risk indices: A framework for identifying individuals with a high dementia risk SO ALZHEIMERS & DEMENTIA LA English DT Article ID CARDIOVASCULAR HEALTH COGNITION; OLDER-ADULTS; PROGNOSTIC INDEX; BREAST-CANCER; VALIDATION; PREDICTION; SCORE; MORTALITY C1 [Barnes, Deborah E.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Psychiat, San Francisco, CA 94121 USA. [Covinsky, Kenneth E.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Whitmer, Rachel A.] Kaiser Div Res, Oakland, CA USA. [Kuller, Lewis H.; Lopez, Oscar L.] Univ Pittsburgh, Pittsburgh, PA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. RP Barnes, DE (reprint author), Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Psychiat, 4150 Clement St,151R, San Francisco, CA 94121 USA. EM deborah.bames@ucsf.edu FU National Heart, Lung, and Blood Institute [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295]; National Institute on Aging [AG15928]; National Institute of Neurological Disorders and Stroke; National Institutes of Health [K01 AG024069]; Alzheimer's Association [IIRG-06-27306]; NIH/NCRR UCSF-CTSI [UL1 RR024131] FX The Cardiovascular Health Study (CHS) was supported by contract numbers N01-HC-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, and grant AG15928 from the National Institute on Aging with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. Dr Barnes is funded through a K01 Career Development Award (K01 AG024069) from the National Institutes of Health and an Alzheimer's Association award (IIRG-06-27306). This project also was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 21 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2010 VL 6 IS 2 BP 138 EP 141 DI 10.1016/j.jalz.2010.01.005 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 582DR UT WOS:000276576400009 PM 20298975 ER PT J AU Setoguchi, S Higgins, JM Mogun, H Mootha, VK Avorn, J AF Setoguchi, Soko Higgins, John M. Mogun, Helen Mootha, Vamsi K. Avorn, Jerry TI Propranolol and the risk of hospitalized myopathy: Translating chemical genomics findings into population-level hypotheses SO AMERICAN HEART JOURNAL LA English DT Article ID VALIDITY AB Background A recent large-scale, chemical screening study raised the hypothesis that propranolol may increase the risk of myopathy. We tested this hypothesis in a large population to assess whether (1) propranolol use is associated with an increased risk of myopathy and (2) the concurrent use of propranolol with a statin may further increase risk of myopathy. Methods New users of propranolol and other beta-blockers (BBs) aged >= 65 were identified using data from Medicare and drug benefit programs in 2 states (1994-2005). The primary end point studied was hospitalization for myopathy or rhabdomyolysis. We used stratified Cox proportional hazards regression to estimate the multivariate-adjusted effect of propranolol compared to other BBs and controlled for demographic variables, risk factors for myopathy, other comorbidities, and health service use measures. We also assessed whether co-use of propranolol and statin further increases the risk, by including an interaction term for use of propranolol and statins. Results We identified 9,304 initiators of propranolol and 130,070 initiators of other BBs and found 30 cases of hospitalized myopathy in 15,477 person-years (PYs) of propranolol use and 523 in 343,132 PYs of other BB use. Comparing propranolol with other BB users, the adjusted hazard ratio was 1.45 (95% CI 1.00-2.11) for myopathy and 1.48 (95% CI 0.82-2.67) for rhabdomyolysis. We could not detect interaction between propranolol and statins due to limited power. Similar results were observed when propranolol users were compared to other antihypertensive drug users. Conclusions Propranolol may be associated with a 45% increased risk of hospitalized myopathy in the elderly. Our study illustrates how results from in vitro chemical screens can be translated into hypotheses about drug toxicity at the population level. (Am Heart J 2010; 159: 428-33.) C1 [Setoguchi, Soko; Mogun, Helen; Avorn, Jerry] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02130 USA. [Higgins, John M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Mootha, Vamsi K.] MIT & Harvard, Broad Inst, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Setoguchi, S (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02130 USA. EM ssetoguchi@partners.org FU Divisional fund; American Diabetes Association/Smith Family Foundation FX Divisional fund; American Diabetes Association/Smith Family Foundation. NR 12 TC 3 Z9 3 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAR PY 2010 VL 159 IS 3 BP 428 EP 433 DI 10.1016/j.ahj.2009.12.008 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 571XH UT WOS:000275788900014 PM 20211305 ER PT J AU Acharjee, S Qin, JE Murphy, SA McCabe, C Cannon, CP AF Acharjee, Subroto Qin, Jie Murphy, Sabina A. McCabe, Carolyn Cannon, Christopher P. TI Distribution of Traditional and Novel Risk Factors and Their Relation to Subsequent Cardiovascular Events in Patients With Acute Coronary Syndromes (from the PROVE IT-TIMI 22 Trial) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID C-REACTIVE PROTEIN; HEART-DISEASE; CHOLESTEROL LEVELS; RANDOMIZED-TRIAL; FOLLOW-UP; MEN; PREDICTION; WOMEN; SIMVASTATIN; PREVENTION AB Current guidelines recommend risk stratification largely based on traditional risk factors such as those in the Framingham Risk Score. We studied the distribution of 12 traditional and non-traditional risk markers (age >= 65 years, male gender, family history of premature coronary heart disease, low-density lipoprotein cholesterol >= 70 mg/di, high-density lipoprotein cholesterol <40 mg/di in men and <50 mg/dl in women, systolic blood pressure > 130 mm Hg, diabetes mellitus, smoking, C-reactive protein >= 2 mg/L, triglycerides >150 mg/di, prediabetes defined as a fasting glucose level 100 to 125 mg/di or hemoglobin Ale >6, and obesity defined as body mass index >= 30 kg/m(2)) in 3,675 patients from the PROVE IT-TIMI 22 trial at 4 months and evaluated the risk of cardiovascular events stratified by the number of risk factors. The median number of risk factors was 5. In individual risk factor subgroups, men, smokers, hypertensives, and patients with increased low-density lipoprotein cholesterol had just that added risk factor compared to their counterparts (median 5 vs 4). In contrast, patients with diabetes, prediabetes, and increased triglycerides, C-reactive protein, or body mass index had not only that, but also another added risk factor (median 6 vs 4). A higher risk factor count was strongly related with increased rate of death, myocardial infarction, unstable angina, stroke, or revascularization, from 0% to 38.6% at 2 years for 0 to >= 9 risk factors (p < 0.0001). In conclusion, with the observed "clustering" of risk factors and the link between increasing risk factor count and adverse outcomes in a patient with 1 diagnosed risk factor, a comprehensive review of traditional and novel risk factors is important to fully assess cardiovascular risk. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:619-623) C1 [Qin, Jie; Murphy, Sabina A.; McCabe, Carolyn; Cannon, Christopher P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Acharjee, Subroto] SUNY Buffalo, Dept Med, Sch Med, Buffalo, NY 14260 USA. RP Cannon, CP (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. EM cpcannon@partners.org FU Bristol-Myers Squibb, New York, New York; Sankiyo, Parsippany, New York FX The PROVE IT-TIMI 22 Study was supported by a research grant from Bristol-Myers Squibb, New York, New York; and Sankiyo, Parsippany, New York. NR 23 TC 10 Z9 10 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 1 PY 2010 VL 105 IS 5 BP 619 EP 623 DI 10.1016/j.amjcard.2009.10.042 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602KD UT WOS:000278137100007 PM 20185006 ER PT J AU Krempf, M Parhofer, KG Steg, G Bhatt, DL Ohman, M Rother, J Goto, S Pasquet, B Wilson, PWF AF Krempf, Michel Parhofer, Klaus G. Steg, Gabriel Bhatt, Deepak L. Ohman, Magnus Roether, Joachim Goto, Shinya Pasquet, Blandine Wilson, Peter W. F. CA Reach Registry Investigators TI Cardiovascular Event Rates in Diabetic and Nondiabetic Individuals With and Without Established Atherothrombosis (from the REduction of Atherothrombosis for Continued Health [REACH] Registry) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; PRIOR MYOCARDIAL-INFARCTION; METABOLIC SYNDROME; SEX-DIFFERENCES; FOLLOW-UP; RISK; MORTALITY; OUTPATIENTS; PREVALENCE; HISTORY AB The objective of this study was to determine cardiovascular event rates in diabetic patients and nondiabetic subjects from the REACH Registry with established coronary artery disease, cerebrovascular disease, peripheral arterial disease, or multiple risk factors for atherothrombosis. REACH is an international, prospective, and contemporaneous cohort of patients with >= 3 atherothrombotic risk factors only or established atherothrombotic disease, of which 30,043 have diabetes. The main outcomes after 1-year follow-up were cardiovascular death, myocardial infarction, stroke, major adverse cardiovascular events (MACEs; cardiovascular death, myocardial infarction, or stroke), and MACEs/hospitalization. The MACE rate at 1 year was positively related to the number of atherothrombotic anatomic sites in diabetic patients and nondiabetic subjects, and the rate was higher in those with (3.8%) than without (3.0%, p <0.001) diabetes. Diabetic patients with risk factors only had a lower MACE rate than nondiabetic subjects or diabetic patients with established atherothrombotic disease (2.2% vs 4.0% or 6.0%, respectively, p <0.001 for the 2 comparisons). These differences persisted after adjusting for gender and age. In conclusion, diabetic patients in the REACH Registry have an increased risk of cardiovascular events compared to nondiabetic subjects related to the number of atherothrombotic sites. Although increasing risk, diabetes may not be truly equivalent to previous atherothrombotic events on new cardiovascular event rates. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:667-671) C1 [Krempf, Michel] Inst Thorax, INSERM, UMR915, Nantes, France. [Krempf, Michel] Univ Nantes, CHU, Nantes, France. [Steg, Gabriel] Univ Paris 07, INSERM, U698, Ctr Hosp Bichat Claude, Paris, France. [Pasquet, Blandine] Univ Paris 07, Dept Epidemiol, Hop Bichat Claude Bernard, Paris, France. [Parhofer, Klaus G.] Univ Munich, Klinikum Grosshadern, Dept Internal Med 2, D-8000 Munich, Germany. [Roether, Joachim] Hannover Med Sch, Klinikum Minden, Minden, Germany. [Goto, Shinya] Tokai Univ, Sch Med, Dept Med, Kanagawa 2591100, Japan. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ohman, Magnus] Duke Clin Res Inst, Durham, NC USA. [Ohman, Magnus] Duke Univ, Med Ctr, Durham, NC USA. [Wilson, Peter W. F.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Krempf, M (reprint author), Inst Thorax, INSERM, UMR915, Nantes, France. EM nadine.denoual@univ-nantes.fr FU Sanofi-Aventis (Paris, France); Bristol-Myers Squibb (Paris, France); Waksman Foundation (Tokyo, Japan) FX The REACH Registry is sponsored by Sanofi-Aventis (Paris, France), Bristol-Myers Squibb (Paris, France), and the Waksman Foundation (Tokyo, Japan). NR 20 TC 24 Z9 26 U1 1 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 1 PY 2010 VL 105 IS 5 BP 667 EP 671 DI 10.1016/j.amjcard.2009.10.048 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602KD UT WOS:000278137100015 PM 20185014 ER PT J AU Gritli, S Ben Salah, M Shili, A Robson, CD Ferjaoui, M Hendaoui, L Belhani, A Baltagi-Ben Jilani, S Gusella, JF MacRae, CA AF Gritli, Sami Ben Salah, Mamia Shili, Abdessalem Robson, Caroline D. Ferjaoui, Mohamed Hendaoui, Lotfi Belhani, Ali Baltagi-Ben Jilani, Sarrah Gusella, James F. MacRae, Calum A. TI Association of the Long QT Syndrome With Goiter and Deafness SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID FAMILIAL EUTHYROID GOITER; CONGENITAL DEAFNESS; PENDRED-SYNDROME; ELECTROCARDIOGRAPHIC ABNORMALITIES; VENTRICULAR REPOLARIZATION; MENTAL-RETARDATION; THYROID-FUNCTION; LINKAGE; VARIABILITY; DELETION AB We report on the long QT syndrome occurring in conjunction with nontoxic multinodular goiter and sensorineural deafness in several siblings of a large family. Autosomal and X-linked recessive and dominant modes of inheritance are possible for the different phenotypes. The affected family members had various phenotype combinations, suggesting variable expressivity and incomplete penetrance. (C) 2010 Published by Elsevier Inc. (Am J Cardiol 2010;105:681-686) C1 [Gritli, Sami; MacRae, Calum A.] Massachusetts Gen Hosp, Dev Biol Lab, Cardiovasc Res Ctr, Charlestown, MA USA. [Gritli, Sami; MacRae, Calum A.] Harvard Univ, Sch Med, Charlestown, MA USA. [Gritli, Sami; Belhani, Ali] Hop Mongi Slim, Serv Cardiol, La Marsa, Tunisia. [Gritli, Sami; Baltagi-Ben Jilani, Sarrah] Hop Charles Nicolle, Dept Pathol, Div Genet Immunol & Cell Biol, Tunis, Tunisia. [Gritli, Sami; Gusella, James F.] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Gritli, Sami; Gusella, James F.] Harvard Univ, Sch Med, Boston, MA USA. [Ben Salah, Mamia; Ferjaoui, Mohamed] Hop Charles Nicolle, Serv Otorhinolaryngol, Tunis, Tunisia. [Shili, Abdessalem] Inst Natl Agron, Biol Marine Lab, Tunis, Tunisia. [Robson, Caroline D.] Childrens Hosp, Div Neuroradiol, Boston, MA 02115 USA. [Hendaoui, Lotfi] Hop Mongi Slim, Serv Imagerie Med, La Marsa, Tunisia. RP Gritli, S (reprint author), Massachusetts Gen Hosp, Dev Biol Lab, Cardiovasc Res Ctr, Charlestown, MA USA. EM gritli@helix.mgh.harvard.edu OI Robson, Caroline/0000-0001-5592-249X NR 28 TC 1 Z9 1 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 MAR 1 PY 2010 VL 105 IS 5 BP 681 EP 686 DI 10.1016/j.amjcard.2009.10.034 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602KD UT WOS:000278137100018 PM 20185017 ER PT J AU Dal Cin, P Aster, JC DeAngelo, DJ AF Dal Cin, Paola Aster, Jon C. DeAngelo, Daniel J. TI When to Go FISHing SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Editorial Material ID IN-SITU HYBRIDIZATION; MYELODYSPLASTIC-SYNDROME PATIENTS; CONVENTIONAL CYTOGENETICS; DELETION; 5Q C1 [Dal Cin, Paola; Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [DeAngelo, Daniel J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dal Cin, Paola; Aster, Jon C.; DeAngelo, Daniel J.] Harvard Univ, Sch Med, Boston, MA USA. RP Dal Cin, P (reprint author), Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. NR 13 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2010 VL 133 IS 3 BP 351 EP 353 DI 10.1309/AJCPUD3WU1NIUKCJ PG 3 WC Pathology SC Pathology GA 557RM UT WOS:000274687800001 PM 20154272 ER PT J AU Paulus, JK Asomaning, K Kraft, P Johnson, BE Lin, XH Christiani, DC AF Paulus, Jessica K. Asomaning, Kofi Kraft, Peter Johnson, Bruce E. Lin, Xihong Christiani, David C. TI Parity and Risk of Lung Cancer in Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE lung neoplasms; parity; reproduction; smoking; women ID ESTROGEN-RECEPTOR-BETA; REPRODUCTIVE FACTORS; CIGARETTE-SMOKING; UNITED-STATES; POSTMENOPAUSAL WOMEN; PROSPECTIVE COHORT; HORMONAL FACTORS; SEX-DIFFERENCES; BREAST-CANCER; CHINESE WOMEN AB Patterns of lung cancer incidence suggest that gender-associated factors may influence lung cancer risk. Given the association of parity with risk of some women's cancers, the authors hypothesized that childbearing history may also be associated with lung cancer. Women enrolled in the Lung Cancer Susceptibility Study at Massachusetts General Hospital (Boston, Massachusetts) between 1992 and 2004 (1,004 cases, 848 controls) were available for analysis of the association between parity and lung cancer risk. Multivariate logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. After results were controlled for age and smoking history, women with at least 1 child had 0.71 times the odds of lung cancer as women without children (odds ratio = 0.71, 95% confidence interval: 0.52, 0.97). A significant linear trend was found: Lung cancer risk decreased with increasing numbers of children (P < 0.001). This inverse association was stronger in never smokers (P = 0.12) and was limited to women over age 50 years at diagnosis (P = 0.17). Age at first birth was not associated with risk. The authors observed a protective association between childbearing and lung cancer, adding to existing evidence that reproductive factors may moderate lung cancer risk in women. C1 [Paulus, Jessica K.; Kraft, Peter; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Asomaning, Kofi; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Kraft, Peter; Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Christiani, David C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Paulus, JK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM jpaulus@hsph.harvard.edu FU National Institutes of Health [R01CA74386, T32ES07069, P50 CA 090578] FX This study was supported by National Institutes of Health grants R01CA74386, T32ES07069, and P50 CA 090578. NR 46 TC 13 Z9 13 U1 0 U2 0 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 MAR 1 PY 2010 VL 171 IS 5 BP 557 EP 563 DI 10.1093/aje/kwp441 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558YY UT WOS:000274786500006 PM 20123687 ER PT J AU Laine, L Spiegel, B Rostom, A Moayyedi, P Kuipers, EJ Bardou, M Sung, J Barkun, AN AF Laine, Loren Spiegel, Brennan Rostom, Alaa Moayyedi, Paul Kuipers, Ernst J. Bardou, Marc Sung, Joseph Barkun, Alan N. TI Methodology for Randomized Trials of Patients With Nonvariceal Upper Gastrointestinal Bleeding: Recommendations From an International Consensus Conference SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Review ID ENDOSCOPIC THERAPY; PEPTIC-ULCER; HEMORRHAGE; MULTICENTER; PANTOPRAZOLE; PREVENTION; INFUSION; BLOOD AB The aim of this document is to provide a methodological framework for the design, performance, analysis, interpretation, and communication of randomized trials that assess management of patients with nonvariceal upper gastrointestinal bleeding. Literature searches were performed and an iterative process with electronic and face-to-face meetings was used to achieve consensus among panel members as part of an International Consensus Conference on Nonvariceal Upper Gastrointestinal Bleeding. Recommendations of the panel include the following. Randomized trials must explicitly state their primary hypothesis. A nonmanipulable randomization schedule with concealed allocation should be used. Stratification (e.g., for age and stigmata of hemorrhage) may be considered, especially in smaller studies. The patient and personnel providing care or recording information should be blinded. Inclusion criteria should be overt bleeding with endoscopy performed within 24 h or less. One type of lesion (e.g., ulcer) should be studied with stigmata to be included predefined. Use of placebo/no therapy vs. active controls depends on current standard practice. Standardizing study and key non-study interventions should ensure uniform provision of interventions. Criteria for repeat endoscopy and subsequent interventions should be predefined. The primary end point should be further bleeding (persistent and recurrent bleeding) with primary assessment at 7 days; mortality, with primary assessment at 30 days, would be appropriate in very large trials. Sample size calculation based on assumptions regarding primary end point results with regard to study intervention and control must be provided, and all patients enrolled must be accounted for. In general, the primary population for analysis is all patients randomized, although a per-protocol population may be used if this is the more conservative approach (e.g., equivalence study). C1 [Laine, Loren] Univ So Calif, Div Gastrointestinal & Liver Dis, Keck Sch Med, Los Angeles, CA 90033 USA. [Spiegel, Brennan] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Spiegel, Brennan] VA Greater Los Angeles Healthcare Syst, Div Digest Dis, Los Angeles, CA USA. [Rostom, Alaa] Univ Calgary, Div Gastroenterol, Calgary, AB, Canada. [Moayyedi, Paul] McMaster Univ, Med Ctr, Div Gastroenterol, Hamilton, ON, Canada. [Kuipers, Ernst J.] Erasmus MC Univ Med Ctr, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands. [Kuipers, Ernst J.] Erasmus MC Univ Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Bardou, Marc] CHU Dijon, Ctr Invest Clin, Dijon, France. [Sung, Joseph] Chinese Univ Hong Kong, Inst Digest Dis, Shatin, Hong Kong, Peoples R China. [Barkun, Alan N.] McGill Univ, Div Gastroenterol, Montreal, PQ, Canada. RP Laine, L (reprint author), Univ So Calif, Div Gastrointestinal & Liver Dis, Keck Sch Med, 2025 Zonal Ave, Los Angeles, CA 90033 USA. EM llaine@usc.edu RI Hossain, Sarah /C-7332-2009; Moayyedi, Paul/M-6178-2014 OI Hossain, Sarah /0000-0003-1355-0979; Moayyedi, Paul/0000-0002-3616-9292 FU Canadian Association of Gastroenterology; European Association for Gastroenterology and Endoscopy; Asian Pacific Society of Digestive Endoscopy; Canadian Institutes of Health Research, Institute of Diabetes, Metabolism and Nutrition; AstaZeneca Molndal; Abbott Canada; Olympus Canada FX This work was supported by the Canadian Association of Gastroenterology; the European Association for Gastroenterology and Endoscopy; the Asian Pacific Society of Digestive Endoscopy; the Canadian Institutes of Health Research, Institute of Diabetes, Metabolism and Nutrition; and arm's length contributions to the above sponsoring societies from AstaZeneca Molndal, Abbott Canada, and Olympus Canada. NR 29 TC 18 Z9 19 U1 0 U2 3 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 MAR PY 2010 VL 105 IS 3 BP 540 EP 550 DI 10.1038/ajg.2009.702 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 567PE UT WOS:000275458300012 PM 20029415 ER PT J AU O'Neil, CE Nicklas, TA Kleinman, R AF O'Neil, Carol E. Nicklas, Theresa A. Kleinman, Ronald TI Relationship Between 100% Juice Consumption and Nutrient Intake and Weight of Adolescents SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE 100% Juice Intake; Dietary Adequacy; Weight; Adolescents ID FRUIT JUICE; ENERGY-INTAKE; VEGETABLE CONSUMPTION; BEVERAGE CONSUMPTION; CHILDRENS GROWTH; AGED CHILDREN; UNITED-STATES; OBESITY; ASSOCIATION; OVERWEIGHT AB Purpose. This study investigated the associations among 100% juice consumption, nutrient intake, and measures of weight in adolescents. Design. A cross-sectional secondary analysis of data from adolescents aged 12 to 18 Years (n = 3939) participating in, the National Health and Nutrition Examination Survey 1999-2002 was conducted to assess nutrient awl weight in categories of 100% juice consumption. Methods. Least square means and logistic regression analyses were generated, and were adjusted for gender, age, ethnicity, and energy intake. Analyses were Bonferroni corrected with an effective p value of .0125. Results. Twenty-eight percent of adolescents (51% male, 42% Hispanic, 25% non-Hispanic while, 29% non-Hispanic black) consumed 100% juice the day of the recall. the mean amount of 100% juice consumed was 3.7 ounces (2.2% of energy intake). Compared with non-juice consumers, carbohydrate, fiber, vitamins C and B6, folate, potassium, copper, magnesium, and iron intakes of juice consumers were higher, and intakes of fat and saturated fatty acids were lower. Those consuming greater than 6 ounces of juice consumed more servings of fruit and less discretionary fat and added sugar than nonconsumers. No differences were found in weight by juice consumption group. Conclusion. In conclusion, when compared with non-juice consumers, adolescents consuming 100% juice did not show mean increased weight measures. Juice provided valuable nutrients, and consumption was associatd with lower intakes of total fat, saturated fatty acids, discretionary fat, and added surgars and with higher intakes of whole fruit; however, consumption was not associated with decreased intake of milk, meal, or grains. (Am J Health promot 2010;24[4]:231-237.) C1 [Nicklas, Theresa A.] Baylor Univ, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [O'Neil, Carol E.] Louisiana State Univ, AgCtr, Baton Rouge, LA 70803 USA. [Kleinman, Ronald] Harvard Univ, Sch Med, MassGen Hosp Children, Boston, MA USA. RP Nicklas, TA (reprint author), Baylor Univ, Dept Pediat, Childrens Nutr Res Ctr, 1100 Bates Ave, Houston, TX 77030 USA. EM tnicklas@bcm.unc.edu NR 40 TC 24 Z9 25 U1 1 U2 8 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 MAR-APR PY 2010 VL 24 IS 4 BP 231 EP 237 DI 10.4278/ajhp.080603-QUAN-76 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 572DA UT WOS:000275806000002 PM 20232604 ER PT J AU Jacobs, NL Holtan, SG Porrata, LF Markovic, SN Tefferi, A Steensma, DP AF Jacobs, Nisha L. Holtan, Shernan G. Porrata, Luis F. Markovic, Svetomir N. Tefferi, Ayalew Steensma, David P. TI Host immunity affects survival in myelodysplastic syndromes: Independent prognostic value of the absolute lymphocyte count SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID SCORING SYSTEM; BONE-MARROW; T-CELLS; DIFFERENTIATION; TIME AB The prognostic significance of the peripheral blood absolute lymphocyte count (ALC) has been carefully examined in lymphoid malignancies, but the importance of the baseline ALC in chronic myeloid neoplasms is less clear. In a recent analysis of myelodysplastic syndromes (MDS) associated with deletion of chromosome 5q, we observed that an ALC < 1.2 x 10(9) cells/L at diagnosis is independently associated with poorer survival. Clinicopathological data from 503 patients with non-del(5q) MDS evaluated at Mayo Clinic between 1996 and 2007 were reviewed to determine the prognostic impact of ALC at diagnosis in non-del(5q) MDS. Patients with MDS and an ALC at diagnosis >= 1.2x 10(9) (N = 248) experienced a superior overall survival (OS) compared with patients with an ALC < 1.2 x 10(9)/L (N = 255, median OS of 26.6 months versus 18.5 months, P < 0.001, respectively). ALC at diagnosis was an independent predictor for OS when compared with the International Prognostic Scoring System and the WHO-based Prognostic Scoring System. This study suggests that ALC at diagnosis is a prognostic factor for OS in MDS, and argues in favor of further studies to assess the role of host immunity in MDS clinical outcomes. Am. J. Hematol. 85:160-163,2010. (c) 2009 Wiley-Liss, Inc. C1 [Steensma, David P.] Dana Farber Canc Inst, Dept Oncol, Div Hematol Malignancies, Leukemia Grp, Boston, MA 02115 USA. [Jacobs, Nisha L.] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Holtan, Shernan G.; Porrata, Luis F.; Markovic, Svetomir N.; Tefferi, Ayalew] Mayo Clin, Grad Sch Med, Div Hematol, Dept Med, Rochester, MN USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Dept Oncol, Div Hematol Malignancies, Leukemia Grp, 44 Binney St,Suite D1B30 Mayer 1B21, Boston, MA 02115 USA. EM david_steensma@dfci.harvard.edu OI Steensma, David/0000-0001-5130-9284 NR 22 TC 12 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD MAR PY 2010 VL 85 IS 3 BP 160 EP 163 DI 10.1002/ajh.21618 PG 4 WC Hematology SC Hematology GA 568GK UT WOS:000275510100003 PM 20131304 ER PT J AU Castellone, DD Van Cott, EM AF Castellone, Donna D. Van Cott, Elizabeth M. TI Laboratory monitoring of new anticoagulants SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID DIRECT THROMBIN INHIBITORS; CLOTTING TIME; FONDAPARINUX; ASSAY; RIVAROXABAN; ARGATROBAN; WARFARIN; THERAPY AB Maintaining a balance between bleeding and clotting has always been a challenge in treating coagulation disorders. A perturbation in that balance can be associated with substantial morbidity and mortality. As a result, anticoagulant monitoring is extremely important, and inappropriate testing may lead to complications. There are now a variety of new anticoagulant drugs in clinical use including several direct thrombin inhibitors (DTIs), such as argatroban, bivalirudin, and hirudin, as well as a Factor Xa inhibitor, fondaparinux. There are pitfalls associated with some of the currently used laboratory monitoring tests, and newer alternative laboratory monitoring tests have been investigated (Walenga and Hoppensteadt, Semin Thromb Hemost 2004;30:683-695). In addition, laboratory testing can assist with transitioning patients from DTI to warfarin therapy. Am. J. Hematol. 85:185-187, 2010. (c) 2009 Wiley-Liss, Inc. C1 [Castellone, Donna D.] Siemens Healthcare Diagnost, Med Clin & Stat Affairs, Tarrytown, NY 10591 USA. [Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Dept Pathol, Coagulat Lab, Boston, MA 02114 USA. RP Castellone, DD (reprint author), Siemens Healthcare Diagnost, Med Clin & Stat Affairs, 511 Benedict Ave, Tarrytown, NY 10591 USA. EM donna.castellone@siemens.com FU NIH [PHS R01 DK63088, PHS RR-08084, PHS U54 HL070871] FX NIH; PHS R01 DK63088, PHS RR-08084, and PHS U54 HL070871. NR 17 TC 36 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAR PY 2010 VL 85 IS 3 BP 185 EP 187 DI 10.1002/ajh.21607 PG 3 WC Hematology SC Hematology GA 568GK UT WOS:000275510100009 PM 20131309 ER PT J AU Steensma, DP AF Steensma, David P. TI ASH 2009 meeting report - Top 10 clinically oriented abstracts in myelodysplastic syndromes SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; PROGNOSTIC SCORING SYSTEM; ANTITHYMOCYTE GLOBULIN; 5Q DELETION; CHROMOSOME 5Q; PHASE-III; LOW-RISK; LENALIDOMIDE; AZACITIDINE; EFFICACY AB Among the 4,097 abstracts presented orally or in poster format at the December 2009 American Society of Hematology (ASH) annual meeting in New Orleans, LA, 139 abstracts (36 presentations in six oral sessions and 103 posters in three poster sessions) were assigned to the general category of myelodysplastic syndromes (MDS). Here, I summarize and discuss 10 clinically relevant abstracts related to MDS, all of which are published in their entirety in the November 20, 2009 issue of Blood (volume 114, issue 22) and are identified here by their abstract numbers. These 10 abstracts-six oral presentations and four posters-concern prognostic modeling, treatment with hypomethylating agents (azacitidine or decitabine), and therapy with immunomodulatory or immunosuppressive drugs (lenalidomide or alemtuzumab). C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Steensma, DP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies, 44 Binney St,Suite D1B30,Mayer 1B21, Boston, MA 02115 USA. EM david_steesma@dfci.harvard.edu OI Steensma, David/0000-0001-5130-9284 NR 44 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAR PY 2010 VL 85 IS 3 BP 196 EP 201 PG 6 WC Hematology SC Hematology GA 568GK UT WOS:000275510100019 ER PT J AU Weigelt, JA Lipsky, BA Tabak, YP Derby, KG Kim, M Gupta, V AF Weigelt, John A. Lipsky, Benjamin A. Tabak, Ying P. Derby, Karen G. Kim, Myoung Gupta, Vikas TI Surgical site infections: Causative pathogens and associated outcomes SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Surgical site infection; outcomes research; methicillin-resistant Staphylococcus aureus; hospital mortality; hospital length of stay; hospital costs ID RESISTANT STAPHYLOCOCCUS-AUREUS; ECONOMIC OUTCOMES; UNITED-STATES; SURVEILLANCE; PREVENTION; HOSPITALS; IMPACT; MORTALITY; DISCHARGE; SURGERY AB Background: Surgical site infections (SSIs) are associated with substantial morbidity, mortality, and cost. Few studies have examined the causative pathogens, mortality, and economic burden among patients rehospitalized for SSIs. Methods: From 2003 to 2007, 8302 patients were readmitted to 97 US hospitals with a culture-confirmed SSI. We analyzed the causative pathogens and their associations with in-hospital mortality, length of stay (LOS), and cost. Results: The proportion of methicillin-resistant Staphylococcus aureus (MRSA) significantly increased among culture-positive SSI patients during the study period (16.1% to 20.6%, respectively, P<.0001). MRSA (compared with other) infections had higher raw mortality rates (1.4% vs 0.8%, respectively, P=.03), longer LOS (median, 6 vs 5 days, respectively, P<.0001), and higher hospital costs ($7036 vs $6134, respectively, P<.0001). The MRSA infection risk-adjusted attributable LOS increase was 0.93 days (95% confidence interval [CI]: 0.65-1.21; P<.0001), and cost increase was $1157 (95% CI: $641-$1644; P<.0001). Other significant independent risk factors increasing cost and LOS included illness severity, transfer from another health care facility, previous admission (<30 days), and other polymicrobial infections (P<.05). Conclusion: SSIs caused by MRSA increased significantly and were independently associated with economic burden. Admission illness severity, transfer from another health care setting, and recent hospitalization were associated with higher mortality, increased LOS, and cost. C1 [Weigelt, John A.] Med Coll Wisconsin, Dept Surg, Div Trauma Crit Care, Milwaukee, WI 53226 USA. [Lipsky, Benjamin A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Lipsky, Benjamin A.] Univ Washington, Seattle, WA 98195 USA. [Tabak, Ying P.; Derby, Karen G.; Gupta, Vikas] Cardinal Hlth Clin Res Serv, Marlborough, MA USA. [Kim, Myoung] Ortho McNeil Janssen Sci Affairs LLC, Raritan, NJ USA. RP Weigelt, JA (reprint author), Med Coll Wisconsin, Dept Surg, Div Trauma Crit Care, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. EM jweigelt@mcw.edu OI Lipsky, Benjamin A./0000-0001-9886-5114 FU OMJUS FX Dr. Weigelt is an advisory board member, on the speaker's bureau, received research support from OMJUS; Dr. Lipsky is an advisory board member and has received research support from OMJUS; Dr. Kim is a current employee of OMJUS; Ms. Derby and Drs. Tabak and Gupta are currently employees of Cardinal Health, Inc. Dr. Lipsky is an employee of the US Government. This paper does not represent the views of the US Government. NR 24 TC 44 Z9 48 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD MAR PY 2010 VL 38 IS 2 BP 112 EP 120 DI 10.1016/j.ajic.2009.06.010 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 559WR UT WOS:000274859500005 PM 19889474 ER PT J AU Johansen, KL Finkelstein, FO Revicki, DA Gitlin, M Evans, C Mayne, TJ AF Johansen, Kirsten L. Finkelstein, Fredric O. Revicki, Dennis A. Gitlin, Matthew Evans, Christopher Mayne, Tracy J. TI Systematic Review and Meta-analysis of Exercise Tolerance and Physical Functioning in Dialysis Patients Treated With Erythropoiesis-Stimulating Agents SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Review DE Chronic kidney disease; erythropoiesis-stimulating agents; epoetin alfa; exercise tolerance; quality of life ID QUALITY-OF-LIFE; RECOMBINANT-HUMAN-ERYTHROPOIETIN; ANEMIC HEMODIALYSIS-PATIENTS; SICKNESS IMPACT PROFILE; CHRONIC KIDNEY-DISEASE; CORONARY-ARTERY DISEASE; CHRONIC HEART-FAILURE; CHRONIC-RENAL-FAILURE; HEALTH-STATUS MEASURE; MAINTENANCE HEMODIALYSIS AB Background: The role of erythropoiesis-stimulating agents (ESAs) in treating the anemia of chronic kidney disease has been reevaluated in view of recent studies suggesting that the use of these agents may be associated with increased morbidity and mortality. This potential increased risk needs to be weighed against the potential benefit of ESAs in improving various aspects of health-related quality of life, in particular, exercise tolerance and physical functioning. Study Design: A systematic review and meta-analysis of exercise tolerance and physical functioning. Setting & Participants: Adults on maintenance dialysis therapy. Selection Criteria for Studies: Outcomes measured before and after ESA treatment were required. Studies of physical function were required to include at least 25 participants. Intervention: Treatment with any ESA. Outcomes: Exercise tolerance measured using VO2peak (oxygen consumption per minute at the peak workload during the test), duration of exercise, or 6-minute walk distance or physical functioning assessed using >= 1 patient-or clinician-reported outcome measure that included a physical function domain. Results: 28 articles met criteria for inclusion for evaluation of exercise tolerance, and 14 articles, for physical function. Meta-analysis showed a 23.8% increase in VO2peak from before to after erythropoietin therapy initiation (15 studies) and a nonsignificant 8.2% increase comparing a higher with a lower hemoglobin target (3 studies). For physical functioning, 4 studies met criteria for inclusion in the meta-analysis: there was a 10.5% increase in Karnofsky score from before to after erythropoietin therapy initiation. Limitations: Many studies of exercise tolerance did not include control groups. A wide variety of instruments was used to assess physical function. Conclusions: Partial correction of anemia through ESA treatment has a consistent and positive impact on VO2peak. ESA treatment improves patient-and clinician-assessed physical functioning. Am J Kidney Dis 55: 535-548. (C) 2010 by the National Kidney Foundation, Inc. C1 [Johansen, Kirsten L.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Finkelstein, Fredric O.] Yale Univ, Hosp St Raphael, New Haven, CT USA. [Revicki, Dennis A.] United BioSource Corp, Bethesda, MD USA. [Gitlin, Matthew; Mayne, Tracy J.] Amgen Inc, Thousand Oaks, CA USA. [Evans, Christopher] Mapi Values, Boston, MA USA. RP Johansen, KL (reprint author), Univ Calif San Francisco, San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM kirsten.johansen@ucsf.edu FU Amgen Inc. FX This study was conceived by employees of Amgen Inc, which markets ESAs; Dr Gitlin is an employee of Amgen Inc. Dr Mayne formerly was an employee of Amgen Inc. Drs Johansen and Finkelstein have received research support from Amgen Inc. Dr Revicki and his employer United Biosource Corp, as well as Dr Evans and his employer MapiValues, have received consulting fees and research support from Amgen Inc. NR 70 TC 35 Z9 37 U1 3 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2010 VL 55 IS 3 BP 535 EP 548 DI 10.1053/j.ajkd.2009.12.018 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 563DW UT WOS:000275109000017 PM 20133033 ER PT J AU Jolly, SE Burrows, NR Chen, SC Li, SY Jurkovitz, CT Narva, AS Norris, KC Shlipak, MG AF Jolly, Stacey E. Burrows, Nilka Rios Chen, Shu-Cheng Li, Suying Jurkovitz, Claudine T. Narva, Andrew S. Norris, Keith C. Shlipak, Michael G. TI Racial and Ethnic Differences in Albuminuria in Individuals With Estimated GFR Greater Than 60 mL/min/1.73 m(2): Results From the Kidney Early Evaluation Program (KEEP) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Albuminuria; health disparities; Kidney Early Evaluation Program (KEEP); screening ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE VALUES; RENAL-DISEASE; NONDIABETIC INDIVIDUALS; CARDIOVASCULAR EVENTS; GENERAL-POPULATION; AMERICAN-INDIANS; NATIONAL-HEALTH; HEART-FAILURE; UNITED-STATES AB Background: Albuminuria is an important marker for chronic kidney disease and progression to end-stage renal disease in the general population; understanding racial and ethnic differences can help inform efforts to reduce health disparities. We sought to estimate independent associations of race/ethnicity with albuminuria to determine whether observed differences were attributable to known kidney disease risk factors. Methods: This cross-sectional study included 64,161 Kidney Early Evaluation Program (KEEP) participants, 2000-2008, with estimated glomerular filtration rate >= 60 mL/min/1.73 m(2), not on regular dialysis therapy, and without a previous kidney transplant. Albuminuria (urine albumin-creatinine ratio >= 30 mg/g) was examined by self-reported race and ethnicity. Covariates were age, sex, educational level, body mass index, diabetes status or glucose level, hypertension status or blood pressure measurement, smoking status, health insurance status, and geographic region. Results: Albuminuria prevalences were 8% (n = 2,303) in whites, 11% (n = 2,310) in African Americans, 9% (n = 730) in Hispanics, 10% (n = 381) in Asians, and 15% (n = 344) in American Indians/ Alaska Natives. Compared with whites, odds of albuminuria were higher for all groups after multivariate adjustment. Odds were highest for American Indians/Alaska Natives (adjusted OR, 1.93; 95% CI, 1.70-2.20), then Asians (adjusted OR, 1.42; 95% CI, 1.26-1.61), African Americans (adjusted OR, 1.38; 95% CI, 1.29-1.47), and Hispanics (adjusted OR, 1.19; 95% CI, 1.08-1.31). Conclusions: In the KEEP study population, albuminuria prevalence was higher in African Americans, Hispanics, Asians, and American Indians/Alaska Natives than in non-Hispanic whites, suggesting a need for screening for early detection of kidney damage, especially in people at increased risk, in the community primary care setting. Am J Kidney Dis 55(S2):S15-S22. (c) 2010 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Jolly, Stacey E.] Cleveland Clin, Inst Med, Cleveland, OH 44195 USA. [Burrows, Nilka Rios] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Chen, Shu-Cheng; Li, Suying] Minneapolis Med Res Fdn Inc, Chron Dis Res Grp, Minneapolis, MN USA. [Jurkovitz, Claudine T.] Christiana Care Hlth Syst, Ctr Outcomes Res, Newark, DE USA. [Narva, Andrew S.] NIDDK, Bethesda, MD USA. [Norris, Keith C.] Charles R Drew Univ Med & Sci, Dept Internal Med, Los Angeles, CA 90059 USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. RP Jolly, SE (reprint author), Cleveland Clin, Inst Med, 9500 Euclid Ave,G10, Cleveland, OH 44195 USA. EM jollys@ccf.org FU National Kidney Foundation Inc; Amgen; Abbott; Novartis; Siemens; Genentech; Genzyme; Nephroceuticals; Pfizer; LifeScan; Suplena; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK 066488] FX The KEEP is a program of the National Kidney Foundation Inc and is supported by Amgen, Abbott, Novartis, Siemens, Genentech, Genzyme, Nephroceuticals, Pfizer, LifeScan, and Suplena. Dr Shlipak's work was supported by the American Heart Association Established Investigator Award and R01 DK 066488 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 41 TC 18 Z9 19 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2010 VL 55 IS 3 SU 2 BP S15 EP S22 DI 10.1053/j.ajkd.2009.09.034 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 559WU UT WOS:000274859800003 PM 20172444 ER PT J AU Copeland, LA Berg, GD Johnson, DM Bauer, RL AF Copeland, Laurel A. Berg, Gregory D. Johnson, Donna M. Bauer, Richard L. TI An Intervention for VA Patients With Congestive Heart Failure SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID PROPENSITY SCORE; READMISSION; POPULATION; CARDIOMYOPATHY; MANAGEMENT; MORTALITY; ADMISSION; OUTCOMES; RISK; CARE AB Objective: To assess the effect of a telephone intervention to improve quality of life among patients with congestive heart failure (CHF). Study Design: Prospective randomized study. Methods: Single-site recruitment of 458 patients using Veterans Health Administration care into a randomized controlled trial with a 1-year pre-intervention data collection period and a 1-year intervention and follow-up period. To compensate for imbalanced study groups, propensity scores were included in adjusted models of quality of life, satisfaction with care, inpatient utilization, survival, and costs of care. Results: Patients aged 45 to 95 years participated in the study; 22% were of Hispanic race/ethnicity, and 7% were African American. All but 5 were male, consistent with the older population among veterans. At baseline, 40% were in Goldman Specific Activity Scale class I, 42% were in class III, 6% were in class II or IV, and 12% were unclassified. Patients scored a mean (SD) of 14 (1.5) points below the norm on the physical component score. After the yearlong intervention, no differences in clinical outcomes were noted between the intervention group and the control group. The CHF-related costs were higher for the intervention group, as were overall costs that included the cost of the intervention. Intervention group patients reported better compliance with weight monitoring and exercise recommendations. Conclusions: A risk-stratified intervention for patients with CHF resulted in potential behavioral improvements but no survival benefit. A high-cost high-intensity intervention may be required to improve survival for patients with CHF. Inclusion of the costs of interventions is recommended for future researchers. (Am J Manag Care. 2010; 16(3): 158-165) C1 [Copeland, Laurel A.; Bauer, Richard L.] S Texas Vet Hlth Care Syst, Dept Vet Affairs, VERDICT Res Ctr, San Antonio, TX 78229 USA. [Copeland, Laurel A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Bauer, Richard L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Berg, Gregory D.; Johnson, Donna M.] McKesson Corp, Broomfield, CO USA. RP Copeland, LA (reprint author), S Texas Vet Hlth Care Syst, Dept Vet Affairs, VERDICT Res Ctr, 7400 Merton Minter 11C6, San Antonio, TX 78229 USA. EM laurel.copeland@va.gov OI Copeland, Laurel/0000-0002-9478-0209 FU Veterans Health Administration, Health Services Research and Development; Office of the Chief of Staff and the VERDICT Research Center, South Texas Veterans Health Care System; McKesson Corporation; Veterans Health Administration [MRP-05-145, IIR-05-326] FX This study was supported by the Veterans Health Administration, Health Services Research and Development Program; by the Office of the Chief of Staff and the VERDICT Research Center, South Texas Veterans Health Care System; and by the McKesson Corporation, which developed the intervention tested.; Dr Copeland was supported by Health Services Research and Development Program career development grants MRP-05-145 and IIR-05-326 from the Veterans Health Administration. NR 28 TC 12 Z9 12 U1 0 U2 3 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 MAR PY 2010 VL 16 IS 3 BP 158 EP 165 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 567XY UT WOS:000275483400001 PM 20225911 ER PT J AU Pevnick, JM Asch, SM Adams, JL Mattke, S Patel, MH Ettner, SL Bell, DS AF Pevnick, Joshua M. Asch, Steven M. Adams, John L. Mattke, Soeren Patel, Mihir H. Ettner, Susan L. Bell, Douglas S. TI Adoption and Use of Stand-Alone Electronic Prescribing in a Health Plan-Sponsored Initiative SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID MEDICAL-RECORDS; PHYSICIANS; CARE; QUALITY; ERRORS AB Objectives: To quantify rates of stand-alone e-prescribing (SEP) adoption and use among primary care physicians (PCPs) participating in a SEP initiative and to determine which physician and patient characteristics were associated with higher rates of each. Study Design: Using records from an insurer-led SEP initiative, we compared the characteristics of 297 PCPs who adopted SEP through the initiative with the characteristics of 1892 eligible PCPs who did not. Among 297 adopters, we studied the extent of SEP use. Methods: Dependent variables included each physician's adoption of SEP and his or her e-prescribing use ratio (the ratio of electronic prescriptions to pharmacy claims in the same period). Independent variables included characteristics of PCPs (specialty, practice size, and prescribing volume) and their patients (patient age, sex, race/ethnicity, and household income). Results: Solo practitioners, pediatricians, and physicians with more patients from predominantly African American zip codes were under-represented among SEP adopters. The mean (SD) e-prescribing use ratio among adopters was 0.23 (0.28). Twenty percent of physicians maintained e-prescribing use ratios above 0.50. Available physician characteristics explained little of the variance in use, but physicians in smaller practices had greater use (P = .02). Conclusions: Certain categories of physicians may need more tailored incentives to adopt SEP. On average, adopters used the SEP system for only about one-quarter of their prescriptions. Some adopters achieved high levels of SEP use, and further research is needed to elucidate the factors that enabled this. (Am J Manag Care. 2010; 16(3): 182-189) C1 [Pevnick, Joshua M.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Pevnick, Joshua M.; Asch, Steven M.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Asch, Steven M.; Adams, John L.; Bell, Douglas S.] RAND Hlth, Santa Monica, CA USA. [Mattke, Soeren] RAND Hlth, Boston, MA USA. [Patel, Mihir H.] Horizon Blue Cross Blue Shield New Jersey, Newark, NJ USA. [Asch, Steven M.; Ettner, Susan L.; Bell, Douglas S.] Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. RP Pevnick, JM (reprint author), Cedars Sinai Med Ctr, 8700 Beverly Blvd,Rm B113, Los Angeles, CA 90048 USA. EM jpevnick@gmail.com RI Bell, Douglas/G-6702-2013 OI Bell, Douglas/0000-0002-5063-8294 FU Agency for Healthcare Research and Quality [1U18HS016391-01]; Department of Veterans Affairs FX This project was funded by grant 1U18HS016391-01 from the Agency for Healthcare Research and Quality as part of a larger set of e-prescribing pilot studies. This work was also supported by a health services research and development fellowship from the Department of Veterans Affairs (Dr Pevnick). NR 22 TC 10 Z9 10 U1 1 U2 2 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 MAR PY 2010 VL 16 IS 3 BP 182 EP 189 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 567XY UT WOS:000275483400003 PM 20225913 ER PT J AU Kaplan, L Foster, R Shen, YP Parry, DM McMaster, ML O'Leary, MC Gusella, JF AF Kaplan, Lee Foster, Rosemary Shen, Yiping Parry, Dilys M. McMaster, Mary L. O'Leary, Melanie Collins Gusella, James F. TI Monozygotic Twins Discordant for Neurofibromatosis 1 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE neurofibromatosis type 1; monozygotic twins; discordance; post-zygotic mutation ID SEGMENTAL NEUROFIBROMATOSIS; NF1 GENE; TYPE-1 NF1; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; NONSENSE MUTATION; MOSAICISM; POLYMORPHISMS; METHYLATION; FREQUENCY; SEQUENCE AB We present monozygotic twins discordant for the autosomal dominant disorder neurofibromatosis type 1 (NF1). The affected twin was diagnosed with NF1 at age 12, based upon accepted clinical criteria for the disorder. Both twins were re-examined at ages 35 and 57, at which times the unaffected twin continued to show no clinical manifestations of NF1. Short tandem repeat marker (STR) genotyping at 10 loci on chromosome 17 and 10 additional loci dispersed across the genome revealed identical genotypes for the twins, confirming their monozygosity. The affected twin has three children, two of whom also have NF1, while the unaffected twin has two children, both unaffected. Using lymphoblastoid, fibroblast, and buccal cell samples collected from both twins and from other family members in three generations, we discovered a pathogenic nonsense mutation in exon 40 of the NF1 gene. This mutation was found in all cell samples from the affected twin and her affected daughter, and in lymphoblastoid and buccal cells but not fibroblasts from the unaffected twin. We also found a novel non-synonymous change in exon 16 of the NF1 gene that was transmitted from the unaffected mother to both twins and co-segregated with the pathogenic mutation in the ensuing generation. All cells from the twins were heterozygous for this apparent exon 16 polymorphism and for single nucleotide polymorphisms (SNPs) within 2.5 kb flanking the site of the exon 40 nonsense mutation. This suggests that the NF1 gene of the unaffected twin differed in the respective lymphoblastoid cells and fibroblasts only at the mutation site itself, making post-zygotic mutation leading to mosaicism the most likely mechanism of phenotypic discordance. Although the unaffected twin is a mosaic, the distribution of the mutant allele among different cells and tissues appears to be insufficient to cause overt clinical manifestations of NF1. (C) 2010 Wiley-Liss, Inc. C1 [Kaplan, Lee; Shen, Yiping; O'Leary, Melanie Collins; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kaplan, Lee; Shen, Yiping; O'Leary, Melanie Collins; Gusella, James F.] Harvard Univ, Sch Med, Ctr Neurofibromatosis & Allied Disorders, Boston, MA USA. [Foster, Rosemary] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Foster, Rosemary] Ctr Regenerat Med, Boston, MA USA. [Foster, Rosemary] Harvard Stem Cell Inst, Boston, MA USA. [Shen, Yiping] Childrens Hosp, DNA Diagnost Lab, Dept Lab Med, Boston, MA 02115 USA. [Parry, Dilys M.; McMaster, Mary L.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Gusella, JF (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, CPZN-5830,185 Cambridge St, Boston, MA 02114 USA. EM gusella@helix.mgh.harvard.edu FU NINDS [NS22224, NS24279]; Neurofibromatosis, Inc., Northeast; S. Sydney De Young Foundation FX The authors would like to thank the family members who have contributed samples and time in the clinic so that we could perform this research project. Also we thank Mary Anne Anderson and the CHGR Cell Culture Resource for making the stable cell lines, James Mull for technical assistance, and Tammy Gillis and the CHGR Genomics Resource for DNA sequence analysis. Funded by grants from the NINDS (NS22224, NS24279), Neurofibromatosis, Inc., Northeast, and the S. Sydney De Young Foundation. NR 43 TC 20 Z9 20 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2010 VL 152A IS 3 BP 601 EP 606 DI 10.1002/ajmg.a.33271 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 576OV UT WOS:000276155200010 PM 20186797 ER PT J AU Wan, ES Pober, BR Washko, GR Raby, BA Silverman, EK AF Wan, Emily S. Pober, Barbara R. Washko, George R. Raby, Benjamin A. Silverman, Edwin K. TI Pulmonary Function and Emphysema in Williams-Beuren Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE elastin; emphysema; pulmonary function tests; Williams syndrome ID AUTOSOMAL-DOMINANT INHERITANCE; CUTIS LAXA; ELASTIN; DISEASE; LUNG; HEMIZYGOSITY; DELETIONS; MUTATION; RISK; GENE AB Williams-Beuren syndrome (WBS) is caused by a submicroscopic deletion on chromosome 7q11.23 that encompasses the entire elastin (ELN) gene. Elastin, a key component of elastic fibers within the lung, is progressively destroyed in emphysema. Defects in the elastin gene have been associated with increased susceptibility towards developing chronic obstructive pulmonary disease (COPD) and emphysema in both humans and mice. We postulate that hemizygosity at the elastin gene locus may increase susceptibility towards the development of COPD and emphysema in subjects with WBS. We describe an adult subject with WBS who was a lifelong non-smoker and was found to have moderate emphysema. We also examined the pulmonary function of a separate cohort of adolescents and young adults with WBS. Although no significant spirometric abnormalities were identified, a significant proportion of subjects reported respiratory symptoms. Thus, while significant obstructive disease does not appear to be common in relatively young adults with WBS, subclinical emphysema and lung disease may exist which possibly could worsen with advancing age. Further investigation may elucidate the pathogenesis of non-smoking-related emphysema. (C) 2010 Wiley-Liss, Inc. C1 [Wan, Emily S.; Raby, Benjamin A.; Silverman, Edwin K.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Wan, Emily S.; Washko, George R.; Raby, Benjamin A.; Silverman, Edwin K.] Brigham & Womens Hosp, Dept Med, Pulm & Crit Care Div, Boston, MA 02115 USA. [Pober, Barbara R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Silverman, EK (reprint author), 181 Longwood Ave,4th Floor, Boston, MA 02115 USA. EM ed.silverrnan@channing.harvard.edu FU NHLBI NIH HHS [T32 HL007427-19, R01 HL075478-06, R01 HL075478] NR 25 TC 8 Z9 8 U1 0 U2 1 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 MAR PY 2010 VL 152A IS 3 BP 653 EP 656 DI 10.1002/ajmg.a.33300 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 576OV UT WOS:000276155200017 PM 20186780 ER PT J AU Brown, AB Biederman, J Valera, EM Doyle, AE Bush, G Spencer, T Monuteaux, MC Mick, E Whitfield-Gabrieli, S Makris, N LaViolette, PS Oscar-Berman, M Faraone, SV Seidman, LJ AF Brown, Ariel B. Biederman, Joseph Valera, Eve M. Doyle, Alysa E. Bush, George Spencer, Thomas Monuteaux, Michael C. Mick, Eric Whitfield-Gabrieli, Susan Makris, Nikos LaViolette, Peter S. Oscar-Berman, Marlene Faraone, Stephen V. Seidman, Larry J. TI Effect of Dopamine Transporter Gene (SLC6A3) Variation on Dorsal Anterior Cingulate Function in Attention-Deficit/Hyperactivity Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE dopamine transporter gene; functional magnetic resonance imaging; genetics; adhd; anterior cingulate ID DEFICIT HYPERACTIVITY DISORDER; MULTISOURCE INTERFERENCE TASK; GENOTYPE INFLUENCES; WORKING-MEMORY; HUMAN BRAIN; ADULT ADHD; METHYLPHENIDATE; CHILDREN; METAANALYSIS; ASSOCIATION AB Although attention-deficit/hyperactivity disorder (ADHD) is associated both with brain alterations in attention and executive function (EF) circuitry and with genetic variations within the dopamine system (including the dopamine transporter gene [SLC6A3]), few studies have directly investigated how genetic variations are linked to brain alterations. We sought to examine how a polymorphism in the 3' untranslated region (UTR) of SLC6A3, associated with ADHD in meta-analysis, might contribute to variation in dorsal anterior cingulate cortex (dACC) function in subjects with ADHD. We collected fMRI scans of 42 individuals with ADHD, all of European descent and over the age of 17, while they performed the multi-source interference task (MSIT), a cognitive task shown to activate dACC. SLC6A3 3'UTR variable number tandem repeat (VNTR) polymorphisms were genotyped and brain activity was compared for groups based on allele status. ADHD individuals homozygous for the 10R allele showed significant hypoactivation in the left dACC compared to 9R-carriers. Exploratory analysis also showed trends toward hypoactivation in the 10R homozygotes in left cerebellar vermis and right lateral prefrontal cortex. Further breakdown of genotype groups showed similar activation in individuals heterozygous and homozygous for the 911 allele. Alterations in activation of attention and EF networks found previously to be involved in ADHD are likely influenced by SLC6A3 genotype. This genotype may contribute to heterogeneity of brain alterations found within ADHD samples. (C) 2009 Wiley-Liss, Inc. C1 [Brown, Ariel B.; Biederman, Joseph; Valera, Eve M.; Doyle, Alysa E.; Spencer, Thomas; Monuteaux, Michael C.; Mick, Eric; LaViolette, Peter S.; Seidman, Larry J.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Adult ADHD, Boston, MA 02114 USA. [Brown, Ariel B.; Biederman, Joseph; Valera, Eve M.; Doyle, Alysa E.; Spencer, Thomas; Monuteaux, Michael C.; Mick, Eric; LaViolette, Peter S.; Seidman, Larry J.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Makris, Nikos] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Brown, Ariel B.; Oscar-Berman, Marlene] Boston Univ, Sch Med, Div Grad Med Sci, PhD Program Behav Neurosci, Boston, MA 02118 USA. [Valera, Eve M.; Bush, George] Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neuroimaging Res Program, Boston, MA 02114 USA. [Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Makris, Nikos] Harvard Univ, Sch Med, Dept Radiol Serv, Boston, MA USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Boston, MA 02114 USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] US Dept Vet Affairs Healthcare Syst, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat,Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr,Publ Psychiat Div, Boston, MA 02115 USA. RP Brown, AB (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, East Campus,149 13th St,Rm 2603, Charlestown, MA 02129 USA. EM ariel@nmr.mgh.harvard.edu OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIMH [MH 62152, MH 57934, MH 071535]; US Department of Health and Human Services; NIAAA [R01-AA07112, K05-AA00219]; National Alliance for Research oil Schizophrenia; Janssen Pharmaceuticals; US Department of Veterans Affairs; March of Dimes Foundation; Mental Illness and Neuroscience Discovery (MIND) Institute; Kimmerly-Neil Fund; Pediatric Psychopharmacology Counci; National Center for Research Resources [P41RR14075] FX Grant sponsor: NIMH; Grant Numbers: MH 62152, MH 57934, MH 071535; Grant sponsor: US Department of Health and Human Services; Grant sponsor: NIAAA; Grant Numbers: R01-AA07112, K05-AA00219; Grant sponsor: National Alliance for Research oil Schizophrenia and Depression Distinguished Investigator Award; Grant sponsor: Janssen Pharmaceuticals; Grant sponsor: Medical Research Service of the US Department of Veterans Affairs; Grant sponsor: March of Dimes Foundation; Grant sponsor: Mental Illness and Neuroscience Discovery (MIND) Institute; Grant sponsor: Kimmerly-Neil Fund for the Study of Cognition and Psychiatric Disorders in Children; Grant sponsor: Pediatric Psychopharmacology Council Fund; Grant sponsor: National Center for Research Resources; Grant number: P41RR14075. NR 59 TC 24 Z9 25 U1 2 U2 9 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 MAR PY 2010 VL 153B IS 2 BP 365 EP 375 DI 10.1002/ajmg.b.31022 PG 11 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 566NI UT WOS:000275377900002 PM 19676101 ER PT J AU Bekris, LM Galloway, NM Montine, TJ Schellenberg, GD Yu, CE AF Bekris, Lynn M. Galloway, Nichole M. Montine, Thomas J. Schellenberg, Gerard D. Yu, Chang-En TI APOE mRNA and Protein Expression in Postmortem Brain Are Modulated by an Extended Haplotype Structure SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE Alzheimer's disease; APOE; post-mortem brain; TOMM40 ID APOLIPOPROTEIN-E GENE; AMYLOID PRECURSOR PROTEIN; ONSET ALZHEIMERS-DISEASE; TRANSGENIC MICE; E GENOTYPE; MITOCHONDRIAL DYSFUNCTION; PROMOTER POLYMORPHISMS; LINKAGE DISEQUILIBRIUM; ALLELIC EXPRESSION; REGULATORY REGION AB Currently the epsilon 4 allele of the apolipoprotein E gene (APOE) is the strongest genetic risk factor for late onset Alzheimer's disease (AD). However, inheritance of the APOE epsilon 4 allele is not necessary or sufficient for the development of AD. Genetic evidence suggests that multiple loci in a 70 kb region surrounding APOE are associated with AD risk. Even though these loci could represent surrogate markers in linkage disequilibrium with APOE epsilon 4 allele, they could also contribute biological effects independent of the APOE epsilon 4 allele. Our previous study identified multiple SNPs upstream from APOE that are associated with cerebrospinal fluid apoE levels, suggesting that a haplotype structure proximal to APOE can influence apoE expression. In this study, we examined apoE expression in human post-mortem brain (PMB), and constructed chromosome-phase-separated haplotypes of the APOE proximal region to evaluate their effect on PMB apoE expression. ApoE protein expression was found to differ among AD brain regions and to differ between AD and control hippocampus. in addition, an extended APOE proximal haplotype structure, spanning from the TOMM40 gene to the APOE promoter, may modulate apoE expression in a brain region-specific manner and may influence AD disease status. In conclusion, this haplotype-phenotype analysis of apoE expression in PMB suggests that either; (1) the cis-regulation of APOE expression levels extends far upstream of the APOE promoter or (2) an APOE epsilon 4 allele independent mechanism involving the TOMM40 gene plays a role in the risk of AD. (C) 2009 Wiley-Liss, Inc. C1 [Bekris, Lynn M.; Galloway, Nichole M.; Yu, Chang-En] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Bekris, Lynn M.; Yu, Chang-En] Univ Washington, Dept Med, Seattle, WA USA. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Schellenberg, Gerard D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Bekris, LM (reprint author), 1660 S Colombian Way,Box 358280 GRECC S182B, Seattle, WA 98108 USA. EM lbekris@u.washington.edu FU Veterans Affairs Biomedical Laboratory Research Development Merit Review; National Institutes of Health [P50 AG00536] FX Grant sponsor: Veterans Affairs Biomedical Laboratory Research Development Merit Review; Grant sponsor: National Institutes of Health; Grant Number: P50 AG00536. NR 48 TC 32 Z9 32 U1 1 U2 6 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 MAR PY 2010 VL 153B IS 2 BP 409 EP 417 DI 10.1002/ajmg.b.30993 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 566NI UT WOS:000275377900006 PM 19554612 ER PT J AU Sanchez-Mora, C Ribases, M Ramos-Quiroga, JA Casas, M Bosch, R Boreatti-Hummer, A Heine, M Jacob, CP Lesch, KP Fasmer, OB Knappskog, PM Kooij, JJS Kan, C Buitelaar, JK Mick, E Asherson, P Faraone, SV Franke, B Johansson, S Haavik, J Reif, A Bayes, M Cormand, B AF Sanchez-Mora, C. Ribases, M. Ramos-Quiroga, J. A. Casas, M. Bosch, R. Boreatti-Huemmer, A. Heine, M. Jacob, C. P. Lesch, K-P. Fasmer, O. B. Knappskog, P. M. Kooij, J. J. Sandra Kan, C. Buitelaar, J. K. Mick, E. Asherson, P. Faraone, S. V. Franke, B. Johansson, S. Haavik, J. Reif, A. Bayes, M. Cormand, B. TI Meta-Analysis of Brain-Derived Neurotrophic Factor p.Va166Met in Adult ADHD in Four European Populations SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE attention-deficit hyperactivity disorder; adult ADHD; BDNF; case-control association study; meta-analysis ID DEFICIT-HYPERACTIVITY-DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; GENOME-WIDE ASSOCIATION; FAMILY-BASED ASSOCIATION; COMMON VALINE ALLELE; FACTOR BDNF GENE; VAL66MET POLYMORPHISM; BIPOLAR DISORDER; CANDIDATE GENES; MOLECULAR-GENETICS AB Attention-deficit hyperactivity disorder (ADHD) is a multifactorial, neurodevelopmental disorder that often persists into adolescence and adulthood and is characterized by inattention, hyperactivity and impulsiveness. Before the advent of the first genome-wide association studies in ADHD, genetic research had mainly focused on candidate genes related to the dopaminergic and serotoninergic systems, although several other genes had also been assessed. Pharmacological data, analysis of animal models and association studies suggest that Brain-Derived Neurotrophic Factor (BDNF) is also a strong candidate gene for ADHD. Several polymorphisms in BDNF have been reported and studied in psychiatric disorders but the most frequent is the p.Va166Met (rs6265G > A) single nucleotide polymorphism (SNP), with functional effects on the intracellular trafficking and secretion of the protein. To deal with the inconsistency raised among different case-control and family-based association studies regarding the p.Va166Met contribution to ADHD, we performed a meta-analysis of published as well as unpublished data from four different centers that are part of the International Multicentre Persistent ADHD CollaboraTion (IMpACT). A total of 1,445 adulthood ADHD patients and 2,247 sex-matched controls were available for the study. No association between the p.Va166Met polymorphism and ADHD was found in any of the four populations or in the pooled sample. The meta-analysis also showed that the overall gene effect for ADHD was not statistically significant when gender or comorbidity with mood disorders were considered. Despite the potential role of BDNF in ADHD, our data do not support the involvement of p.Va166Met in the pathogenesis of this neuropsychiatric disorder. (C) 2009 Wiley-Liss, Inc. C1 [Sanchez-Mora, C.; Ribases, M.; Ramos-Quiroga, J. A.; Casas, M.; Bosch, R.] Hosp Univ Vall Hebron, Dept Psychiat, Barcelona, Catalonia, Spain. [Sanchez-Mora, C.; Ribases, M.] Hosp Univ Vall Hebron, Psychiat Genet Unit, Barcelona, Catalonia, Spain. [Ramos-Quiroga, J. A.; Casas, M.] Univ Autonoma Barcelona, Dept Psychiat & Legal Med, Catalonia, Spain. [Boreatti-Huemmer, A.; Heine, M.; Jacob, C. P.; Lesch, K-P.; Reif, A.] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany. [Fasmer, O. B.; Haavik, J.] Haukeland Hosp, Div Psychiat, N-5021 Bergen, Norway. [Fasmer, O. B.] Univ Bergen, Dept Clin Med, Sect Psychiat, Bergen, Norway. [Knappskog, P. M.] Haukeland Hosp, Ctr Med Genet & Mol Med, Haukeland, Norway. [Kooij, J. J. Sandra] Program Adult ADHD, Psychomed Programs, PsyQ, The Hague, Netherlands. [Kan, C.; Buitelaar, J. K.; Franke, B.] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Mick, E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Mick, E.] Harvard Univ, Sch Med, Boston, MA USA. [Asherson, P.] Inst Psychiat, MRC Social Genet Dev & Psychiat Ctr, London, England. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. [Franke, B.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Johansson, S.; Haavik, J.] Univ Bergen, Dept Biomed, Bergen, Norway. [Bayes, M.] CRG UPF, Genes & Dis Program, Barcelona, Catalonia, Spain. [Bayes, M.] CIBER Epidemiol & Salud Publ, Barcelona, Catalonia, Spain. [Bayes, M.] Ctr Nacl Genotipado, Barcelona, Catalonia, Spain. [Cormand, B.] Univ Barcelona, Fac Biol, Dept Genet, Catalonia, Spain. [Cormand, B.] CIBER Enfermedades Raras, Barcelona, Catalonia, Spain. [Cormand, B.] Univ Barcelona, Inst Biomed, Catalonia, Spain. RP Cormand, B (reprint author), Univ Barcelona, Fac Biol, Dept Genet, Av Diagonal 645,Edifici Annex,3A Planta, E-08028 Barcelona, Spain. EM bcormand@ub.edu RI Franke, Barbara/D-4836-2009; Buitelaar, Jan/E-4584-2012; Johansson, Stefan/C-4394-2011; Cormand, Bru/H-5338-2015; Lesch, Klaus-Peter/J-4906-2013 OI Franke, Barbara/0000-0003-4375-6572; Buitelaar, Jan/0000-0001-8288-7757; Johansson, Stefan/0000-0002-2298-7008; Cormand, Bru/0000-0001-5318-4382; Lesch, Klaus-Peter/0000-0001-8348-153X FU Instituto de Salud Carlos III-FIS, Spain [PI040524, PI041267, PI080519]; Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR [2005SGR00848]; Deutsche Forschungsgemeinschaft [RE1632/1-1, RE1632/1-3, KFO 125, SFB 581, SFB TRR 58]; BMBF [01GV0605, IZKF 01KS9603, N-4]; EC [NEWMOOD LSHM-CT-2003-503474]; Research Council of Norway; Helse Vest; Hersenstichting Nederland (Fonds Psychische Gezondheid) FX Grant sponsor: Instituto de Salud Carlos III-FIS, Spain; Grant Numbers: PI040524, PI041267, PI080519; Grant sponsor: Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR; Grant Number: 2005SGR00848; Grant sponsor: Deutsche Forschungsgemeinschaft; Grant Numbers: RE1632/1-1, RE1632/1-3, KFO 125, SFB 581, SFB TRR 58; Grant sponsor: BMBF; Grant Numbers: 01GV0605, IZKF 01KS9603, N-4; Grant sponsor: EC; Grant Number: NEWMOOD LSHM-CT-2003-503474; Grant sponsor: Research Council of Norway and Helse Vest; Grant sponsor: Hersenstichting Nederland (Fonds Psychische Gezondheid). NR 55 TC 33 Z9 33 U1 1 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 MAR PY 2010 VL 153B IS 2 BP 512 EP 523 DI 10.1002/ajmg.b.31008 PG 12 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 566NI UT WOS:000275377900017 PM 19603419 ER PT J AU Wang, Y Adamczyk, A Shugart, YY Samuels, JF Grados, MA Greenberg, BD Knowles, JA McCracken, JT Rauch, SL Murphy, DL Rasmussen, SA Cullen, B Pinto, A Fyer, AJ Piacentini, J Pauls, DL Bienvenu, OJ Riddle, M Liang, KY Valle, D Wang, T Nestadt, G AF Wang, Y. Adamczyk, A. Shugart, Y. Y. Samuels, J. F. Grados, M. A. Greenberg, B. D. Knowles, J. A. McCracken, J. T. Rauch, S. L. Murphy, D. L. Rasmussen, S. A. Cullen, B. Pinto, A. Fyer, A. J. Piacentini, J. Pauls, D. L. Bienvenu, O. J. Riddle, M. Liang, K. Y. Valle, D. Wang, T. Nestadt, G. TI A Screen of SLC1A1 for OCD-Related Alleles SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE OCD; SLC1A1; polymorphism ID OBSESSIVE-COMPULSIVE DISORDER; CONFORMATION POLYMORPHISM; TRANSPORTER GENE; ASSOCIATION; AUGMENTATION; LINKAGE AB SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and similar to 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one non-synonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G>C, A27A; c.414A>G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases. (C) 2009 Wiley-Liss, Inc. C1 [Wang, Y.; Samuels, J. F.; Grados, M. A.; Cullen, B.; Bienvenu, O. J.; Riddle, M.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Adamczyk, A.; Valle, D.; Wang, T.] Johns Hopkins Univ, Sch Med, Dept Pediat, Mckusick Nathan Inst Genet Med, Baltimore, MD 21205 USA. [Shugart, Y. Y.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Greenberg, B. D.; Rasmussen, S. A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Knowles, J. A.] Univ So Calif, Dept Psychiat, Los Angeles, CA USA. [McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Rauch, S. L.; Pauls, D. L.] Harvard Univ, Sch Med, Boston, MA USA. [Rauch, S. L.; Pauls, D. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, S. L.; Pauls, D. L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Pinto, A.; Fyer, A. J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Liang, K. Y.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Wang, Y (reprint author), 1629 Thames St,Suite 401, Baltimore, MD 21231 USA. EM ywang37@jhmi.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Adamczyk, Abby/E-4457-2014; Pinto, Anthony/D-2718-2017; OI Adamczyk, Abby/0000-0001-7653-295X; Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 NR 16 TC 18 Z9 19 U1 1 U2 4 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 MAR PY 2010 VL 153B IS 2 BP 675 EP 679 DI 10.1002/ajmg.b.31001 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 566NI UT WOS:000275377900036 PM 19569082 ER PT J AU Holland, R Meyers, D Hildebrand, C Bridges, AJ Roach, MA Vogelman, B AF Holland, Robert Meyers, David Hildebrand, Christopher Bridges, Alan J. Roach, Mary A. Vogelman, Bennett TI Creating Champions for Health Care Quality and Safety SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Article DE systems-based learning; quality improvement; patient safety; graduate medical education; health care quality ID IMPROVEMENT; MEDICINE; PERFORMANCE; COMPETENCE; EDUCATION AB Patient safety and quality of care are public concerns that demand personal responsibility at all levels of the health care organization. Senior residents in our graduate medical education program took responsibility for a capstone quality improvement project designed to transform them into champions for health care quality. Residents (n = 26) participated alone or in pairs in a 1-month faculty-mentored rotation at the Veterans Administration Hospital during the 2007-2008 academic year. They completed a Web-based curriculum, identified a quality-of-care issue, applied Plan-Do-Study-Act cycles, authored a report, and engaged colleagues in their innovations during a department-wide presentation. Results indicated that residents demonstrated significantly enhanced knowledge and attitudes about patient safety and quality improvement and provided consistently positive faculty and rotation evaluations. In addition, residents generated 20 quality improvement project proposals with a 50% rate of hospital-wide implementation, leading to meaningful changes in the systems that affect patient care. C1 [Holland, Robert; Meyers, David; Hildebrand, Christopher; Bridges, Alan J.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. [Roach, Mary A.; Vogelman, Bennett] Univ Wisconsin, Madison Sch Med & Publ Hlth, Madison, WI USA. RP Holland, R (reprint author), William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. EM Robert.Holland@va.gov FU Medical Education and Research Committee (MERC) of the University of Wisconsin-Madison School of Medicine and Public Health FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: Completion of this article was made possible by a grant from the Medical Education and Research Committee (MERC) of the University of Wisconsin-Madison School of Medicine and Public Health as well as by the support of the Education Innovation Project of the Residency Review Committee for Internal Medicine, of which we are a participating residency. NR 18 TC 12 Z9 12 U1 1 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1062-8606 J9 AM J MED QUAL JI Am. J. Med. Qual. PD MAR-APR PY 2010 VL 25 IS 2 BP 102 EP 108 DI 10.1177/1062860609352108 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 566KZ UT WOS:000275370400004 PM 19966115 ER PT J AU Curhan, SG Eavey, R Shargorodsky, J Curhan, GC AF Curhan, Sharon G. Eavey, Roland Shargorodsky, Josef Curhan, Gary C. TI Analgesic Use and the Risk of Hearing Loss in Men SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Analgesics; Hearing loss; Prospective study ID NUTRITION EXAMINATION SURVEY; QUIET-AGED GERBILS; OLDER-ADULTS; COGNITIVE DYSFUNCTION; NATIONAL-HEALTH; INTENSE SOUNDS; UNITED-STATES; OTOTOXICITY; SALICYLATE; ASPIRIN AB BACKGROUND: Hearing loss is a common sensory disorder, yet prospective data oil potentially modifiable risk factors are limited. Regularly used analgesics. the most commonly used drugs in the US, may be ototoxic and contribute to hearing loss. METHODS: We examined the independent association between self-reported professionally diagnosed hearing loss and regular use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen in 26,917 men aged 40-74 years at baseline in 1986. Study participants completed detailed questionnaires at baseline and every 2 years thereafter. Incident cases of new-onset hearing loss were defined as those diagnosed after 1986. Cox proportional hazards multivariate regression was used to adjust for potential confounding factors. RESULTS: During 369,079 person-years of follow-up, 3488 incident cases of hearing loss were reported. Regular use of each analgesic was independently associated with an increased risk of hearing loss. Multivariate-adjusted hazard ratios of hearing loss in regular users (2+ times/week) compared with men Who used the specified analgesic <2 times/week were 1.12 (95% confidence interval [CI], 1.04-1.20) for aspirin, 1.21 (95% CI, 1.11-1.33) for NSAIDs, and 1.22 (95% CI, 1.07-1.39) for acetaminophen. For NSAIDs and acetaminophen, the risk increased with longer duration of regular use. The magnitude of the association was substantially higher in younger men. For men younger than age 50 years, the hazard ratio for hearing loss was 1.33 for regular aspirin use, 1.61 for NSAIDs, and 1.99 for acetaminophen. CONCLUSIONS: Regular use of aspirin, NSAIDs, or acetaminophen increases the risk of hearing loss in men, and the impact is larger on younger individuals. (D 2010 Elsevier Inc. All rights reserved. . The American Journal of Medicine (2010) 123, 231-237 C1 [Curhan, Sharon G.; Shargorodsky, Josef; Curhan, Gary C.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Eavey, Roland] Vanderbilt Univ, Dept Otolaryngol, Nashville, TN USA. [Shargorodsky, Josef] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Curhan, Gary C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Curhan, SG (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM scurhan@partners.org FU National Institutes of Health [P01 CA055075]; Massachusetts Eye and Ear Infirmary Foundation, Boston, Mass FX This work was supported by National Institutes of Health grant P01 CA055075 and the Massachusetts Eye and Ear Infirmary Foundation, Boston, Mass. NR 54 TC 30 Z9 32 U1 4 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2010 VL 123 IS 3 BP 231 EP 237 DI 10.1016/j.amjmed.2009.08.006 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 572EE UT WOS:000275809400012 PM 20193831 ER PT J AU Singh, H Thomas, EJ Sittig, DF Wilson, L Espadas, D Khan, MM Petersen, LA AF Singh, Hardeep Thomas, Eric J. Sittig, Dean F. Wilson, Lindsey Espadas, Donna Khan, Myrna M. Petersen, Laura A. TI Notification of Abnormal Lab Test Results in an Electronic Medical Record: Do Any Safety Concerns Remain? SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Abnormal diagnostic test results; Communication; Diagnostic errors; Electronic medical records; Health information technology; Patient follow-up; Patient safety; Primary care ID INFORMATION-TECHNOLOGY; FOLLOW-UP; COMMUNICATION; ERRORS; DIAGNOSIS AB BACKGROUND: Follow-up of abnormal outpatient laboratory test results is a major patient safety concern. Electronic medical records can potentially address this concern through automated notification. We examined whether automated notifications of abnormal laboratory results (alerts) in an integrated electronic medical record resulted in timely follow-up actions. METHODS: We studied 4 alerts: hemoglobin Alc >= 15%, positive hepatitis C antibody, prostate-specific antigen >= 15 ng/mL and thyroid-stimulating hormone >= 15 mlU/L. An alert tracking system determined whether the alert was acknowledged (ie, provider clicked on and opened the message) within 2 weeks of transmission;. acknowledged alerts were considered read. Within 30 days of result transmission, record review and provider contact determined follow-up actions (eg. patient contact, treatment). Multivariable logistic regression models analyzed predictors for lack of timely follow-up. RESULTS: Between May and December 2008, 78,158 tests (hemoglobin Ale, hepatitis C antibody, thyroid- stimulating hormone, and prostate-specific antigen) were performed, of which 1163 (1.48%) were transmitted as alerts; 10.2% of these (119/1163) were unacknowledged. Timely follow-up was lacking in 79 (6.8%), and was statistically not different for acknowledged and unacknowledged alerts (6.4% vs 10.1 %; P = .13). Of 1163 alerts, 202 (17.4%) arose from unnecessarily ordered (redundant) tests. Alerts for a new versus known diagnosis were more likely to lack timely follow-up (odds ratio 7.35; 95% confidence interval, 4.16-12.97), whereas alerts related to redundant tests were less likely to lack timely follow-up (odds ratio 0.24; 95% confidence interval, 0.07-0.84). CONCLUSIONS: Safety concerns related to timely patient follow-up remain despite automated notification of non-life-threatening abnormal laboratory results in the outpatient setting, Published by, Elsevier Inc. . The American Journal of Medicine (2010) 123, 238-244 C1 [Singh, Hardeep; Wilson, Lindsey; Espadas, Donna; Khan, Myrna M.; Petersen, Laura A.] Baylor Coll Med, Houston VA Hlth Serv Res & Dev Ctr Excellence, Ctr Inquiry Improve Outpatient Safety Effect Elec, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Singh, Hardeep; Wilson, Lindsey; Espadas, Donna; Khan, Myrna M.; Petersen, Laura A.] Baylor Coll Med, Sect Hlth Serv Res, Dept Med, Houston, TX 77030 USA. [Thomas, Eric J.] Univ Texas Houston, Div Gen Med, Dept Med,Univ Texas Med Sch Houston, Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. [Sittig, Dean F.] Univ Texas Sch Hlth Informat Sci, Houston, TX USA. [Sittig, Dean F.] UT Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. RP Singh, H (reprint author), VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.tmc.edu FU NIH [K23CA125585]; VA National Center of Patient Safety; Agency for Health Care Research and Quality Health Services Research Demonstration and Dissemination [R18 HS17244-02]; Houston VA Health Set-vices Research & Development Center of Excellence [HFP90-020] FX The study was supported by an NIH K23 career development award (K23CA125585) to Dr. Singh, the VA National Center of Patient Safety, Agency for Health Care Research and Quality Health Services Research Demonstration and Dissemination Grant (R18 HS17244-02) to Dr. Thomas, and in part by the Houston VA Health Set-vices Research & Development Center of Excellence (HFP90-020). These sources had no role in the design and conduct of the study: collection, management. analysis. and interpretation of the data: and preparation, review, or approval of the manuscript. NR 26 TC 53 Z9 53 U1 4 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2010 VL 123 IS 3 BP 238 EP 244 DI 10.1016/j.amjmed.2009.07.027 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 572EE UT WOS:000275809400013 PM 20193832 ER PT J AU Choi, AI Hernandez, GT Rodriguez, RA O'Hare, AM AF Choi, Andy I. Hernandez, German T. Rodriguez, Rudolph A. O'Hare, Ann M. TI Influence of Hispanic Ethnicity and Diabetic End-stage Renal Disease Reply SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Choi, Andy I.] Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Hernandez, German T.] Texas Tech Univ, Hlth Sci Ctr, Dept Med, Paul L Foster Sch Med, El Paso, TX USA. [Rodriguez, Rudolph A.; O'Hare, Ann M.] Univ Washington, Dept Med, VA Puget Sound Healthcare Syst, Seattle, WA USA. RP Choi, AI (reprint author), Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. NR 2 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 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2010 VL 123 IS 3 BP E21 EP E21 DI 10.1016/j.amjmed.2009.11.002 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 572EE UT WOS:000275809400031 ER PT J AU Little, SE Janakiraman, V Kaimal, A Musci, T Ecker, J Caughey, AB AF Little, Sarah E. Janakiraman, Vanitha Kaimal, Anjali Musci, Thomas Ecker, Jeffrey Caughey, Aaron B. TI The cost-effectiveness of prenatal screening for spinal muscular atrophy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med DE cost-effectiveness; decision analysis; prenatal screening; spinal muscular atrophy ID ECONOMIC-EVALUATION; PREGNANT-WOMEN; AMNIOCENTESIS; DIAGNOSIS; CARE AB OBJECTIVE: We sought to investigate the cost-effectiveness of prenatal screening for spinal muscular atrophy (SMA). STUDY DESIGN: A decision analytic model was created to compare a policy of universal SMA screening to that of no screening. The primary outcome was incremental cost per maternal quality-adjusted life year. Probabilities, costs, and outcomes were estimated through literature review. Univariate and multivariate sensitivity analyses were performed to test the robustness of our model to changes in baseline assumptions. RESULTS: Universal screening for SMA is not cost-effective at $4.9 million per quality-adjusted life year. In all, 12,500 women need to be screened to prevent 1 case of SMA, at a cost of $5.0 million per case averted. Our results were most sensitive to the baseline prevalence of disease. CONCLUSION: Universal prenatal screening for SMA is not cost-effective. For populations at high risk, such as those with a family history, SMA testing may be a cost-effective strategy. C1 [Little, Sarah E.; Janakiraman, Vanitha; Kaimal, Anjali; Ecker, Jeffrey] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Musci, Thomas] San Francisco Perinatal Associates, San Francisco, CA USA. [Caughey, Aaron B.] Univ Calif San Francisco, Sch Med, Decis & Econ Analyses Reprod & Womens Hlth Grp, San Francisco, CA USA. [Caughey, Aaron B.] Univ Calif San Francisco, Sch Med, Ctr Clin & Policy Perinatal Res, San Francisco, CA USA. RP Little, SE (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 25 TC 5 Z9 6 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2010 VL 202 IS 3 AR 253.e1 DI 10.1016/j.ajog.2010.01.032 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 568IV UT WOS:000275516900015 PM 20207244 ER PT J AU Steinberg, G Lee, C Rauh-Hain, JA Ecker, J Khankin, EV Hsu, CD Cohen, B Rana, S Karumanchi, SA Thadhani, R Hacker, MR Lim, KH AF Steinberg, Guy Lee, Chulmin Rauh-Hain, Jose Alejandro Ecker, Jeffrey Khankin, Eliyahu V. Hsu, Chaur-Dong Cohen, Bruce Rana, Sarosh Karumanchi, S. Ananth Thadhani, Ravi Hacker, Michele R. Lim, Kee-Hak TI Early-pregnancy soluble Fas levels in idiopathic small-for-gestational-age pregnancies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE apoptosis; sFas ID PLACENTAL GROWTH-FACTOR; MEDIATED APOPTOSIS; PREECLAMPSIA; SERUM; RISK; CYTOTROPHOBLASTS; RESTRICTION; SURVIVAL; CELLS AB OBJECTIVE: We sought to determine first-and second-trimester serum soluble Fas (sFas) and placental growth factor (PlGF) levels in idiopathic small-for-gestational-age (SGA) pregnancies. STUDY DESIGN: We measured sFas and PlGF levels in women who delivered SGA infants uncomplicated by preeclampsia and in control subjects. For sFas there were 34 cases and 318 control subjects in the first trimester and 9 cases and 11 control subjects in the second trimester. For PlGF there were 31 cases and 281 control subjects in the first trimester and 8 cases and 11 control subjects in the second trimester. RESULTS: SGA pregnancies had lower sFas levels than control subjects in the second trimester (3703 +/- 209 pg/mL vs 4562 +/- 241 pg/mL; P=.015), but not in the first trimester (4892 +/- 191 pg/mL vs 4971 +/- 177 pg/mL; P=.68). There was no difference in PlGF levels between SGA and normal pregnancies in both trimesters. CONCLUSION: Serum sFas levels were lower in idiopathic SGA pregnancies in the second trimester, but not in the first. There was no difference in serum PlGF levels in either trimester. C1 [Steinberg, Guy; Lee, Chulmin; Rauh-Hain, Jose Alejandro; Ecker, Jeffrey; Cohen, Bruce; Rana, Sarosh; Karumanchi, S. Ananth; Thadhani, Ravi; Hacker, Michele R.; Lim, Kee-Hak] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA USA. [Karumanchi, S. Ananth; Thadhani, Ravi] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rauh-Hain, Jose Alejandro; Ecker, Jeffrey; Thadhani, Ravi] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Gen Hosp, Sch Med, Boston, MA 02215 USA. [Hsu, Chaur-Dong] Nassau Univ, Med Ctr, Dept Obstet & Gynecol, E Meadow, NY USA. [Lee, Chulmin] Inje Univ, Sanggye Paik Hosp, Dept Obstet & Gynecol, Seoul, South Korea. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Steinberg, G (reprint author), 330 Brookline Ave,Kirstein 338, Boston, MA 02215 USA. EM guysteinberg@hotmail.com RI Khankin, Eli/M-7648-2013; OI Hacker, Michele/0000-0003-0217-9991; Lee, Chulmin/0000-0003-2510-4271 FU Beth Israel Deaconess Medical Center FX Supported by the Beth Israel Deaconess Medical Center. NR 26 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2010 VL 202 IS 3 AR 299.e1 DI 10.1016/j.ajog.2009.12.017 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 568IV UT WOS:000275516900033 PM 20207247 ER PT J AU Jakobiec, FA Lam, H Bhat, P Pineda, R AF Jakobiec, Frederick A. Lam, Helene Bhat, Pooja Pineda, Roberto TI Non-Syndromic Supernumerary Caruncles Causing Ocular Irritation After Cataract Surgery: A Critical Review of Caruncular Dysgeneses SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Review ID LESIONS AB PURPOSE: To describe a patient with 2 ipsilateral supernumerary caruncles and to determine if they are predictive of associated abnormalities. DESIGN: Retrospective and interventional clinicopathologic study with a critical review of the literature over the past 100 years. METHODS: Assessment of clinical features and histopathologic findings in paraffin-embedded tissue sections stained with hematoxylin and eosin, Masson trichrome, periodic acid-Schiff (PAS) reaction with and without diastase, and Ziehl-Neelsen method. RESULTS: Two placoid lesions causing ocular irritation after routine phacoemulsification were discovered in the inferomedial palpebral conjunctiva. They were totally separate from a normal caruncle. Their surface was studded with yellowish micronodules with projecting white vellus hairs. There were no associated local ophthalmic or systemic abnormalities. Microscopically, they were covered by a goblet cell-rich, nonkeratinizing squamous epithelium with subadjacent pilosebaceous units, the hairs of which were highlighted by the Masson trichrome and Ziehl-Neelsen stains, and small lobules of lacrimal gland tissue. The ocular irritation has not returned after surgery. CONCLUSIONS: A literature review confirms that supernumerary (extra) caruncles coexisting with a normal caruncle are always unilateral and unassociated with any other ocular anomalies, as in the current case. They may, however, cause ocular irritation. They must be distinguished from ectopic (topographically displaced) or dysplastic caruncles that are generally bilateral and often associated with ocular adnexal abnormalities or Golden, har syndrome. Ectopic or dysplastic caruncles, but not supernumerary ones, are characteristically accompanied by plical abnormalities or its absence. Well-documented supernumerary and ectopic caruncles have always been located in the inferior palpebral conjunctiva. (Am J Ophthalmol 2010;149:398-404. (C) 2010 by Elsevier Inc. All rights reserved.) C1 [Jakobiec, Frederick A.; Lam, Helene; Bhat, Pooja; Pineda, Roberto] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Lam, Helene; Bhat, Pooja; Pineda, Roberto] Harvard Univ, Sch Med, Boston, MA USA. [Jakobiec, Frederick A.; Bhat, Pooja] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Pineda, Roberto] Massachusetts Eye & Ear Infirm, Cornea Serv, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Suite 321,3rd Fl,243 Charles St, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 34 TC 5 Z9 6 U1 1 U2 1 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 MAR PY 2010 VL 149 IS 3 BP 398 EP 404 DI 10.1016/j.ajo.2009.09.028 PG 7 WC Ophthalmology SC Ophthalmology GA 565MD UT WOS:000275296400008 PM 20172067 ER PT J AU Daniel, E Thorne, JE Newcomb, CW Pujari, SS Kacmaz, RO Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Suhler, EB Foster, CS Jabs, DA Kempen, JH AF Daniel, Ebenezer Thorne, Jennifer E. Newcomb, Craig W. Pujari, Siddharth S. Kacmaz, R. Oktay Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Foster, C. Stephen Jabs, Douglas A. Kempen, John H. TI Mycophenolate Mofetil for Ocular Inflammation SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID EYE DISEASE; IMMUNOSUPPRESSIVE THERAPY; UVEITIS; AGENT; DRUGS AB PURPOSE: To evaluate mycophenolate mofetil as a single noncorticosteroid immunosuppressive treatment for noninfectious ocular inflammatory diseases. DESIGN: Retrospective cohort study. METHODS: Characteristics of patients with noninfectious ocular inflammation treated with mycophenolate mofetil at 4 subspecialty clinics from 1995 to 2007 were abstracted by expert reviewers in a standardized chart review of every eye at every visit. Main outcomes measured were control of inflammation, corticosteroid-sparing effects, and discontinuation of mycophenolate mofetil (including the reasons for discontinuation). Survival analysis was used to estimate the incidence of outcomes, and to identify risk factors for each. RESULTS: Among 236 patients (397 eyes) treated with mycophenolate mofetil monotherapy, 20.3%, 11.9%, and 39.8% had anterior uveitis, intermediate uveitis, and posterior uveitis or panuveitis respectively; 14% had scleritis; 7.6% had mucous membrane pemphigoid; and 6.4% had other ocular inflammatory diseases. By Kaplan-Meier estimation, complete control of inflammation-sustained over consecutive visits spanning at least 28 days-was achieved in 53% and 73% of patients within 6 months and 1 year respectively. Systemic corticosteroid dosage was reduced to 10 mg of prednisone or less, while maintaining sustained control of inflammation, in 41% and 55% of patients in 6 months and 1 year respectively. Twelve percent of patients discontinued mycophenolate mofetil within the first year because of side effects of therapy. CONCLUSIONS: Given sufficient time, mycophenolate mofetil was effective in managing ocular inflammation in approximately half of the treated patients. Treatment, limiting side effects were observed in 12% of patients and typically were reversible. (Am J Ophthalmol 2010;149: 423-432. (C) 2010 by Elsevier Inc. All rights reserved.) C1 [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Sch Med, Philadelphia, PA 19104 USA. [Daniel, Ebenezer] Univ Penn, Sch Med, Fundus Photograph Reading Ctr, Philadelphia, PA 19104 USA. [Newcomb, Craig W.; Jabs, Douglas A.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Newcomb, Craig W.; Kempen, John H.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Pujari, Siddharth S.; Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Dept Ophthalmol, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 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] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kacmaz, R. Oktay; 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. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Sch Med, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU NEI NIH HHS [R01 EY014943-05, EY014943, R56 EY014943, R01 EY014943] NR 27 TC 77 Z9 81 U1 0 U2 3 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 MAR PY 2010 VL 149 IS 3 BP 423 EP 432 DI 10.1016/j.ajo.2009.09.026 PG 10 WC Ophthalmology SC Ophthalmology GA 565MD UT WOS:000275296400011 PM 20042178 ER PT J AU Baker, AM Klein, RL Haeri, S Moss, KL Boggess, KA AF Baker, Arthur M. Klein, Richard L. Haeri, Sina Moss, Kevin L. Boggess, Kim A. TI Association of Midgestational Paraoxonase 1 Activity with Pregnancies Complicated by Preeclampsia SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE Lipid dysfunction; oxidative stress; paraoxonase; preeclampsia ID DEPENDENT DIABETES-MELLITUS; SERUM PARAOXONASE; ANTIOXIDANT; WOMEN; ARYLESTERASE; COHORT; RISK AB The antioxidant enzyme paraoxonase 1 is a marker of oxidative stress and has been implicated in the pathogenesis of preeclampsia. Our objective was to determine if an association exists between low paraoxonase 1 activity at midgestation and the development of preeclampsia. We conducted a case-control study of 50 women with preeclampsia and 101 women with uncomplicated term deliveries. Maternal serum collected at 15 to 20 weeks was used to measure paraoxonase 1 activity using two substrates: paraoxon and phenylacetate (arylesterase activity). The groups did not differ with respect to maternal demographics. Paraoxonase 1 activity (paraoxon) was significantly higher in women with preeclampsia compared with controls (19.4 +/- 9.4 versus 15.6 +/- 8.0 change in absorbance per minute (dA/min), p = 0.009). When stratified by disease severity, paraoxonase 1 activity (paraoxon) was highest in women with severe preeclampsia (21.6 +/- 9.1 versus 15.6 +/- 8.0 dA/min, p = 0.002). We observed a trend toward higher arylesterase activity in women with preeclampsia compared with controls (0.343 +/- 0.07 versus 0.323 +/- 0.06 dA/min, p = 0.06). Midgestational paraoxonase 1 activity is higher in women with preeclampsia before clinical signs of the disease are present. Prospective studies are needed to determine the significance of paraoxonase 1 in the pathogenesis of preeclampsia. C1 [Baker, Arthur M.; Haeri, Sina; Boggess, Kim A.] Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, Chapel Hill, NC 27599 USA. [Klein, Richard L.] Med Univ S Carolina, Dept Med, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. [Klein, Richard L.] Ralph H Johnson Dept Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. [Moss, Kevin L.] Univ N Carolina, Dept Dent, Chapel Hill, NC 27599 USA. RP Baker, AM (reprint author), Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, 3010 Old Clin Bldg,CB 7516, Chapel Hill, NC 27599 USA. EM abaker2@med.unc.edu FU University of North Carolina; Department of Veterans' Affairs FX This work was supported by a grant from The University of North Carolina Medical Alumni Endowment Fund (A. M. B.) and funding from a Department of Veterans' Affairs MERIT award (R. L. K.). The authors gratefully acknowledge the technical assistance of Ms. Andrea Semler. NR 25 TC 5 Z9 7 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD MAR PY 2010 VL 27 IS 3 BP 205 EP 210 DI 10.1055/s-0029-1236438 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 557JI UT WOS:000274665000004 PM 19685420 ER PT J AU Atkinson, GJ Lee, MY Mehta, MK AF Atkinson, George J. Lee, Michael Y. Mehta, Madhu K. TI Heterotopic Ossification in the Residual Lower Limb in an Adult Nontraumatic Amputee Patient SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Amputation; Ossification; Heterotopic; Adult; Rehabilitation ID BONE; OVERGROWTH; AMPUTATION AB Atkinson GJ, Lee MY, Mehta MK: Heterotopic ossification in the residual lower limb in an adult nontraumatic amputee patient. Am J Phys Med Rehabil 2010;89:245-248. Heterotopic ossification usually occurs in association with various neurologic injuries, trauma, and burns. There have been few reports in the literature of heterotopic bone formation at the distal residual limb in the adult amputee population. All previous cases with a documented cause have involved traumatic amputations. An adult diabetic patient who underwent left below-the-knee amputation for progressive Charcot foot is presented. The patient began to experience residual limb pain and decline in functional mobility 4-5 mos after surgery. Radiographs demonstrated heterotopic bone around the distal tibial and fibular remnant with extension into adjacent soft tissue. Triple-phase bone scan testing and tissue biopsy verified active heterotopic ossification. The patient was treated with etidronate and eventually was able to ambulate with a prosthesis on a regular basis. This case demonstrates that heterotopic ossification may occur and be a source of residual limb pain in the adult nontraumatic amputee population. C1 [Atkinson, George J.; Lee, Michael Y.; Mehta, Madhu K.] Univ N Carolina, Sch Med, Dept Phys Med & Rehabil, Chapel Hill, NC USA. RP Atkinson, GJ (reprint author), S Texas Vet Hlth Care Syst, Dept Phys Med & Rehabil, 1629 Treasure Hills Blvd,Suite B-5, Harlingen, TX 78550 USA. NR 12 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD MAR PY 2010 VL 89 IS 3 BP 245 EP 248 DI 10.1097/PHM.0b013e3181c5657c PG 4 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 569WM UT WOS:000275633500009 PM 19966560 ER PT J AU Liu, JR Wu, XX Franklin, JL Messina, JL Hill, HS Moellering, DR Walton, RG Martin, M Garvey, WT AF Liu, Jiarong Wu, Xuxia Franklin, John L. Messina, Joseph L. Hill, Helliner S. Moellering, Douglas R. Walton, R. Grace Martin, Mitchell Garvey, W. Timothy TI Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE glucose toxicity; type 2 diabetes; insulin signaling ID FUNCTIONAL Q84R POLYMORPHISM; ACTIVATED PROTEIN-KINASE; METABOLIC SYNDROME; CELL-DEATH; GLUT4 TRANSLOCATION; SIGNAL-TRANSDUCTION; 3T3-L1 ADIPOCYTES; TRANSPORT SYSTEM; LIPID-METABOLISM; TRB3 EXPRESSION AB Liu J, Wu X, Franklin JL, Messina JL, Hill HS, Moellering DR, Walton RG, Martin M, Garvey WT. Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance. Am J Physiol Endocrinol Metab 298: E565-E576, 2010. First published December 8, 2009; doi:10.1152/ajpendo. 00467.2009.-Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes. C1 [Wu, Xuxia; Hill, Helliner S.; Moellering, Douglas R.; Walton, R. Grace; Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Messina, Joseph L.; Garvey, W. Timothy] Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Liu, Jiarong; Franklin, John L.; Messina, Joseph L.] Univ Alabama Birmingham, Dept Pathol, Div Mol & Cellular Pathol, Birmingham, AL 35294 USA. [Martin, Mitchell] Hoffmann La Roche Inc, Dept Res Informat Genet & Gen, Preclin Res & Dev, Nutley, NJ 07110 USA. RP Wu, XX (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, 1675 Univ Blvd, Birmingham, AL 35294 USA. EM xuxiawu@uab.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-038764, DK-083562, DK-62071]; National Heart, Lung, and Blood Institute [HL-055782]; American Heart Association; Department of Defense [W81XWH-0510387]; Merit Review Program of the Department of Veterans Affairs; University of Alabama at Birmingham (UAB) Center for Clinical and Translational Science [UL1 RR025777]; UAB Clinical Nutrition Research Unit [P30-DK56336]; UAB Diabetes Research and Training Center [P60-DK079626] FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-038764, DK-083562, and DK-62071 and National Heart, Lung, and Blood Institute Grant HL-055782, American Heart Association Beginning Grant-in-Aid (to X. Wu), the Department of Defense (W81XWH-0510387), and the Merit Review Program of the Department of Veterans Affairs (to W. T. Garvey and J. L. Messina). We also gratefully acknowledge the support of the University of Alabama at Birmingham (UAB) Center for Clinical and Translational Science (UL1 RR025777), the UAB Clinical Nutrition Research Unit (P30-DK56336), and the UAB Diabetes Research and Training Center (P60-DK079626). NR 66 TC 32 Z9 35 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2010 VL 298 IS 3 BP E565 EP E576 DI 10.1152/ajpendo.00467.2009 PG 12 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 557YA UT WOS:000274705200020 PM 19996382 ER PT J AU Bachiller, PR Nakanishi, H Roberts, JD AF Bachiller, Patricia R. Nakanishi, Hidehiko Roberts, Jesse D., Jr. TI Transforming growth factor-beta modulates the expression of nitric oxide signaling enzymes in the injured developing lung and in vascular smooth muscle cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE soluble guanylate cyclase; cGMP-dependent protein kinase I; bronchopulmonary dysplasia; hyperoxia ID DEPENDENT PROTEIN-KINASE; SOLUBLE GUANYLATE-CYCLASE; NEWBORN MOUSE LUNG; PULMONARY-HYPERTENSION; TGF-BETA; RAT LUNG; BRONCHOPULMONARY-DYSPLASIA; ENDOTHELIAL-CELLS; MESSENGER-RNA; FETAL LAMBS AB Bachiller PR, Nakanishi H, Roberts JD Jr. Transforming growth factor-beta modulates the expression of nitric oxide signaling enzymes in the injured developing lung and in vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 298: L324-L334, 2010. First published December 18, 2009; doi:10.1152/ajplung.00181.2009.-Nitric oxide signaling has an important role in regulating pulmonary development and function. Expression of soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI), both critical mediators of nitric oxide (NO) signaling, is diminished in the injured newborn lung through unknown mechanisms. Recent studies suggest that excessive transforming growth factor-beta (TGF-beta) activity inhibits injured newborn lung development. To explore mechanisms that regulate pulmonary NO signaling, we tested whether TGF-beta decreases sGC and PKGI expression in the injured developing lung and pulmonary vascular smooth muscle cells (SMC). We found that chronic oxygen-induced lung injury decreased pulmonary sGC alpha(1) and PKGI immunoreactivity in mouse pups and that exposure to a TGF-beta -neutralizing antibody prevented this reduction of sGC and PKGI protein expression. In addition, TGF-beta(1) decreased expression of NO signaling enzymes in freshly isolated pulmonary microvascular SMC/myofibroblasts, suggesting that TGF-beta has a direct role in modulating NO signaling in the pup lung. Moreover, TGF-beta(1) decreased sGC and PKGI expression in pulmonary artery and aortic SMC from adult rats and mice, suggesting a general role for TGF-beta in modulating NO signaling in vascular SMC. Although other cytokines decrease sGC mRNA stability, TGF-beta did not modulate sGC alpha(1) or PKGI beta mRNA turnover in vascular SMC. These studies indicate for the first time that TGF-beta decreases NO signaling enzyme expression in the injured developing lung and pulmonary vascular SMC. Moreover, they suggest that TGF-beta-neutralizing molecules might counteract the effects of injury on NO signaling in the newborn lung. C1 [Bachiller, Patricia R.; Nakanishi, Hidehiko; Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bachiller, Patricia R.; Nakanishi, Hidehiko; Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Roberts, JD (reprint author), Massachusetts Gen Hosp E, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM roberts@cvrc.mgh.harvard.edu FU National Institutes of Health [5-T32-GM-07592, 1-R01-HL-080316]; INO Therapeutics/Ikaria FX This work was supported by National Institutes of Health Grants 5-T32-GM-07592 (to P. R. Bachiller) and 1-R01-HL-080316 (to J. D. Roberts, Jr.) and INO Therapeutics/Ikaria. NR 86 TC 11 Z9 13 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAR PY 2010 VL 298 IS 3 BP L324 EP L334 DI 10.1152/ajplung.00181.2009 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 559VX UT WOS:000274857200007 PM 20023176 ER PT J AU Paunescu, TG Ljubojevic, M Russo, LM Winter, C McLaughlin, MM Wagner, CA Breton, S Brown, D AF Paunescu, Teodor G. Ljubojevic, Marija Russo, Leileata M. Winter, Christian McLaughlin, Margaret M. Wagner, Carsten A. Breton, Sylvie Brown, Dennis TI cAMP stimulates apical V-ATPase accumulation, microvillar elongation, and proton extrusion in kidney collecting duct A-intercalated cells SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE proton pump; H(+)-ATPase; immunocytochemistry; membrane trafficking; acid-base sensing; phosphorylation ID VACUOLAR H+-ATPASE; SOLUBLE ADENYLYL-CYCLASE; EPIDIDYMAL CLEAR CELLS; B2 SUBUNIT ISOFORM; PROTEIN-KINASE-A; RAT-KIDNEY; EPITHELIAL-CELLS; SECRETING CELLS; BINDING PROTEIN; ACID AB Paunescu TG, Ljubojevic M, Russo LM, Winter C, McLaughlin MM, Wagner CA, Breton S, Brown D. cAMP stimulates apical V-ATPase accumulation, microvillar elongation, and proton extrusion in kidney collecting duct A-intercalated cells. Am J Physiol Renal Physiol 298: F643-F654, 2010. First published January 6, 2010; doi:10.1152/ajprenal.00584.2009.-Kidney proton-secreting A-intercalated cells (A-IC) respond to systemic acidosis by accumulating the vacuolar ATPase (V-ATPase) in their apical membrane and by increasing the length and number of apical microvilli. We show here that the cell-permeant cAMP analog CPT-cAMP, infused in vivo, results in an almost twofold increase in apical V-ATPase accumulation in AE1-positive A-IC within 15 min and that these cells develop an extensive array of apical microvilli compared with controls. In contrast, no significant change in V-ATPase distribution could be detected by immunocytochemistry in B-intercalated cells at the acute time point examined. To show a direct effect of cAMP on A-IC, we prepared cell suspensions from the medulla of transgenic mice expressing EGFP in IC (driven by the B1-subunit promoter of the V-ATPase) and exposed them to cAMP analogs in vitro. Three-dimensional reconstructions of confocal images revealed that cAMP induced a time-dependent growth of apical microvilli, starting within minutes after addition. This effect was blocked by the PKA inhibitor myristoylated PKI. These morphological changes were paralleled by increased cAMP-mediated proton extrusion (pH(i) recovery) by A-IC in outer medullary collecting ducts measured using the ratiometric probe BCECF. These results, and our prior data showing that the bicarbonate-stimulated soluble adenylyl cyclase (sAC) is highly expressed in kidney intercalated cells, support the idea that cAMP generated either by sAC, or by activation of other signaling pathways, is part of the signal transduction mechanism involved in acid-base sensing and V-ATPase membrane trafficking in kidney intercalated cells. C1 [Paunescu, Teodor G.; Ljubojevic, Marija; Russo, Leileata M.; McLaughlin, Margaret M.; Breton, Sylvie; Brown, Dennis] Massachusetts Gen Hosp, MGH Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Paunescu, Teodor G.; Ljubojevic, Marija; Russo, Leileata M.; McLaughlin, Margaret M.; Breton, Sylvie; Brown, Dennis] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Paunescu, Teodor G.; Ljubojevic, Marija; Russo, Leileata M.; McLaughlin, Margaret M.; Breton, Sylvie; Brown, Dennis] Harvard Univ, Sch Med, Boston, MA USA. [Winter, Christian; Wagner, Carsten A.] Univ Zurich, Inst Physiol, Zurich, Switzerland. [Winter, Christian; Wagner, Carsten A.] Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. RP Brown, D (reprint author), Massachusetts Gen Hosp, MGH Ctr Syst Biol, Program Membrane Biol, Simches Res Bldg,185 Cambridge St,CPZN 8020, Boston, MA 02114 USA. EM brown.dennis@mgh.harvard.edu FU National Institutes of Health [DK-73266, DK-42956, DK-38452, HD-40793]; Swiss National Science Foundation [3100A0-122217]; Juvenile Diabetes Research Foundation International; Boston Area Diabetes and Endocrinology Research Center [DK-57521]; Center for the Study of Inflammatory Bowel Disease [DK-43341] FX This work was supported by National Institutes of Health grants DK-73266 (to T. G. Pa. unescu), DK-42956 (to D. Brown), DK-38452 (to S. Breton and D. Brown), and HD-40793 (to S. Breton). C. A. Wagner was supported by the Swiss National Science Foundation (3100A0-122217). L. M. Russo is the recipient of an Advanced Postdoctoral Award from the Juvenile Diabetes Research Foundation International. The Microscopy Core Facility of the Program in Membrane Biology received additional support from the Boston Area Diabetes and Endocrinology Research Center (DK-57521) and from the Center for the Study of Inflammatory Bowel Disease (DK-43341). NR 70 TC 68 Z9 68 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2010 VL 298 IS 3 BP F643 EP F654 DI 10.1152/ajprenal.00584.2009 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 572TM UT WOS:000275856000018 PM 20053793 ER PT J AU Woods, SS Jaen, CR AF Woods, Susan Swartz Jaen, Carlos Roberto TI Increasing Consumer Demand for Tobacco Treatments Ten Design Recommendations for Clinicians and Healthcare Systems SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SMOKING-CESSATION TREATMENTS; DEPENDENCE TREATMENT; PUBLIC-HEALTH; UNITED-STATES; PATIENT; SATISFACTION; SMOKERS; PHYSICIANS; BEHAVIORS; SERVICES AB Health professionals play an important role in addressing patient tobacco use in clinical settings. While there is clear evidence that identifying tobacco use and assisting smokers in quitting affects outcomes, challenges to improve routine, clinician-delivered tobacco intervention persist. The Consumer Demand Initiative has identified simple design principles to increase consumers' use of proven tobacco treatments. Applying these design strategies to activities across the healthcare system, we articulate ten recommendations that can be implemented in the context of most clinical systems where most clinicians work. The recommendations are: (1) reframe the definition of success, (2) portray proven treatments as the best care, (3) redesign the 5A's of tobacco intervention, (4) be ready to deliver the right treatment at the right time, (5) move tobacco from the social history to the problem list, (6) use words as therapy and language that makes sense, (7) fit tobacco treatment into clinical team workflows, (8) embed tobacco treatment into health information technology, (9) make every encounter an opportunity to intervene, and (10) end social disparities for tobacco users. Clinical systems need to change to improve tobacco treatment implementation. The consumer- and clinician-centered recommendations provide a roadmap that focuses on increasing clinician performance through greater understanding of the clinician's role in helping tobacco users, highlighting the value of evidence-based tobacco treatments, employing shared decision-making skills, and integrating routine tobacco treatment into clinical system routines. (Am J Prev Med 2010;38(3S):S385-S392) Published by Elsevier Inc. on behalf of American journal of Preventive Medicine C1 [Woods, Susan Swartz] Portland VA Med Ctr, Portland, OR 97239 USA. [Woods, Susan Swartz] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Jaen, Carlos Roberto] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Woods, SS (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM woodssus@ohsu.edu NR 50 TC 4 Z9 4 U1 0 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 MAR PY 2010 VL 38 IS 3 SU 3 BP S385 EP S392 DI 10.1016/j.amepre.2009.12.003 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OX UT WOS:000275383200013 PM 20176312 ER PT J AU Freeman, MP AF Freeman, Marlene P. TI Nutrition and Psychiatry SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID DIETARY PATTERNS; MENTAL-HEALTH; DEPRESSION; DISORDERS; DISEASE; WOMEN C1 Massachusetts Gen Hosp, Newton, MA 02461 USA. RP Freeman, MP (reprint author), Massachusetts Gen Hosp, 1226 99 Needham St, Newton, MA 02461 USA. EM mfreeman@partners.org NR 11 TC 11 Z9 11 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2010 VL 167 IS 3 BP 244 EP 247 DI 10.1176/appi.ajp.2009.09121746 PG 4 WC Psychiatry SC Psychiatry GA 562MR UT WOS:000275056300003 PM 20194485 ER PT J AU Perlis, RH Ostacher, M Fava, M Nierenberg, AA Sachs, GS Rosenbaum, JF AF Perlis, Roy H. Ostacher, Michael Fava, Maurizio Nierenberg, Andrew A. Sachs, Gary S. Rosenbaum, Jerrold F. TI Assuring That Double-Blind Is Blind SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID PLACEBO-CONTROLLED TRIAL; CLINICAL-TRIALS; MEDICATION; PATIENT C1 [Perlis, Roy H.] Massachusetts Gen Hosp, Bipolar Clin, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Bipolar Clin, Dept Psychiat, 50 Staniford St,5th Floor, Boston, MA 02114 USA. EM rperlis@partners.org OI Ostacher, Michael/0000-0003-0353-7535 NR 10 TC 26 Z9 27 U1 1 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2010 VL 167 IS 3 BP 250 EP 252 DI 10.1176/appi.ajp.2009.09060820 PG 3 WC Psychiatry SC Psychiatry GA 562MR UT WOS:000275056300005 PM 20194487 ER PT J AU Ostacher, MJ Perlis, RH Nierenberg, AA Calabrese, J Stange, JP Salloum, I Weiss, RD Sachs, GS AF Ostacher, Michael J. Perlis, Roy H. Nierenberg, Andrew A. Calabrese, Joseph Stange, Jonathan P. Salloum, Ihsan Weiss, Roger D. Sachs, Gary S. CA STEP-BD Investigators TI Impact of Substance Use Disorders on Recovery From Episodes of Depression in Bipolar Disorder Patients: Prospective Data From the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID 1ST HOSPITALIZATION; ALCOHOL-USE; ABUSE; MANIA; NONADHERENCE; COMORBIDITY; PREDICTORS AB Objective: Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder. Method: Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode. Results: During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state. Conclusions: Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study. C1 [Ostacher, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02178 USA. RP Ostacher, MJ (reprint author), Massachusetts Gen Hosp, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM mostacher@partners.org OI Ostacher, Michael/0000-0003-0353-7535 FU National Institute on Alcoholism and Alcohol Abuse [K23AA016340-01A1]; NIMH [N01MH8001, N01MH80001]; National Institute on Drug Abuse [DA022288, DA15968] FX This study was supported by grant K23AA016340-01A1 from the National Institute on Alcoholism and Alcohol Abuse (Dr. Ostacher), NIMH grant N01MH8001 (Dr. Sachs), and grants DA022288 and DA15968 from the National Institute on Drug Abuse (Dr. Weiss). STEP-BD was funded with Federal funds from NIMH under Contract N01MH80001. Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the NIMH. NR 23 TC 44 Z9 45 U1 0 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 MAR PY 2010 VL 167 IS 3 BP 289 EP 297 DI 10.1176/appi.ajp.2009.09020299 PG 9 WC Psychiatry SC Psychiatry GA 562MR UT WOS:000275056300010 PM 20008948 ER PT J AU Kligerman, S Abbott, G AF Kligerman, Seth Abbott, Gerald TI A Radiologic Review of the New TNM Classification for Lung Cancer SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE International Association for the Study of Lung Cancer (IASLC); lung cancer; staging; TNM ID FORTHCOMING 7TH EDITION; STAGING PROJECT; INTERNATIONAL-ASSOCIATION; BRONCHIOLOALVEOLAR CARCINOMA; SURGICAL RESECTION; MALIGNANT-TUMORS; CHANGING EPIDEMIOLOGY; PROLONGED SURVIVAL; SINGLE INSTITUTION; PROGNOSTIC-FACTORS AB OBJECTIVE. In 2009, a new TNM staging system was published by the International Union Against Cancer and the American Joint Committee on Cancer. The new edition will encompass non-small cell lung cancer, small cell lung cancer, and bronchopulmonary carcinoids. This article will review many important changes that have been made in the revised staging system. CONCLUSION. It is important that radiologists learn the new system and understand the reasons for the changes to provide more accurate clinical staging. C1 [Kligerman, Seth] Univ Maryland, Med Ctr, Dept Diagnost Radiol, Baltimore, MD 21201 USA. [Abbott, Gerald] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Abbott, Gerald] Harvard Univ, Sch Med, Boston, MA USA. RP Kligerman, S (reprint author), Univ Maryland, Med Ctr, Dept Diagnost Radiol, 22 S Greene St,Rm N2W78, Baltimore, MD 21201 USA. EM sethkligerman@hotmail.com NR 59 TC 21 Z9 21 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAR PY 2010 VL 194 IS 3 BP 562 EP 573 DI 10.2214/AJR.09.3354 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 558KN UT WOS:000274741100006 PM 20173129 ER PT J AU Gee, MS Kim, JY Gervais, DA Hahn, PF Mueller, PR AF Gee, Michael S. Kim, John Y. Gervais, Debra A. Hahn, Peter F. Mueller, Peter R. TI Management of Abdominal and Pelvic Abscesses That Persist Despite Satisfactory Percutaneous Drainage Catheter Placement SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE abscess; catheter; drainage; intervention ID FOLLOW-UP AB OBJECTIVE. The purposes of this study were to determine the frequency with which percutaneous abdominopelvic abscess drainage catheters must be replaced because of inadequate drainage, to assess the effect of percutaneous catheter exchange on clinical outcome, and to determine the predictors of clinical success after catheter exchange. MATERIALS AND METHODS. A database of interventional radiology procedures performed at a single tertiary care hospital from 2001 to 2006 was searched to identify the cases of patients who underwent percutaneous catheter drainage of abdominal or pelvic abscesses that was followed by exchange of the drainage catheter at a later date. The electronic medical records and imaging studies of these patients were retrospectively reviewed to determine the abscess characteristics, details of drainage catheter manipulation, and clinical outcome. RESULTS. Among the 3,027 percutaneous abscess drainage catheters placed, 82 were exchanged because of lack of improvement (imaging evidence of undrained fluid and persistent fever and leukocytosis), for an overall frequency of catheter exchange of 2.7% of abscesses in 3.7% of patients. The success rate of catheter replacement, defined as resolution of the fluid collection without open surgical drainage, was 76.8% (63/82). Prognostic factors favorably influencing the clinical success of catheter exchange included a larger number of drainage catheter sideholes, absence of a fistula, low residual abscess volume after initial catheter drainage, and low CT attenuation of abscess fluid. CONCLUSION. In cases of persistent abscess despite adequate catheter placement, percutaneous catheter exchange over a wire is useful for salvage after the large majority of primary failures. In addition, performance of CT and fluoroscopic catheter injection before catheter exchange facilitates recognition of the predictors of a likely response to catheter exchange. C1 [Gee, Michael S.; Kim, John Y.; Gervais, Debra A.; Hahn, Peter F.; Mueller, Peter R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Gee, MS (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,Ellison 237, Boston, MA 02114 USA. EM msgee@partners.org NR 13 TC 12 Z9 12 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAR PY 2010 VL 194 IS 3 BP 815 EP 820 DI 10.2214/AJR.09.3282 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 558KN UT WOS:000274741100042 PM 20173165 ER PT J AU Lim, R AF Lim, Ruth TI Discrepancy Rates of On-Call Radiology Residents' Interpretations of CT Angiography Studies of the Neck and Circle of Willis Reply SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Letter ID URINARY-TRACT-INFECTION; VOIDING CYSTOURETHROGRAPHY; VESICOURETERAL REFLUX; CHILDREN C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Lim, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAR PY 2010 VL 194 IS 3 BP W283 EP W283 DI 10.2214/AJR.09.4058 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 558KN UT WOS:000274741100052 PM 20198742 ER PT J AU Wu, JL Seon, JK Gadikota, HR Hosseini, A Sutton, KM Gill, TJ Li, GA AF Wu, Jia-Lin Seon, Jong Keun Gadikota, Hemanth R. Hosseini, Ali Sutton, Karen M. Gill, Thomas J. Li, Guoan TI In Situ Forces in the Anteromedial and Posterolateral Bundles of the Anterior Cruciate Ligament Under Simulated Functional Loading Conditions SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE anterior cruciate ligament; double bundle; in situ force; muscle load ID ANATOMIC DOUBLE-BUNDLE; KNEE FLEXION ANGLES; SEMITENDINOSUS TENDON; VIVO KINEMATICS; 2 GRAFTS; RECONSTRUCTION; 2-BUNDLE; SINGLE; ACL; POSTERIOR AB Background: The in situ forces of the anteromedial (AM) and posterolateral bundles (PL) of the anterior cruciate ligament (ACL) under simulated functional loads such as simulated muscle loads have not been reported. These data are instrumental for improvement of the anatomical double-bundle ACL reconstruction. Hypothesis: The load-sharing patterns of the 2 bundles are complementary under simulated muscle loads. Study Design: Descriptive laboratory study. Methods: Eight cadaveric knees in this study were sequentially studied using a robotic testing system. Each knee was tested under 3 external loading conditions including (1) a 134-N anterior tibial load; (2) combined rotational loads of 10 N.m of valgus and 5 N.m internal tibial torques; and (3) a 400-N quadriceps muscle load with the knee at 0 degrees, 15 degrees, 30 degrees, 60 degrees, and 90 degrees of flexion. The in situ forces of the 2 bundles of ACL were determined using the principle of superposition. Results: Under the anterior tibial load, the PL bundle carried peak loads at full extension and concurrently had significantly lower force than the AM bundle throughout the range of flexion (P < .05). Under the combined rotational loads, the PL bundle contributed to carrying the load between 0 degrees and 30 degrees, although less than the AM bundle. Under simulated muscle loads, both bundles carried loads between 0 degrees and 30 degrees. There was no significant difference between the 2 bundle forces at all flexion angles (P > .05). Conclusion: Under externally applied loads, in general, the AM bundle carried a greater portion of the load at all flexion angles, whereas the PL bundle only shared the load at low flexion angles. The bundles functioned in a complementary rather than a reciprocal manner to each other. Clinical Relevance: The data appear to support the concept that both bundles function in a complementary manner. Thus, how to re-create the 2 bundle functions in an ACL reconstruction should be further investigated. C1 [Wu, Jia-Lin; Seon, Jong Keun; Gadikota, Hemanth R.; Hosseini, Ali; Sutton, Karen M.; Gill, Thomas J.; Li, Guoan] Massachusetts Gen Hosp, Bioengn Lab, Dept Orthopaed Surg, Boston, MA 02114 USA. [Wu, Jia-Lin; Seon, Jong Keun; Gadikota, Hemanth R.; Hosseini, Ali; Sutton, Karen M.; Gill, Thomas J.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA USA. [Wu, Jia-Lin] Triserv Gen Hosp, Natl Def Med Ctr, Dept Orthopaed Surg, Taipei, Taiwan. [Seon, Jong Keun] Chonnam Natl Univ, Hwasun Hosp, Dept Orthopaed Surg, Kwangju, South Korea. [Hosseini, Ali] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Massachusetts Gen Hosp, Bioengn Lab, Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU National Institutes of Health [AR055612, AR051078] FX The authors gratefully acknowledge the support of the National Institutes of Health (AR055612 & AR051078). NR 33 TC 25 Z9 25 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0363-5465 J9 AM J SPORT MED JI Am. J. Sports Med. PD MAR PY 2010 VL 38 IS 3 BP 558 EP 563 DI 10.1177/0363546509350110 PG 6 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 559ED UT WOS:000274803800017 PM 20044500 ER PT J AU Wang, LL Filippi, RZ Zurakowski, D Archibald, T Vargas, SO Voss, SD Shamberger, RC Davies, K Kozakewich, H Perez-Atayde, AR AF Wang, Larry L. Filippi, Renee Zon Zurakowski, David Archibald, Tonora Vargas, Sara O. Voss, Stephan D. Shamberger, Robert C. Davies, Kimberly Kozakewich, Harry Perez-Atayde, Antonio R. TI Effects of Neoadjuvant Chemotherapy on Hepatoblastoma: A Morphologic and Immunohistochemical Study SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE children; hepatocellular carcinoma; cholangiocarcinoma; beta-catenin; cytokeratin; hepatoblastoma ID BETA-CATENIN; CHILDHOOD HEPATOBLASTOMA; THERAPY; RHABDOMYOSARCOMA; TUMORS; FEATURES; CELLS; GENE AB Neoadjuvant chemotherapy followed by resection has become the mainstay in the treatment of hepatoblastoma (HB). The changes after chemotherapy typically result in tumor necrosis and a fibrohistiocytic response. We have observed that treated HBs undergo additional morphologic changes that have not been described. Herein, we report a 15-year retrospective study of HBs in 22 children who received neoadjuvant chemotherapy according to the Children's Oncology Group protocols. The medical records, diagnostic imaging, and histopathology were reviewed. Besides treated HBs having characteristic necrosis and fibrohistiocytic response, two-thirds had areas of cytoarchitectural differentiation ("maturation'') mimicking non-neoplastic liver, and a quarter had alterations mimicking hepatocellular carcinoma. Nuclear expression of beta-catenin and keratin profiles were useful in distinguishing residual tumor with "maturation'' from non-neoplastic liver and therefore in the assessment of surgical margins. Statistical analysis revealed that larger pretreatment and posttreatment imaged tumor size, larger tumor size at pathologic examination, and vascular invasion were significant univariate predictors of metastatic disease, whereas pretreatment imaged tumor size and vascular invasion were also significant independent predictors (multivariate logistic regression analysis). Multifocality, greater posttreatment necrosis and hepatocellular carcinoma-like morphology were more \often associated with metastatic disease, but did not reach statistical significance. C1 [Wang, Larry L.; Filippi, Renee Zon; Archibald, Tonora; Vargas, Sara O.; Kozakewich, Harry; Perez-Atayde, Antonio R.] Childrens Hosp, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Zurakowski, David; Shamberger, Robert C.] Childrens Hosp, Dana Farber Canc Inst, Dept Surg, Boston, MA 02115 USA. [Zurakowski, David] Childrens Hosp, Dana Farber Canc Inst, Dept Anesthesia, Boston, MA 02115 USA. [Davies, Kimberly] Childrens Hosp, Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. [Voss, Stephan D.] Childrens Hosp, Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Perez-Atayde, AR (reprint author), Childrens Hosp, Dana Farber Canc Inst, Dept Pathol, 300 Longwood Ave, Boston, MA 02115 USA. EM Antonio.perezatayde@childrens.harvard.edu NR 25 TC 17 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2010 VL 34 IS 3 BP 287 EP 299 DI 10.1097/PAS.0b013e3181ce5f1e PG 13 WC Pathology; Surgery SC Pathology; Surgery GA 570RZ UT WOS:000275697000001 PM 20118773 ER PT J AU Klimstra, DS Modlin, IR Adsay, NV Chetty, R Deshpande, V Gonen, M Jensen, RT Kidd, M Kulke, MH Lloyd, RV Moran, C Moss, SF Oberg, K O'Toole, D Rindi, G Robert, ME Suster, S Tang, LH Tzen, CY Washington, MK Wiedenmann, B Yao, J AF Klimstra, David S. Modlin, Irvin R. Adsay, N. Volkan Chetty, Runjan Deshpande, Vikram Goenen, Mithat Jensen, Robert T. Kidd, Mark Kulke, Matthew H. Lloyd, Ricardo V. Moran, Cesar Moss, Steven F. Oberg, Kjell O'Toole, Dermot Rindi, Guido Robert, Marie E. Suster, Saul Tang, Laura H. Tzen, Chin-Yuan Washington, Mary Kay Wiedenmann, Betram Yao, James TI Pathology Reporting of Neuroendocrine Tumors: Application of the Delphic Consensus Process to the Development of a Minimum Pathology Data Set SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE neuroendocrine tumor; consensus; carcinoid tumor; Delphic; classification ID PANCREATIC ENDOCRINE TUMORS; SMALL-CELL CARCINOMA; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; MOLECULAR TARGETED THERAPY; PROGNOSTIC-FACTORS; GASTROINTESTINAL-TRACT; LOW-GRADE; GASTROENTEROPANCREATIC TUMORS; CLASSIFICATION-SYSTEM; PRECURSOR LESIONS AB Epithelial neuroendocrine tumors (NETs) have been the subject of much debate regarding their optimal classification. Although multiple systems of nomenclature, grading, and staging have been proposed, none has achieved universal acceptance. To help define the underlying common features of these classification systems and to identify the minimal pathology data that should be reported to ensure consistent clinical management and reproducibility of data from therapeutic trials, a multidisciplinary team of physicians interested in NETs was assembled. At a group meeting, the participants discussed a series of "yes'' or "no'' questions related to the pathology of NETs and the minimal data to be included in the reports. After discussion, anonymous votes were taken, using the Delphic principle that 80% agreement on a vote of either yes or no would define a consensus. Questions that failed to achieve a consensus were rephrased once or twice and discussed, and additional votes were taken. Of 108 questions, 91 were answerable either yes or no by more than 80% of the participants. There was agreement about the importance of proliferation rate for tumor grading, the landmarks to use for staging, the prognostic factors assessable by routine histology that should be reported, the potential for tumors to progress biologically with metastasis, and the current status of advanced immunohistochemical and molecular testing for treatment-related biomarkers. The lack of utility of a variety of immunohistochemical stains and pathologic findings was also agreed upon. A consensus could not be reached for the remaining 17 questions, which included both minor points related to extent of disease assessment and some major areas such as terminology, routine immunohistochemical staining for general neuroendocrine markers, use of Ki67 staining to assess proliferation, and the relationship of tumor grade to degree of differentiation. On the basis of the results of the Delphic voting, a minimum pathology data set was developed. Although there remains disagreement among experts about the specific classification system that should be used, there is agreement about the fundamental pathology data that should be reported. Examination of the areas of disagreement reveals significant opportunities for collaborative study to resolve unanswered questions. C1 [Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, Surg Pathol Serv, New York, NY 10065 USA. [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Modlin, Irvin R.; Kidd, Mark] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. [Robert, Marie E.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Adsay, N. Volkan] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. [Chetty, Runjan] Toronto Gen Hosp, Dept Pathol, Toronto, ON, Canada. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jensen, Robert T.] Natl Inst Diabet Digest & Kidney Dis, Bethesda, MD USA. [Lloyd, Ricardo V.] Mayo Clin, Dept Pathol, Rochester, MN USA. [Moran, Cesar] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Yao, James] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Moss, Steven F.] Brown Univ, Rhode Isl Hosp, Dept Med, Providence, RI 02903 USA. [Oberg, Kjell] Univ Upsalla, Dept Med Sci, Upsalla, Sweden. [O'Toole, Dermot] St James Hosp, Dept Med, Dublin, Ireland. [O'Toole, Dermot] Trinity Coll Dublin, Dublin, Ireland. [Rindi, Guido] Univ Parma, Dept Pathol & Lab Med, I-43100 Parma, Italy. [Suster, Saul] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Tzen, Chin-Yuan] Cathay Gen Hosp, Dept Pathol, Taipei, Taiwan. [Washington, Mary Kay] Vanderbilt Univ Sch Med, Dept Pathol, Nashville, TN USA. [Wiedenmann, Betram] Univ Berlin, Charite Hosp, Dept Internal Med, Berlin, Germany. RP Klimstra, DS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, Surg Pathol Serv, 1275 York Ave, New York, NY 10065 USA. EM klimstrd@mskcc.org RI Gonen, Mithat/E-4826-2012; OI RINDI, Guido/0000-0003-2996-4404 FU Novartis Corporation FX Supported by Novartis Corporation. NR 100 TC 151 Z9 173 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2010 VL 34 IS 3 BP 300 EP 313 DI 10.1097/PAS.0b013e3181ce1447 PG 14 WC Pathology; Surgery SC Pathology; Surgery GA 570RZ UT WOS:000275697000002 PM 20118772 ER PT J AU Cerroni, L Barnhill, R Elder, D Gottlieb, G Heenan, P Kutzner, H LeBoit, PE Mihm, M Rosai, J Kerl, H AF Cerroni, Lorenzo Barnhill, Raymond Elder, David Gottlieb, Geoffrey Heenan, Peter Kutzner, Heinz LeBoit, Philip E. Mihm, Martin, Jr. Rosai, Juan Kerl, Helmut TI Melanocytic Tumors of Uncertain Malignant Potential Results of a Tutorial Held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008 SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE atypical Spitz tumor; malignant melanoma; melanocytic tumor of uncertain malignant potential; atypical blue nevus; deep penetrating nevus ID MINIMAL DEVIATION MELANOMA; ATYPICAL SPITZ TUMOR; PIGMENTED-EPITHELIOID-MELANOCYTOMA; SENTINEL LYMPH-NODES; SPINDLE CELL; BLUE NEVUS; NEVI/TUMORS; PERSPECTIVE; DIAGNOSIS; CONSENSUS AB Several reports demonstrated the difficulties and lack of agreement in the histopathologic diagnosis of particular melanocytic tumors (atypical Spitz tumors, atypical blue nevi, deep penetrating nevi). These lesions are often referred to as "melanocytic tumors of uncertain malignant potential'' (MELTUMP). We studied a large number of such tumors to find out whether repeatable histopathologic criteria for distinction of benign from malignant cases exist. Fifty-seven cases of MELTUMP were classified within 3 groups according to behavior as follows: (a) favorable (no evidence of metastatic disease after a follow-up of >= 5 y), (b) unfavorable (tumor-related death and/or large metastatic deposits in the lymph nodes and/or visceral metastases), (c) borderline (small nodal deposits of tumor cells <= 0.2 mm). There were no significant differences in tumor thickness and presence or absence of ulceration between the different groups. The only 3 histopathologic criteria that were statistically different between the groups of favorable and unfavorable cases were presence of mitoses, mitoses near the base, and an inflammatory reaction, all of them found more frequently in cases with unfavorable behavior. The major outcome of this study of a series of "MELTUMPs'' suggests as a preliminary observation that these lesions as a group exist and that they may be biologically different from conventional melanoma and benign melanocytic nevi. The terminology remains highly controversial, reflecting the uncertainty in classification and interpretation of these atypical melanocytic tumors. C1 [Cerroni, Lorenzo; Kerl, Helmut] Med Univ Graz, Dept Dermatol, A-8036 Graz, Austria. [Barnhill, Raymond] Univ Paris 07, Hop St Louis, Dept Dermatol, Paris, France. [Barnhill, Raymond] Univ Paris 07, Hop St Louis, Dept Pathol, Paris, France. [Elder, David] Univ Penn Hlth Syst, Dept Pathol & Lab Med, Philadelphia, PA USA. [Gottlieb, Geoffrey] Ackerman Acad Dermatopathol, New York, NY USA. [LeBoit, Philip E.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [LeBoit, Philip E.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Mihm, Martin, Jr.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Heenan, Peter] Cutaneous Pathol, Nedlands, WA, Australia. [Kutzner, Heinz] Dermatopathol Gemeinschaftslabor, Friedrichshafen, Germany. [Rosai, Juan] Ctr Diagnost Italiano, Ctr Consulenze Anat Patolog, Milan, Italy. RP Cerroni, L (reprint author), Med Univ Graz, Dept Dermatol, Auenbruggerpl 8, A-8036 Graz, Austria. EM lorenzo.cerroni@medunigraz.at NR 37 TC 84 Z9 84 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2010 VL 34 IS 3 BP 314 EP 326 DI 10.1097/PAS.0b013e3181cf7fa0 PG 13 WC Pathology; Surgery SC Pathology; Surgery GA 570RZ UT WOS:000275697000003 PM 20118771 ER PT J AU Snuderl, M Kolman, OK Chen, YB Hsu, JJ Ackerman, AM Dal Cin, P Ferry, JA Harris, NL Hasserjian, RP Zukerberg, LR Abramson, JS Hochberg, EP Lee, H Lee, AI Toomey, CE Sohani, AR AF Snuderl, Matija Kolman, Olga K. Chen, Yi-Bin Hsu, Jessie J. Ackerman, Adam M. Dal Cin, Paola Ferry, Judith A. Harris, Nancy Lee Hasserjian, Robert P. Zukerberg, Lawrence R. Abramson, Jeremy S. Hochberg, Ephraim P. Lee, Hang Lee, Alfred I. Toomey, Christiana E. Sohani, Aliyah R. TI B-cell Lymphomas With Concurrent IGH-BCL2 and MYC Rearrangements Are Aggressive Neoplasms With Clinical and Pathologic Features Distinct From Burkitt Lymphoma and Diffuse Large B-cell Lymphoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE MYC; BCL2; diffuse large B-cell lymphoma; Burkitt lymphoma; cytogenetics; high-grade B-cell lymphoma ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; OF-THE-LITERATURE; POLYMERASE-CHAIN-REACTION; FOLLICULAR LYMPHOMA; C-MYC; POOR-PROGNOSIS; MALIGNANT-LYMPHOMAS; TRANSLOCATIONS; T(14/18) AB B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as "double-hit'' lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathologic features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathologic spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we carried out case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32 to 91). Six patients had a history of grade 1 to 2 follicular lymphoma; review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 mo) was inferior to both BL (P = 0.002) and IPI-matched DLBCL (P = 0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (P < 0.0001), Mum1/IRF4 (P = 0.006), Ki-67 < 95% (P < 0.0001), and absence of EBV-EBER (P = 0.006). DHL commonly contained the t(8; 22) rather than the t(8; 14) seen in most BL controls (P = 0.001), and exhibited a higher number of chromosomal aberrations (P = 0.0009). DHL is a high-grade B-cell neoplasm with a poor prognosis, resistance to multiagent chemotherapy, and clinical and pathologic features distinct from other high-grade B-cell neoplasms. Familiarity with the morphologic and immunophenotypic spectrum of DHL is important in directing testing to detect concurrent IGH-BCL2 and MYC rearrangements when a karyotype is unavailable. The aggressive clinical behavior and combination of genetic abnormalities seen in these cases may warrant categorization as a separate entity in future classifications and call for novel therapeutic approaches. C1 [Snuderl, Matija; Kolman, Olga K.; Ferry, Judith A.; Harris, Nancy Lee; Hasserjian, Robert P.; Zukerberg, Lawrence R.; Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Hsu, Jessie J.; Lee, Hang] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Chen, Yi-Bin; Ackerman, Adam M.; Abramson, Jeremy S.; Hochberg, Ephraim P.; Lee, Alfred I.; Toomey, Christiana E.] Massachusetts Gen Hosp, Ctr Canc, Ctr Hematol Malignancies, Boston, MA USA. [Dal Cin, Paola] Brigham & Womens Hosp, Dept Pathol, Ctr Adv Mol Diagnost, Boston, MA 02115 USA. [Snuderl, Matija; Kolman, Olga K.; Dal Cin, Paola; Ferry, Judith A.; Harris, Nancy Lee; Hasserjian, Robert P.; Zukerberg, Lawrence R.; Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hsu, Jessie J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Sohani, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St,WRN 219, Boston, MA 02114 USA. EM arsohani@partners.org OI Snuderl, Matija/0000-0003-0752-0917 FU NCI NIH HHS [R37 CA076404]; NIGMS NIH HHS [T32 GM074897, T32 GM074897-07] NR 58 TC 175 Z9 189 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2010 VL 34 IS 3 BP 327 EP 340 DI 10.1097/PAS.0b013e3181cd3aeb PG 14 WC Pathology; Surgery SC Pathology; Surgery GA 570RZ UT WOS:000275697000004 PM 20118770 ER PT J AU Mortensen, EM Garcia, S Leykum, L Nakashima, B Restrepo, MI Anzueto, A AF Mortensen, Eric M. Garcia, Sean Leykum, Luci Nakashima, Brandy Restrepo, Marcos I. Anzueto, Antonio TI Association of Hypoglycemia With Mortality for Subjects Hospitalized With Pneumonia SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Pneumonia; Hypoglycemia; Mortality ID COMMUNITY-ACQUIRED PNEUMONIA; ELDERLY-PATIENTS; GLUCOSE; SEPSIS; SEVERITY; OUTCOMES AB Background: Previous research has shown that hypoglycemia is associated with worse outcomes for the elderly, in sepsis, and in children with pneumonia. The purpose of this study was to examine whether hypoglycemia (<70 mg/dL) is associated with increased 30-day mortality, after adjusting for potential confounders, for adults hospitalized with pneumonia. Methods: A retrospective cohort study conducted at 2 tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, and had a chest x-ray consistent with, community-acquired pneumonia. Our primary analysis was a multivariable logistic regression with the dependent variable of 30-day mortality and with independent variable of hypoglycemia, diabetes, severity of illness determined using the pneumonia severity index, and pneumonia-related processes of care. Results: Data were abstracted on 787 subjects at the 2 hospitals. Mortality was 8.1% at 30 days. At presentation, 55% of subjects were at low risk, 33% were at moderate risk, and 12% were at high risk. In our cohort, 2.8% (n = 22) had hypoglycemia at presentation. Unadjusted mortality for those who were hypoglycemic was 27.3% versus 8.6% for those who were not (P = 0.0003). In the multivariable analysis, hypoglycemia (odds ratio: 4.1, 95% confidence interval: 1.4-11.7) was significantly associated with 30-day mortality. Conclusions: After adjusting for severity of illness and other potential confounders, hypoglycemia is significantly associated with 30-day mortality for patients hospitalized with pneumonia. Patients with hypoglycemia should be placed in closely monitored settings even when by pneumonia specific risk systems they would normally be discharged. C1 [Mortensen, Eric M.; Garcia, Sean; Leykum, Luci; Restrepo, Marcos I.; Anzueto, Antonio] ALMD UTHSCSA, S Texas Vet Hlth Care Syst, VERDICT Res Program, Med Serv,Audie L Murphy Div, San Antonio, TX 78229 USA. [Mortensen, Eric M.] Univ Texas Hlth Sci Ctr San Antonio, Div Gen Internal Med, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Crit Care Med, San Antonio, TX 78229 USA. [Garcia, Sean; Leykum, Luci] Univ Texas Hlth Sci Ctr San Antonio, Hosp Med, San Antonio, TX 78229 USA. RP Mortensen, EM (reprint author), ALMD UTHSCSA, S Texas Vet Hlth Care Syst, VERDICT Res Program, Med Serv,Audie L Murphy Div, 7400 Merton Minter Blvd 11C6, San Antonio, TX 78229 USA. EM mortensene@uthscsa.edu RI Restrepo, Marcos/H-4442-2014; OI Mortensen, Eric/0000-0002-3880-5563 FU Department of Veteran Affairs; Howard Hughes Medical Institute [00378-001]; NHLBI [NO1-HR-16153]; CTSA [KL2 RR025766] FX This study was supported by a Department of Veteran Affairs Veterans Integrated Service Network 17 new faculty grant and a Howard Hughes Medical Institute faculty-start up grant 00378-001 (EMM); in part, by the NHLBI grant NO1-HR-16153 (to AA); by a Department of Veteran Affairs Veterans Integrated Service Network 17 new faculty grant and a CTSA Award Number KL2 RR025766 (to MIR); and supported with resources and the use of facilities at the South Texas Veterans Health Care System. NR 22 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD MAR PY 2010 VL 339 IS 3 BP 239 EP 243 DI 10.1097/MAJ.0b013e3181ca43fe PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 567CD UT WOS:000275419000009 PM 20220334 ER PT J AU Sis, B Mengel, M Haas, M Colvin, RB Halloran, PF Racusen, LC Solez, K Baldwin, WM Bracamonte, ER Broecker, V Cosio, F Demetris, AJ Drachenberg, C Einecke, G Gloor, J Glotz, D Kraus, E Legendre, C Liapis, H Mannon, RB Nankivell, BJ Nickeleit, V Papadimitriou, JC Randhawa, P Regele, H Renaudin, K Rodriguez, ER Seron, D Seshan, S Suthanthiran, M Wasowska, BA Zachary, A Zeevi, A AF Sis, B. Mengel, M. Haas, M. Colvin, R. B. Halloran, P. F. Racusen, L. C. Solez, K. Baldwin, W. M., III Bracamonte, E. R. Broecker, V. Cosio, F. Demetris, A. J. Drachenberg, C. Einecke, G. Gloor, J. Glotz, D. Kraus, E. Legendre, C. Liapis, H. Mannon, R. B. Nankivell, B. J. Nickeleit, V. Papadimitriou, J. C. Randhawa, P. Regele, H. Renaudin, K. Rodriguez, E. R. Seron, D. Seshan, S. Suthanthiran, M. Wasowska, B. A. Zachary, A. Zeevi, A. TI Banff '09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material DE Acute allograft rejection; acute cellular rejection; acute rejection; allograft rejection; antibody mediated rejection; Banff; Banff lesions; Banff schema; classification; chronic allograft rejection; donor specific antibody; genomic markers; GeneChip; heart allograft; microarrays; proteomics; pancreas allograft; transplantation ID DONOR-SPECIFIC ANTIBODIES; HUMAN-LEUKOCYTE ANTIGEN; RENAL-ALLOGRAFT PATHOLOGY; POSITIVE CROSS-MATCH; TRANSPLANT GLOMERULOPATHY; KIDNEY-TRANSPLANTATION; C4D DEPOSITION; ACTIVATING ANTIBODIES; CARDIAC TRANSPLANTS; HUMORAL REJECTION AB The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future. C1 [Sis, B.; Mengel, M.; Solez, K.] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. [Sis, B.; Mengel, M.; Halloran, P. F.] Univ Alberta, Dept Med, Div Nephrol & Immunol, Alberta Transplant Appl Genom Ctr, Edmonton, AB, Canada. [Haas, M.] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Colvin, R. B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Colvin, R. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Racusen, L. C.; Wasowska, B. A.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Baldwin, W. M., III] Cleveland Clin, Dept Immunol, Lerner Res Inst, Cleveland, OH 44106 USA. [Bracamonte, E. R.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Broecker, V.] Hannover Med Sch, Dept Pathol, Hannover, Germany. [Cosio, F.; Gloor, J.] Mayo Fdn & Clin, Div Nephrol & Hypertens, Rochester, NY USA. [Demetris, A. J.; Randhawa, P.; Zeevi, A.] Univ Pittsburgh, Dept Pathol, Div Transplantat Pathol, Pittsburgh, PA USA. [Drachenberg, C.; Papadimitriou, J. C.] Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA. [Einecke, G.] Hannover Med Sch, Dept Nephrol, Hannover, Germany. [Glotz, D.] Hosp St Louis, Dept Nephrol, Paris, France. [Kraus, E.; Zachary, A.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Legendre, C.] Hop Necker Enfants Malad, Serv Transplantat, Paris, France. [Legendre, C.] Univ Paris 05, Paris, France. [Liapis, H.] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO USA. [Mannon, R. B.] Univ Alabama, Div Nephrol, Birmingham, AL USA. [Nankivell, B. J.] Westmead Hosp, Ctr Transplant Res & Renal Res, Sydney, NSW, Australia. [Nickeleit, V.] Univ N Carolina, Dept Lab Med & Pathol, Chapel Hill, NC USA. [Regele, H.] Univ Vienna, Inst Pathol, Vienna, Austria. [Renaudin, K.] CHU Hotel Dieu, Dept Pathol, Nantes, France. [Rodriguez, E. R.] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA. [Seron, D.] Hosp Gen Valle Hebron, Dept Nephrol, Barcelona, Spain. [Seshan, S.] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Suthanthiran, M.] Cornell Univ, Weill Med Coll, Div Nephrol, Dept Med, New York, NY 10021 USA. RP Sis, B (reprint author), Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. EM bsis@ualberta.ca RI Glotz, Denis/F-7881-2011; Halloran, Philip/J-1390-2012 OI Halloran, Philip/0000-0003-1371-1947 NR 49 TC 399 Z9 427 U1 2 U2 21 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2010 VL 10 IS 3 BP 464 EP 471 DI 10.1111/j.1600-6143.2009.02987.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 556VK UT WOS:000274621200007 PM 20121738 ER PT J AU Hirohashi, T Uehara, S Chase, CM DellaPelle, P Madsen, JC Russell, PS Colvin, RB AF Hirohashi, T. Uehara, S. Chase, C. M. DellaPelle, P. Madsen, J. C. Russell, P. S. Colvin, R. B. TI Complement Independent Antibody-Mediated Endarteritis and Transplant Arteriopathy in Mice SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Chronic transplant arteriopathy; complement; C4d; heart transplantation ID CHRONIC ALLOGRAFT NEPHROPATHY; MURINE CARDIAC ALLOGRAFTS; CAPILLARY DEPOSITION; ENDOTHELIAL-CELLS; C4D DEPOSITION; HLA ANTIBODIES; CORONARY ATHEROSCLEROSIS; HUMORAL REJECTION; FRAGMENT C4D; MOUSE HEARTS AB Complement fixation, as evidenced by C4d in the microvasculature, is a widely accepted criterion of antibody-mediated rejection. Complement fixation has been shown to be essential in acute antibody-mediated rejection, but its role in chronic rejection has not been addressed. Previous studies showed that passive transfer of complement fixing monoclonal IgG2a anti-H-2Kk into B6.RAG1-/- KO recipients of B10.BR hearts led to progressive chronic transplant arteriopathy (CTA) over 14-28 days, accompanied by C4d deposition. The present studies were designed to test whether complement was required for these lesions. We report that a noncomplement fixing donor-specific alloantibody (DSA, monoclonal IgG1 anti-H-2Kk) injected into B6.RAG1-/- KO recipients of B10.BR hearts also promotes CTA, without C4d deposition. Furthermore, a passive transfer of DSA (monoclonal IgG2a anti-H-2Kk) initiated endarteritis followed by CTA in B6.RAG1-/- mice genetically deficient in the third component of complement (RAG1-/-C3-/-). These studies indicate that antibody to class I MHC antigens can trigger chronic arterial lesions in vivo without complement participation, in contrast to acute antibody-mediated rejection. This pathway may be relevant to C4d-negative chronic rejection sometimes observed in patients with DSA, and argues that lack of C4d deposition does not exclude antibody-mediated chronic rejection. C1 [DellaPelle, P.; Colvin, R. B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hirohashi, T.; Uehara, S.; Chase, C. M.; DellaPelle, P.; Madsen, J. C.; Russell, P. S.; Colvin, R. B.] Harvard Univ, Sch Med, Boston, MA USA. [Hirohashi, T.; Uehara, S.; Chase, C. M.; Madsen, J. C.; Russell, P. S.] Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Boston, MA 02114 USA. [Hirohashi, T.; Uehara, S.; Chase, C. M.; Madsen, J. C.; Russell, P. S.] Massachusetts Gen Hosp, Dept Surg, Cardiac Surg Div, Boston, MA 02114 USA. [Uehara, S.] Osaka Univ, Dept Pediat Surg, Grad Sch Med, Osaka, Japan. RP Colvin, RB (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM colvin@helix.mgh.harvard.edu FU Roche Organ Transplant Research Foundation; NIH [RO1 HL071932]; American Society of Transplantation FX This work was supported by grants from the Roche Organ Transplant Research Foundation, NIH grant RO1 HL071932 and by a Basic Science Grant from the American Society of Transplantation (TH). NR 44 TC 49 Z9 51 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2010 VL 10 IS 3 BP 510 EP 517 DI 10.1111/j.1600-6143.2009.02958.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 556VK UT WOS:000274621200012 PM 20055805 ER PT J AU Mollov, JL Lucas, CL Haspot, F Kurtz, J Gaspar, C Guzman, A Sykes, M AF Mollov, J. L. Lucas, C. L. Haspot, F. Kurtz, J. Gaspar, C. Guzman, A. Sykes, M. TI Recipient Dendritic Cells, But Not B Cells, Are Required Antigen-Presenting Cells for Peripheral Alloreactive CD8+T-Cell Tolerance SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Allograft tolerance; anti-CD154 monoclonal antibody; B cell; bone marrow transplantation; CD8; dendritic cell ID CD8(+) T-CELLS; LYMPHOCYTE DEVELOPMENT; TRYPTOPHAN CATABOLISM; MONOCLONAL-ANTIBODY; SELF-TOLERANCE; IN-VIVO; TRANSPLANTATION; DELETION; MARROW; ENGRAFTMENT AB Induction of mixed allogeneic chimerism is a promising approach for achieving donor-specific tolerance, thereby obviating the need for life-long immunosuppression for solid organ allograft acceptance. In mice receiving a low dose (3Gy) of total body irradiation, allogeneic bone marrow transplantation combined with anti-CD154 tolerizes peripheral CD4 and CD8 T cells, allowing achievement of mixed chimerism with specific tolerance to donor. With this approach, peripheral CD8 T-cell tolerance requires recipient MHC class II, CD4 T cells, B cells and DCs. Recipient-type B cells from chimeras that were tolerant to donor still promoted CD8 T-cell tolerance, but their role could not be replaced by donor-type B cells. Using recipients whose B cells or DCs specifically lack MHC class I and/or class II or lack CD80 and CD86, we demonstrate that dendritic cells (DCs) must express CD80/86 and either MHC class I or class II to promote CD8 tolerance. In contrast, B cells, though required, did not need to express MHC class I or class II or CD80/86 to promote CD8 tolerance. Moreover, recipient IDO and IL-10 were not required. Thus, antigen presentation by recipient DCs and not by B cells is critical for peripheral alloreactive CD8 T cell tolerance. C1 [Mollov, J. L.; Lucas, C. L.; Haspot, F.; Kurtz, J.; Gaspar, C.; Guzman, A.; Sykes, M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02115 USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02115 USA. EM megan.sykes@tbrc.mgh.harvard.edu FU National Institutes of Health [R01 HL49915, T32DK007540-21]; AST/Wyeth Basic Science; National Defense Science and Engineering; Foundation pour la Recherche Medicale; American Society of Blood and Marrow Transplantation FX This work was supported by National Institutes of Health Grant R01 HL49915. J.L.M. was supported by the 2008 AST/Wyeth Basic Science Fellowship Grant and a National Institutes of Health Training Grant T32DK007540-21. CLL was supported by the National Defense Science and Engineering Graduate Fellowship. FH was supported by fellowships from the Foundation pour la Recherche Medicale and the American Society of Blood and Marrow Transplantation. NR 31 TC 10 Z9 10 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2010 VL 10 IS 3 BP 518 EP 526 DI 10.1111/j.1600-6143.2009.02967.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 556VK UT WOS:000274621200013 PM 20121730 ER PT J AU Gray, KM Watson, NL Carpenter, MJ LaRowe, SD AF Gray, Kevin M. Watson, Noreen L. Carpenter, Matthew J. LaRowe, Steven D. TI N-Acetylcysteine (NAC) in Young Marijuana Users: An Open-Label Pilot Study SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Letter ID DOUBLE-BLIND; DEPENDENCE; PLACEBO C1 [Gray, Kevin M.; Watson, Noreen L.; Carpenter, Matthew J.; LaRowe, Steven D.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Carpenter, Matthew J.] Med Univ S Carolina, Hollings Canc Ctr, 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, Dept Psychiat & Behav Sci, 67 President St,POB 250861, Charleston, SC 29425 USA. EM graykm@musc.edu FU NCRR NIH HHS [M01 RR001070, M01 RR001070-31, M01 RR01070]; NIDA NIH HHS [R01 DA026777, K12 DA000357, K12 DA000357-09, K23 DA020482, K23 DA020482-03, R01 DA026777-01] NR 10 TC 45 Z9 47 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD MAR-APR PY 2010 VL 19 IS 2 BP 187 EP 189 DI 10.1111/j.1521-0391.2009.00027.x PG 3 WC Substance Abuse SC Substance Abuse GA 556VJ UT WOS:000274621100011 PM 20163391 ER PT J AU Cote, CJ AF Cote, Charles J. TI Safety After Chloral Hydrate Sedation of Former Preterm and Term Infants for Magnetic Resonance Imaging: Are the Data Clear? SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID POSTOPERATIVE APNEA; ADVERSE SEDATION; RISK-FACTORS; CHILDREN; EVENTS; MANAGEMENT; PEDIATRICS; RECOVERY; IMPROVE C1 [Cote, Charles J.] Massachusetts Gen Hosp, MassGeneral Hosp Children, Div Pediat Anesthesia, Boston, MA 02114 USA. [Cote, Charles J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Management, Boston, MA USA. RP Cote, CJ (reprint author), Massachusetts Gen Hosp, MassGeneral Hosp Children, Div Pediat Anesthesia, 55 Fruit St, Boston, MA 02114 USA. EM cjcote@partners.org NR 19 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2010 VL 110 IS 3 BP 671 EP 673 DI 10.1213/ANE.0b013e3181cd4428 PG 3 WC Anesthesiology SC Anesthesiology GA 563MS UT WOS:000275137200009 PM 20185647 ER PT J AU Reust, DL Reeves, ST Abernathy, JH Dixon, JA Gaillard, WF Mukherjee, R Koval, CN Stroud, RE Spinale, FG AF Reust, Daryl L. Reeves, Scott T. Abernathy, James H., III Dixon, Jennifer A. Gaillard, William F., II Mukherjee, Rupak Koval, Christine N. Stroud, Robert E. Spinale, Francis G. TI Temporally and Regionally Disparate Differences in Plasmin Activity by Tranexamic Acid SO ANESTHESIA AND ANALGESIA LA English DT Article ID EPSILON-AMINOCAPROIC ACID; CARDIAC-SURGERY; CARDIOPULMONARY BYPASS; BLOOD-TRANSFUSION; RENAL-FAILURE; REPERFUSION; FIBRINOLYSIS; METAANALYSIS; THROMBOSIS; INHIBITOR AB BACKGROUND: A major complication associated with cardiac surgery is excessive and prolonged bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis, primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamic acid (TXA), has been a pharmacological mainstay in cardiac surgical patients. Despite its almost ubiquitous use, the temporal and regional modulation of PLact profiles by TXA remains unexplored. Accordingly, we developed a fluorogenic-microdialysis system to measure in vivo dynamic changes in PLact after TXA administration in a large animal model. METHODS: Pigs (25-35 kg) were randomly assigned to receive TXA (30 mg/kg, diluted into 50 mL normal saline; n = 9) or vehicle (50 mL normal saline; n = 7). Microdialysis probes were placed in the liver, myocardium, kidney, and quadriceps muscle compartments. The microdialysate infusion contained a validated plasmin-specific fluorogenic peptide. The fluorescence emission (standard fluorogenic units [SFU]) of the interstitial fluid collected from the microdialysis probes, which directly reflects PLact, was determined at steady-state baseline and 30, 60, 90, and 120 min after TXA/vehicle infusion. Plasma PLact was determined at the same time points using the same fluorogenic substrate approach. RESULTS: TXA reduced plasma PLact at 30 min after infusion by >110 SFU compared with vehicle values (P < 0.05). Specifically, there was a decrease in liver PLact at 90 and 120 min after TXA infusion of >150 SFU (P < 0.05) and 175 SFU (P < 0.05), respectively. The decrease in liver PLact occurred 60 min after the maximal decrease in plasma PLact. In contrast, kidney, heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 min. CONCLUSIONS: Using a large animal model and in vivo microdialysis measurements of PLact, the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLact profiles within the plasma and selected interstitial compartments. Second, TXA caused region-specific changes in PLact profiles. These temporal and regional differences in the effects of TXA may have important therapeutic considerations when managing fibrinolysis in the perioperative period. (Anesth Analg 2010; 110: 694-701) C1 [Spinale, Francis G.] Med Univ S Carolina, Dept Cardiothorac Surg, Div Cardiothorac Surg, Charleston, SC 29403 USA. [Reust, Daryl L.; Reeves, Scott T.; Abernathy, James H., III] Med Univ S Carolina, Dept Anesthesiol & Perioperat Med, Charleston, SC 29403 USA. [Dixon, Jennifer A.; Gaillard, William F., II; Mukherjee, Rupak; Koval, Christine N.; Stroud, Robert E.; Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Spinale, FG (reprint author), Med Univ S Carolina, Dept Cardiothorac Surg, Div Cardiothorac Surg, Strom Thurmond Res Bldg,114 Doughty St,Room 625, Charleston, SC 29403 USA. EM wilburnm@musc.edu FU NIH [HL059165, HL078650]; Veterans' Affairs Health Administration FX Supported in part by NIH grants HL059165 and HL078650 and a Merit Award form the Veterans' Affairs Health Administration. NR 32 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2010 VL 110 IS 3 BP 694 EP 701 DI 10.1213/ANE.0b013e3181c7eb27 PG 8 WC Anesthesiology SC Anesthesiology GA 563MS UT WOS:000275137200012 PM 20185649 ER PT J AU Almeida-Chen, G Niezgoda, J Diaz-Gomez, JL Motta, P AF Almeida-Chen, Gracie Niezgoda, Julie Diaz-Gomez, Jose L. Motta, Pablo TI The Role of Echocardiography in the Management of an Embolized Atrial Septal Helex (R) Occluder SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID PATENT FORAMEN OVALE; PULMONARY-ARTERY; CLOSURE C1 [Motta, Pablo] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat Cardiovasc Anesthesiol, Houston, TX 77030 USA. [Almeida-Chen, Gracie] Cleveland Clin, Dept Cardiothorac Anesthesiol, Cleveland, OH 44106 USA. [Niezgoda, Julie] Cleveland Clin, Dept Pediat & Congenital Heart Anesthesiol, Cleveland, OH 44106 USA. [Diaz-Gomez, Jose L.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Motta, P (reprint author), Texas Childrens Hosp, Baylor Coll Med, Dept Pediat Cardiovasc Anesthesiol, 6621 Fannin,WT 17417 B, Houston, TX 77030 USA. EM pxmotta@texaschildrens.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2010 VL 110 IS 3 BP 734 EP 736 DI 10.1213/ANE.0b013e3181cb3edc PG 3 WC Anesthesiology SC Anesthesiology GA 563MS UT WOS:000275137200022 PM 20042445 ER PT J AU Schmidt, U Bittner, E Pivi, S Marota, JJA AF Schmidt, Ulrich Bittner, Edward Pivi, Silvia Marota, John J. A. TI Hemodynamic Management and Outcome of Patients Treated for Cerebral Vasospasm with Intraarterial Nicardipine and/or Milrinone SO ANESTHESIA AND ANALGESIA LA English DT Article ID ANEURYSMAL SUBARACHNOID HEMORRHAGE; CLINICAL-EXPERIENCE; NIMODIPINE; THERAPY; EFFICACY; DEFICITS; SAFETY AB BACKGROUND: Vasospasm is a potentially devastating complication after aneurysmal subarachnoid hemorrhage. Although endovascular treatment with intraarterial nicardipine and milrinone is an accepted clinical treatment strategy, there is little information either on hemodynamic management during treatment or on outcome and consequences of the hemodynamic management. We tested 2 hypotheses: (1) intraarterial administration of nicardipine and milrinone to treat cerebral vasospasm would require increased administration of vasoconstrictor to support arterial blood pressure at target levels; and (2) high-dose vasopressors administered to increase blood pressure in these patients would lead to systemic acidosis and end-organ ischemic damage. METHODS: We conducted a single-center, retrospective review of consecutive patients with clinically symptomatic vasospasm after aneurysmal subarachnoid hemorrhage that failed medical management with "triple H therapy" and subsequently received intraarterial nicardipine and/or milrinone between March 2005 and July 2007. RESULTS: Of 160 endovascular interventions in 73 patients (aged 52 +/- 10 years; 50 women), 96 received only nicardipine, 5 only milrinone, and 59 both drugs. General anesthesia with muscle relaxation was performed for 93% of procedures. During treatment, both the number and dose of vasopressors required to maintain arterial blood pressure at target levels increased; the median dose of phenylephrine increased from 200 (n = 121) to 325 mu g/min (n = 122), norepinephrine increased from 12 (n = 60) to 24.5 mu g/min (n = 87), and vasopressin infusions increased from 7 to 24. Nonetheless, arterial blood pressure decreased 13% during treatment. In >90% of procedures, the postprocedure angiogram showed improved vessel caliber. A single patient demonstrated troponin T increase; no patients had a decrease in renal function, bowel or peripheral ischemia, systemic acidosis, or acute stroke. Overall mortality was 11%. CONCLUSIONS: Intraarterial administration of nicardipine and/or milrinone requires use of vasopressors to maintain arterial blood pressure. Despite high doses of vasoconstrictors, treatment has low mortality, minimal end-organ ischemic damage or systemic acidosis, and results in improved caliber of cerebral vessels affected by vasospasm. (Anesth Analg 2010;110:895-902) C1 [Schmidt, Ulrich; Bittner, Edward; Pivi, Silvia; Marota, John J. A.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Schmidt, Ulrich; Bittner, Edward; Pivi, Silvia; Marota, John J. A.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. RP Marota, JJA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St,GRJ-422, Boston, MA 02114 USA. EM jmarota@partners.org NR 23 TC 22 Z9 26 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2010 VL 110 IS 3 BP 895 EP 902 DI 10.1213/ANE.0b013e3181cc9ed8 PG 8 WC Anesthesiology SC Anesthesiology GA 563MS UT WOS:000275137200046 PM 20185665 ER PT J AU Cappiello, E O'Rourke, N Segal, S Tsen, LC AF Cappiello, Eric O'Rourke, Nollag Segal, Scott Tsen, Lawrence C. TI Are the Conclusions Supported by the Statistics? Response SO ANESTHESIA AND ANALGESIA LA English DT Letter C1 [Cappiello, Eric; O'Rourke, Nollag; Segal, Scott; Tsen, Lawrence C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Cappiello, E (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM ltsen@zeus.bwh.harvard.edu NR 2 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2010 VL 110 IS 3 BP 969 EP 969 DI 10.1213/ANE.0b013e3181c8f778 PG 1 WC Anesthesiology SC Anesthesiology GA 563MS UT WOS:000275137200059 ER PT J AU Scholz, J Yaksh, TL AF Scholz, Joachim Yaksh, Tony L. TI Preclinical Research on Persistent Postsurgical Pain What We Don't Know, but Should Start Studying SO ANESTHESIOLOGY LA English DT Editorial Material ID POSTOPERATIVE PAIN; NEUROPATHIC PAIN; ANIMAL-MODELS; PREVENTION; EXPRESSION; ALLODYNIA; CONSENSUS; SURGERY C1 [Scholz, Joachim] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. [Yaksh, Tony L.] Univ Calif San Diego, Dept Anesthesiol & Pharmacol, La Jolla, CA 92093 USA. RP Scholz, J (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. EM scholz.joachim@mgh.harvard.edu FU NIDA NIH HHS [R01 DA002110-29, R01 DA002110]; NINDS NIH HHS [R01 NS050408-03, R01 NS050408, R01 NS016541, R37 NS016541, R01 NS016541-23] NR 14 TC 13 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2010 VL 112 IS 3 BP 511 EP 513 DI 10.1097/ALN.0b013e3181cf4266 PG 3 WC Anesthesiology SC Anesthesiology GA 565CN UT WOS:000275266800002 PM 20124975 ER PT J AU Kehlet, H Rathmell, JP AF Kehlet, Henrik Rathmell, James P. TI Persistent Postsurgical Pain The Path Forward through Better Design of Clinical Studies SO ANESTHESIOLOGY LA English DT Editorial Material ID PREVENTION C1 [Kehlet, Henrik] Univ Copenhagen Hosp, Rigshosp, Sect Surg Pathophysiol, DK-2100 Copenhagen, Denmark. [Rathmell, James P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Kehlet, H (reprint author), Univ Copenhagen Hosp, Rigshosp, Sect Surg Pathophysiol, DK-2100 Copenhagen, Denmark. EM jrathmell@partners.org NR 7 TC 56 Z9 57 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2010 VL 112 IS 3 BP 514 EP 515 DI 10.1097/ALN.0b013e3181cf423d PG 2 WC Anesthesiology SC Anesthesiology GA 565CN UT WOS:000275266800003 PM 20124977 ER PT J AU Yu, BL Shahid, M Egorina, EM Sovershaev, MA Raher, MJ Lei, C Wu, MX Bloch, KD Zapol, WM AF Yu, Binglan Shahid, Mohd Egorina, Elena M. Sovershaev, Mikhail A. Raher, Michael J. Lei, Chong Wu, Mei X. Bloch, Kenneth D. Zapol, Warren M. TI Endothelial Dysfunction Enhances Vasoconstriction Due to Scavenging of Nitric Oxide by a Hemoglobin-based Oxygen Carrier SO ANESTHESIOLOGY LA English DT Article ID SICKLE-CELL-DISEASE; HEMORRHAGIC-SHOCK; HIGH-FAT; BLOOD; HYPERTENSION; SUBSTITUTES; RESISTANCE; DEATH; RISK; MICE AB Background: To date, there is no safe and effective hemoglobin-based oxygen carrier (HBOC) to substitute for erythrocyte transfusion. It is uncertain whether a deficiency of endothelial nitric oxide bioavailability (endothelial dysfunction) prevents or augments HBOC-induced vasoconstriction. Methods: Hemodynamic effects of infusion of PolyHeme (1.08 g hemoglobin/kg; Northfield Laboratories, Evanston, IL) or murine tetrameric hemoglobin (0.48 g hemoglobin/kg) were determined in awake healthy lambs, awake mice, and anesthetized mice. In vitro, a cumulative dose-tension response was obtained by sequential addition of PolyHeme or tetrameric hemoglobin to phenylephrine-precontracted murine aortic rings. Results: Infusion of PolyHeme did not cause systemic hypertension in awake lambs but produced acute systemic and pulmonary vasoconstriction. Infusion of PolyHeme did not cause systemic hypertension in healthy wild-type mice but induced severe systemic vasoconstriction in mice with endothelial dysfunction (either db/db mice or high-fat fed wild-type mice for 4-6 weeks). The db/db mice were more sensitive to systemic vasoconstriction than wild-type mice after the infusion of either tetrameric hemoglobin or PolyHeme. Murine aortic ring studies confirmed that db/db mice have an impaired response to an endothelial-dependent vasodilator and an enhanced vasoconstrictor response to HBOC. Conclusions: Reduction in low molecular weight hemoglobin concentrations to less than 1% is insufficient to abrogate the vasoconstrictor effects of HBOC infusion in healthy awake sheep or in mice with reduced vascular nitric oxide levels associated with endothelial dysfunction. These findings suggest that testing HBOCs in animals with endothelial dysfunction can provide a more sensitive indication of their potential vasoconstrictor effects. C1 [Yu, Binglan; Shahid, Mohd; Egorina, Elena M.; Sovershaev, Mikhail A.; Raher, Michael J.; Lei, Chong; Wu, Mei X.; Bloch, Kenneth D.; Zapol, Warren M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. RP Zapol, WM (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, 55 Fruit St,Thier 503, Boston, MA 02114 USA. EM wzapol@partners.org FU U.S. Public Health Service, National Institutes of Health, Bethesda, Maryland [HL-42397] FX Received from Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. Submitted for publication July 13, 2009. Accepted for publication November 18, 2009. Supported by U.S. Public Health Service Grant HL-42397 from the National Institutes of Health, Bethesda, Maryland (to Dr. Zapol). Dr. Zapol receives royalties on patents licensed by Massachusetts General Hospital to Linde Corporation, Munich, Germany, and Ikaria, Clinton, New Jersey, on inhaled nitric oxide. Dr. Bloch has received grants from Ikaria and Linde to study inhaled nitric oxide. Northfield Corp. (Evanston, Illinois) funded the animal charges and provided the PolyHeme at no cost. NR 17 TC 37 Z9 38 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2010 VL 112 IS 3 BP 586 EP 594 DI 10.1097/ALN.0b013e3181cd7838 PG 9 WC Anesthesiology SC Anesthesiology GA 565CN UT WOS:000275266800014 PM 20179495 ER PT J AU Cotten, JF Forman, SA Laha, JK Cuny, GD Husain, S Miller, KW Nguyen, HH Kelly, EW Stewart, D Liu, AP Raines, DE AF Cotten, Joseph F. Forman, Stuart A. Laha, Joydev K. Cuny, Gregory D. Husain, Shaukat Miller, Keith W. Nguyen, Hieu H. Kelly, Elizabeth W. Stewart, Deirdre Liu, Aiping Raines, Douglas E. TI Carboetomidate A Pyrrole Analog of Etomidate Designed Not to Suppress Adrenocortical Function SO ANESTHESIOLOGY LA English DT Article ID CRITICALLY-ILL PATIENTS; CARCINOMA-CELL-LINE; ANESTHETIC ETOMIDATE; CRYSTAL-STRUCTURE; INHIBITION; INDUCTION; RESPONSES; IMIDAZOLE; BINDING; COORDINATION AB Background: Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11 beta-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11 beta-hydroxylase. Methods: The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type alpha(1)beta(2)gamma(2l) and etomidate-insensitive mutant alpha(1)beta(2)M286W gamma(2l) human gamma-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results: Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant gamma-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions: Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable. C1 [Cotten, Joseph F.; Forman, Stuart A.; Laha, Joydev K.; Cuny, Gregory D.; Husain, Shaukat; Miller, Keith W.; Nguyen, Hieu H.; Kelly, Elizabeth W.; Stewart, Deirdre; Liu, Aiping; Raines, Douglas E.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Raines, DE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB444, Boston, MA 02114 USA. EM draines@partners.org FU National Institutes of Health, Bethesda, Maryland [R01-GM087316, P01-GM58448]; Foundation for Anesthesia Education and Research, Rochester, Minnesota; Partners Healthcare, Boston, Massachusetts; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts FX Received from the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. Submitted for publication August 23, 2009. Accepted for publication December 8, 2009. Supported by grants R01-GM087316 and P01-GM58448 from the National Institutes of Health, Bethesda, Maryland; the Foundation for Anesthesia Education and Research, Rochester, Minnesota; Partners Healthcare, Boston, Massachusetts; and the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. The Massachusetts General Hospital has submitted a patent application for carboetomidate and related analogs. Six authors (Raines, Cotten, Forman, Cuny, Husain, and Miller), and their respective laboratories, departments, and institutions could receive royalties relating to the development or sale of these drugs. NR 35 TC 32 Z9 36 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2010 VL 112 IS 3 BP 637 EP 644 DI 10.1097/ALN.0b013e3181cf40ed PG 8 WC Anesthesiology SC Anesthesiology GA 565CN UT WOS:000275266800020 PM 20179500 ER PT J AU Costa, ELV Musch, G Winkler, T Schroeder, T Harris, RS Jones, HA Venegas, JG Melo, MFV AF Costa, Eduardo L. V. Musch, Guido Winkler, Tilo Schroeder, Tobias Harris, R. Scott Jones, Hazel A. Venegas, Jose G. Melo, Marcos F. Vidal TI Mild Endotoxemia during Mechanical Ventilation Produces Spatially Heterogeneous Pulmonary Neutrophilic Inflammation in Sheep SO ANESTHESIOLOGY LA English DT Article ID ACUTE LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; FREQUENCY OSCILLATORY VENTILATION; TIDAL VOLUMES; REGIONAL VENTILATION; CYTOKINE RESPONSE; KINETICS; LIPOPOLYSACCHARIDE; MODEL; PET AB Background: There is limited information on the regional inflammatory effects of mechanical ventilation and endotoxemia on the production of acute lung injury. Measurement of (18)F-fluorodeoxyglucose ((18)F-FDG) uptake with positron emission tomography allows for the regional, in vivo and noninvasive, assessment of neutrophilic inflammation. The authors tested whether mild endotoxemia combined with large tidal volume mechanical ventilation bounded by pressures within clinically acceptable limits could yield measurable and anatomically localized neutrophilic inflammation. Methods: Sheep were mechanically ventilated with plateau pressures = 30-32 cm H(2)O and positive end-expiratory pressure = 0 for 2 h. Six sheep received intravenous endotoxin (10 ng.kg(-1).min(-1)), whereas six did not (controls), in sequentially performed studies. The authors imaged with positron emission tomography the intrapulmonary kinetics of infused (13)N-nitrogen and (18)F-FDG to compute regional perfusion and (18)F-FDG uptake. Transmission scans were used to assess aeration. Results: Mean gas fraction and perfusion distribution were similar between groups. In contrast, a significant increase in (18)F-FDG uptake was observed in all lung regions of the endotoxin group. In this group, (18)F-FDG uptake in the middle and dorsal regions was significantly larger than that in the ventral regions. Multivariate analysis showed that the (18)F-FDG uptake was associated with regional aeration (P < 0.01) and perfusion (P < 0.01). Conclusions: Mild short-term endotoxemia in the presence of heterogeneous lung aeration and mechanical ventilation with pressures within clinically acceptable limits produces marked spatially heterogeneous increases in pulmonary neutrophilic inflammation. The dependence of inflammation on aeration and perfusion suggests a multifactorial basis for that finding. 18F-FDG uptake may be a sensitive marker of pulmonary neutrophilic inflammation in the studied conditions. C1 [Musch, Guido; Winkler, Tilo; Venegas, Jose G.; Melo, Marcos F. Vidal] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Harris, R. Scott] Harvard Univ, Sch Med, Boston, MA USA. RP Melo, MFV (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM mvidalmelo@partners.org RI Winkler, Tilo/B-5337-2009; OI Winkler, Tilo/0000-0002-7276-5550; Schroeder, Tobias/0000-0002-4439-8060 FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland [HL 5R01HL086827, K08HL076464] FX Received from Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Submitted for publication April 6, 2009. Accepted for publication November 18, 2009. Supported by the National Heart, Lung, and Blood Institute from the National Institutes of Health, Bethesda, Maryland (grant HL 5R01HL086827), and by the National Institutes of Health grant K08HL076464 (to G. M.). Presented in part at the Annual Meeting of the American Society of Anesthesiologists, Orlando, Florida, October 18, 2008. NR 55 TC 33 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2010 VL 112 IS 3 BP 658 EP 669 DI 10.1097/ALN.0b013e3181cbd1d4 PG 12 WC Anesthesiology SC Anesthesiology GA 565CN UT WOS:000275266800023 PM 20179503 ER PT J AU Givrad, TK Maarek, JMI Moore, WH Holschneider, DP AF Givrad, Tina K. Maarek, Jean-Michel I. Moore, William H. Holschneider, Daniel P. TI Powering an Implantable Minipump with a Multi-layered Printed Circuit Coil for Drug Infusion Applications in Rodents SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Electromagnetic field; Class-E oscillator; Infusion pump; Printed coil; Radio frequency identification device ID CHALLENGE; RATS AB We report the use of a multi-layer printed coil circuit for powering (36-94 mW) an implantable microbolus infusion pump (MIP) that can be activated remotely for use in drug infusion in nontethered, freely moving small animals. This implantable device provides a unique experimental tool with applications in the fields of animal behavior, pharmacology, physiology, and functional brain imaging. Two different designs are described: a battery-less pump usable when the animal is inside a home-cage surrounded by a primary inductive coil and a pump powered by a rechargeable battery that can be used for studies outside the home-cage. The use of printed coils for powering of small devices by inductive power transfer presents significant advantages over similar approaches using hand-wound coils in terms of ease of manufacturing and uniformity of design. The high efficiency of a class-E oscillator allowed powering of the minipumps without the need for close physical contact of the primary and secondary coils, as is currently the case for most devices powered by inductive power transfer. C1 [Givrad, Tina K.; Maarek, Jean-Michel I.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Moore, William H.] Univ So Calif, Alfred E Mann Inst, Los Angeles, CA 90089 USA. [Holschneider, Daniel P.] Univ So Calif, Dept Psychiat, Los Angeles, CA 90089 USA. [Holschneider, Daniel P.] Univ So Calif, Dept Neurol, Los Angeles, CA 90089 USA. [Holschneider, Daniel P.] Univ So Calif, Dept Cell & Neurobiol, Los Angeles, CA 90089 USA. [Holschneider, Daniel P.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Holschneider, Daniel P.] Greater Los Angeles VA Med Ctr, Los Angeles, CA 90073 USA. RP Givrad, TK (reprint author), Univ So Calif, Dept Biomed Engn, 1042 Downey Way 140, Los Angeles, CA 90089 USA. EM givrad@usc.edu FU NIBIB [1 RO1 NS050171] FX Supported by the NIBIB (1 RO1 NS050171). We would like to thank Drs. Jun Yang, Zhou Wang and Theodore Sadler and Ms. Yumei Guo for their contributions NR 15 TC 8 Z9 8 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD MAR PY 2010 VL 38 IS 3 BP 707 EP 713 DI 10.1007/s10439-009-9876-x PG 7 WC Engineering, Biomedical SC Engineering GA 571JA UT WOS:000275746900015 PM 20033778 ER PT J AU Ahuja, SS AF Ahuja, Seema S. TI Quantification of plaque volume by micro-CT techniques SO ANNALS OF CLINICAL AND LABORATORY SCIENCE LA English DT Meeting Abstract C1 [Ahuja, Seema S.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Ahuja, Seema S.] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC CLINICAL SCIENTISTS PI MIDDLEBURY PA PO BOX 1287, MIDDLEBURY, VT 05753 USA SN 0091-7370 J9 ANN CLIN LAB SCI JI Ann. Clin. Lab. Sci. PD SPR PY 2010 VL 40 IS 2 MA 25 BP 192 EP 192 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 588CC UT WOS:000277043100039 ER PT J AU Pollak, DD Rogan, MT Egner, T Perez, DL Yanagihara, TK Hirsch, J AF Pollak, Daniela D. Rogan, Michael T. Egner, Tobias Perez, David L. Yanagihara, Ted K. Hirsch, Joy TI A translational bridge between mouse and human models of learned safety SO ANNALS OF MEDICINE LA English DT Article DE Amygdala; dorsolateral prefrontal cortex; functional magnetic resonance imaging (fMRI); learned safety; translational research ID MAJOR DEPRESSION; INCREASED AMYGDALA; COGNITIVE CONTROL; BRAIN; FMRI; FEAR; ANXIETY; CORTEX AB Background. Learned safety is established by negatively correlating the occurrence of a neutral stimulus and a noxious stimulus, which renders the previously neutral stimulus a 'safety signal'. While the neurophysiological and molecular mechanisms have been characterized in mice, it is currently not known how the neural substrates involved compare between mice and people. Methods. Here we attempt to adapt the original animal protocol to humans and use functional magnetic resonance imaging to examine neural responses to the conditioned stimulus in safety conditioned and fear conditioned subjects. Diffusion tensor imaging (DTI) was used in a parallel group of subjects as a first approach to delineate the underlying neural circuitry. Results. Learned safety is associated with dampened amygdala and increased dorsolateral prefrontal cortex and caudate responses and paralleled by pupillary constriction. A neural connection between the amygdala and the dorsolateral prefrontal cortex is suggested by DTI. Conclusion. We present a translational bridge between mouse and human models of learned safety in which cellular and molecular insights from animal experiments are extended to the human neural circuitry. This study provides an example of how animal experiments can be used to inform and target human studies, which in turn can corroborate results obtained in experimental animals. C1 [Pollak, Daniela D.] Med Univ Vienna, Ctr Physiol & Pharmacol, Dept Physiol, A-1090 Vienna, Austria. [Pollak, Daniela D.; Rogan, Michael T.; Hirsch, Joy] Columbia Univ, Dept Neurosci, New York, NY USA. [Rogan, Michael T.; Yanagihara, Ted K.; Hirsch, Joy] Columbia Univ, PICS, Program Imaging & Cognit Sci, New York, NY USA. [Egner, Tobias] Duke Univ, Dept Psychol & Neuroscince, Ctr Cognit Neurosci, Durham, NC 27706 USA. [Perez, David L.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Perez, David L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hirsch, Joy] Columbia Univ, Dept Radiol, New York, NY USA. [Hirsch, Joy] Columbia Univ, Dept Psychol, New York, NY 10027 USA. RP Pollak, DD (reprint author), Med Univ Vienna, Ctr Physiol & Pharmacol, Dept Physiol, Schwarzspanierstr 17, A-1090 Vienna, Austria. EM daniela.pollak@meduniwien.ac.at RI Egner, Tobias/A-5237-2009; OI Egner, Tobias/0000-0001-7956-3241; Hirsch, Joy/0000-0002-1418-6489 FU Austrian Academy of Science; Austrian Science Fund; Columbia University; Columbia University Medical School FX Daniela D. Pollak was supported by the Austrian Academy of Science (Max-Kade-Fellowship) and the Austrian Science Fund (Erwin-SchroedingerFellowship). Tobias Egner was supported by a Columbia University fMRI Research Fellowship. Ted Yanagihara was supported by the Medical Scientist Training Program, Columbia University Medical School. Imaging funds were provided by education grants to Joy Hirsch, Director, fMRI Research Center, Columbia University (now PICS, Program for Imaging & Cognitive Sciences) for translational and applied studies. The extremely skillful and dedicated expertise of Stephen Dashnaw in carrying out the imaging experiments is highly appreciated. NR 28 TC 24 Z9 24 U1 2 U2 9 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0785-3890 EI 1365-2060 J9 ANN MED JI Ann. Med. PD MAR PY 2010 VL 42 IS 2 BP 115 EP U10 DI 10.3109/07853890903583666 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 560LZ UT WOS:000274905500003 PM 20121549 ER PT J AU Rentz, DM Locascio, JJ Becker, JA Moran, EK Eng, E Buckner, RL Sperling, RA Johnson, KA AF Rentz, Dorene M. Locascio, Joseph J. Becker, John A. Moran, Erin K. Eng, Elisha Buckner, Randy L. Sperling, Reisa A. Johnson, Keith A. TI Cognition, Reserve, and Amyloid Deposition in Normal Aging SO ANNALS OF NEUROLOGY LA English DT Article ID PITTSBURGH COMPOUND-B; POSITRON-EMISSION-TOMOGRAPHY; ADULT READING TEST; ALZHEIMERS-DISEASE; PREMORBID INTELLIGENCE; OLDER PERSONS; ELDERLY SUBJECTS; HEALTHY-YOUNG; DEMENTIA; MEMORY AB Objective: To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association. Methods: In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies. Results: We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test. Interpretation: Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment. ANN NEUROL 2010;67:353-364 C1 [Rentz, Dorene M.; Locascio, Joseph J.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Rentz, Dorene M.; Eng, Elisha; Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02114 USA. [Locascio, Joseph J.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Becker, John A.; Moran, Erin K.; Buckner, Randy L.; Johnson, Keith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Buckner, Randy L.] Harvard Univ, Dept Psychol, Boston, MA 02114 USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Boston, MA 02114 USA. [Buckner, Randy L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckner, Randy L.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Buckner, Randy L.] Howard Hughes Med Inst, Cambridge, MA USA. RP Johnson, KA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Div Nucl Med & Mol Imaging, White 427,33 Fruit St, Boston, MA 02114 USA. OI Kennedy, Kristen/0000-0001-5373-9026 FU National Institute on Aging [AG027435-S1, AG00513421, AG021910]; Howard Hughes Medical Institute; Alzheimer Association [HRG-06-32444, HRG-08-90934]; Charles H. Farnsworth Trust, Boston Massachusetts FX This work was supported by the National Institute on Aging (grant AG027435-S1, R.A.S., KA.J.; grant AG00513421, R.A.S., KA.J.; and grant AG021910, R.L.B.), an anonymous medical foundation the Howard Hughes Medical Institute (R.L.B.), the Alzheimer Association HRG-06-32444 (grant HRG-06-32444, R.A.S., KA.J. and grant HRG-08-90934, D.M.R., KA.J.), and the Charles H. Farnsworth Trust, Boston Massachusetts (D.M.R.). NR 73 TC 187 Z9 189 U1 6 U2 23 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2010 VL 67 IS 3 BP 353 EP 364 DI 10.1002/ana.21904 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 577IS UT WOS:000276216800011 PM 20373347 ER PT J AU Glover, LE Newton, K Krishnan, G Bronson, R Boyle, A Krivickas, LS Brown, RH AF Glover, Louise E. Newton, Kimberly Krishnan, Gomathi Bronson, Roderick Boyle, Alexandra Krivickas, Lisa S. Brown, Robert H., Jr. TI Dysferlin Overexpression in Skeletal Muscle Produces a Progressive Myopathy SO ANNALS OF NEUROLOGY LA English DT Article ID GIRDLE MUSCULAR-DYSTROPHY; ENDOPLASMIC-RETICULUM STRESS; ADENOASSOCIATED VIRAL VECTORS; MIYOSHI MYOPATHY; IN-VITRO; MEMBRANE REPAIR; TRANSGENIC MICE; ACTIN GENE; EXPRESSION; PROTEIN AB Objective: The dose-response effects of dysferlin transgenesis were analyzed to determine if the dysferlin-deficient myopathies are good candidates for gene replacement therapy. Methods: We have generated 3 lines of transgenic mice, expressing low, mid, and high levels of full-length human dysferlin from a muscle-specific promoter. Transgenic skeletal muscle was analyzed and scored for morphological and functional deficits. Results: Overexpression of dysferlin in mice resulted in a striking phenotype of kyphosis, irregular gait, and reduced muscle mass and strength. Moreover, protein dosage correlated with phenotype severity. In contrast to dysferlin-null skeletal muscle, no evidence of sarcolemmal impairment was revealed. Rather, increased levels of Ca(2+)-regulated, dysferlin-binding proteins and endoplasmic reticulum stress chaperone proteins were observed in muscle lysates from transgenic mice as compared with controls. Interpretation: Expression levels of dysferlin are important for appropriate function without deleterious or cytotoxic effects. As a corollary, we propose that future endeavors in gene replacement for correction of dysferlinopathy should be tailored to take account of this. ANN NEUROL 2010;67:384-393 C1 [Brown, Robert H., Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. [Glover, Louise E.; Newton, Kimberly; Boyle, Alexandra; Brown, Robert H., Jr.] Massachusetts Gen Hosp, Day Neuromuscular Res Lab, Charlestown, MA USA. [Glover, Louise E.] Univ Colorado Denver, Dept Gastroenterol & Hepatol, Aurora, CO USA. [Krishnan, Gomathi; Krivickas, Lisa S.] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Bronson, Roderick] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Brown, Robert H., Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. RP Brown, RH (reprint author), Univ Massachusetts, Sch Med, Dept Neurol, 55 Lake Ave N, Worcester, MA 01655 USA. EM Robert.Brown@umassmed.edu FU CB Day Company; NIH (National Institute of Neurological Diseases and Stroke); Muscular Dystrophy Association [MDA 4062] FX This study was supported by the CB Day Company, the NIH (National Institute of Neurological Diseases and Stroke), and the Muscular Dystrophy Association (MDA 4062). NR 44 TC 22 Z9 22 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2010 VL 67 IS 3 BP 384 EP 393 DI 10.1002/ana.21926 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 577IS UT WOS:000276216800014 PM 20373350 ER PT J AU Gardner, RC Schmahmann, JD AF Gardner, Raquel C. Schmahmann, Jeremy D. TI Arginine Test Is Not Reliable for Diagnosing Cerebellar Multiple System Atrophy SO ANNALS OF NEUROLOGY LA English DT Article ID GROWTH-HORMONE-SECRETION; ADULT-ONSET ATAXIA; BODY-MASS INDEX; PARKINSONS-DISEASE; PROGRESSION; ETIOLOGY AB We evaluated the arginine growth hormone (GH) stimulation test for the diagnosis of cerebellar-type multiple system atrophy (MSAc) in patients with ataxia. Fourteen subjects with MSAc, 11 with idiopathic late-onset cerebellar ataxia (ILOCA), 10 with familial ataxia, and 10 healthy controls were tested. After pituitary GH deficiency was excluded, subjects underwent arginine testing. Peak serum GH response was analyzed. No significant differences in peak GH response were found between subject populations. Thirty-three percent of MSAc subjects mounted responses >10 mu g/l GH. Thirty-six percent of ILOCA subjects and 40 percent of healthy controls mounted responses <4 mu g/l GH. Arginine thus appears to be unreliable for the diagnosis of MSAc. ANN NEUROL 2010;67:404-408 C1 [Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Schmahmann, JD (reprint author), Massachusetts Gen Hosp, Dept Neurol, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM jschmahmann@partners.org FU Doris Duke Clinical Research Fellowship Program; Harvard Medical School Pasteur Program and Office of Enrichment Programs; Birmingham Foundation; Mallinkrodt General Clinical Research Center at Massachusetts General Hospital FX This research was supported by the Doris Duke Clinical Research Fellowship Program (RCG), the Harvard Medical School Pasteur Program and Office of Enrichment Programs (RCG), the Birmingham Foundation (JDS), and the Mallinkrodt General Clinical Research Center at Massachusetts General Hospital (RCG, JDS). NR 20 TC 4 Z9 4 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2010 VL 67 IS 3 BP 404 EP 408 DI 10.1002/ana.21898 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 577IS UT WOS:000276216800017 PM 20373353 ER PT J AU Oh, B Butow, P Mullan, B Clarke, S Beale, P Pavlakis, N Kothe, E Lam, L Rosenthal, D AF Oh, B. Butow, P. Mullan, B. Clarke, S. Beale, P. Pavlakis, N. Kothe, E. Lam, L. Rosenthal, D. TI Impact of Medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: a randomized controlled trial SO ANNALS OF ONCOLOGY LA English DT Article DE cancer; fatigue; inflammation; mood; quality of life ID FUNCTIONAL ASSESSMENT; ESSENTIAL-HYPERTENSION; BLOOD-PRESSURE; THERAPY; CHEMOTHERAPY; PROGRAM; SYMPTOMS; EXERCISE; STRESS; OUTPATIENTS AB Background: Substantial numbers of cancer patients use complementary medicine therapies, even without a supportive evidence base. This study aimed to evaluate in a randomized controlled trial, the use of Medical Qigong (MQ) compared with usual care to improve the quality of life (QOL) of cancer patients. Patients and methods: One hundred and sixty-two patients with a range of cancers were recruited. QOL and fatigue were measured by Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Fatigue, respectively, and mood status by Profile of Mood State. The inflammatory marker serum C-reactive protein (CRP) was monitored serially. Results: Regression analysis indicated that the MQ group significantly improved overall QOL (t(144) = 25.761, P < 0.001), fatigue (t(153) = 25.621, P < 0.001), mood disturbance (t(122) = 2.346, P = 0.021) and inflammation (CRP) (t(99) = 2.042, P < 0.044) compared with usual care after controlling for baseline variables. Conclusions: This study indicates that MQ can improve cancer patients' overall QOL and mood status and reduce specific side-effects of treatment. It may also produce physical benefits in the long term through reduced inflammation. C1 [Oh, B.; Clarke, S.; Beale, P.; Pavlakis, N.] Univ Sydney, Concord Repatriat Gen Hosp, Dept Med, Concord, NSW 2139, Australia. [Oh, B.; Butow, P.; Mullan, B.] Univ Sydney, Sch Psychol, Ctr Med Psychol & Evidence Based Decis Making, Sydney, NSW 2006, Australia. [Oh, B.; Clarke, S.; Beale, P.] Concord Repatriat Gen Hosp, Sydney Canc Ctr, Sydney, NSW, Australia. [Pavlakis, N.] Royal N Shore Hosp, Dept Med Oncol, Sydney, NSW, Australia. [Kothe, E.] Univ Sydney, Sch Psychol, Sydney, NSW 2006, Australia. [Lam, L.] Univ Notre Dame, Sch Med Sydney, Notre Dame, IN 46556 USA. [Rosenthal, D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Oh, B (reprint author), Univ Sydney, Concord Repatriat Gen Hosp, Dept Med, Concord, NSW 2139, Australia. EM bsoh@med.usyd.edu.au RI Kothe, Emily/M-7888-2013; OI Kothe, Emily/0000-0003-1210-0554; Mullan, Barbara/0000-0002-0177-8899 NR 34 TC 52 Z9 53 U1 2 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2010 VL 21 IS 3 BP 608 EP 614 DI 10.1093/annonc/mdp479 PG 7 WC Oncology SC Oncology GA 575DE UT WOS:000276045300026 PM 19880433 ER PT J AU Rubino, F Kaplan, LM Schauer, PR Cummings, DE AF Rubino, Francesco Kaplan, Lee M. Schauer, Philip R. Cummings, David E. CA Diabet Surg Summit Delegates TI The Diabetes Surgery Summit Consensus Conference Recommendations for the Evaluation and Use of Gastrointestinal Surgery to Treat Type 2 Diabetes Mellitus SO ANNALS OF SURGERY LA English DT Article ID ROUX-EN-Y; MALABSORPTIVE GASTRIC BYPASS; BARIATRIC SURGERY; MORBID-OBESITY; NONTEACHING HOSPITALS; SURGICAL OUTCOMES; WEIGHT-LOSS; MELLITUS; MORTALITY; DEFICIENCIES AB Objectives: To develop guidelines for the use of gastrointestinal surgery to treat type 2 diabetes and to craft an agenda for further research. Background: Increasing evidence demonstrates that bariatric surgery can dramatically ameliorate type 2 diabetes. Not surprisingly, gastrointestinal operations are now being used throughout the world to treat diabetes in association with obesity, and increasingly, for diabetes alone. However, the role for surgery in diabetes treatment is not clearly defined and there are neither clear guidelines for these practices nor sufficient plans for clinical trials to evaluate the risks and benefits of such "diabetes surgery." Methods: A multidisciplinary group of 50 voting delegates from around the world gathered in Rome, Italy for the first International Conference on Gastrointestinal Surgery to Treat Type 2 Diabetes-(the "Diabetes Surgery Summit"). During the meeting, available scientific evidence was examined and critiqued by the entire group to assess the strength of evidence and to draft consensus statements. Through an iterative process, draft statements were then serially discussed, debated, edited, reassessed, and finally presented for formal voting. After the Rome meeting, statements that achieved consensus were summarized and distributed to all voting delegates for further input and final approval. These statements were then formally critiqued by representatives of several sientific societies at the 1st World Congress on Interventional Therapies for T2DM (New York, Sept 2008). Input from this discussion was used to generate the current position statement. Results: A Diabetes Surgery Summit (DSS) Position Statement consists of recommendations for clinical and research issues, as well as general concepts and definitions in diabetes surgery. The DSS recognizes the legitimacy of surgical approaches to treat diabetes in carefully selected patients. For example, gastric bypass was deemed a reasonable treatment option for patients with poorly controlled diabetes and a body mass index >= 30 kg/m(2). Clinical trials to investigate the exact role of surgery in patients with less severe obesity and diabetes are considered a priority. Furthermore, investigations on the mechanisms of surgical control of diabetes are strongly encouraged, as they may help advance the understanding of diabetes pathophysiology. Conclusions: The DSS consensus document embodies the foundations of "diabetes surgery," and represents a timely attempt by leading scholars to improve access to surgical options supported by sound evidence, while also preventing harm from inappropriate use of unproven procedures. C1 [Rubino, Francesco] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Surg, Surg Metab Sect, New York, NY USA. [Rubino, Francesco] Univ Cattolica Sacro Cuore, Rome, Italy. [Kaplan, Lee M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston Obes & Nutrician Res Ctr, Boston, MA USA. [Schauer, Philip R.] Cleveland Clin, Lerner Coll Med, Bariatr & Metab Inst, Cleveland, OH 44106 USA. [Cummings, David E.] Univ Washington, VA Puget Sound Hlth Care Syst & Diabet, Obes Ctr Excellence, Dept Med & Diabet,Div Metab, Seattle, WA 98195 USA. RP Rubino, F (reprint author), Cornell Univ, Weill Cornell Med Coll, 525 E 68th St,P-714, New York, NY 10065 USA. EM frr2007@med.cornell.edu FU Covidien; Ethicon; Allergan; Storz; GI Dynamics; Roche; Amylin; Power Medical Interventions FX DSS was supported by a generous grants from the following sponsors: Covidien, Ethicon, Allergan, Storz, GI Dynamics, Roche, Amylin, Power Medical Interventions. NR 44 TC 164 Z9 190 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAR PY 2010 VL 251 IS 3 BP 399 EP 405 DI 10.1097/SLA.0b013e3181be34e7 PG 7 WC Surgery SC Surgery GA 562OD UT WOS:000275060800003 PM 19934752 ER PT J AU Partelli, S Fernandez-Del Castillo, C Bassi, C Mantovani, W Thayer, SP Crippa, S Ferrone, CR Falconi, M Pederzoli, P Warshaw, AL Salvia, R AF Partelli, Stefano Fernandez-Del Castillo, Carlos Bassi, Claudio Mantovani, William Thayer, Sarah P. Crippa, Stefano Ferrone, Cristina R. Falconi, Massimo Pederzoli, Paolo Warshaw, Andrew L. Salvia, Roberto TI Invasive Intraductal Papillary Mucinous Carcinomas of the Pancreas Predictors of Survival and the Role of Lymph Node Ratio SO ANNALS OF SURGERY LA English DT Article ID INDEPENDENT PROGNOSTIC-FACTOR; CLINICOPATHOLOGICAL FEATURES; DUCTAL ADENOCARCINOMA; CANCER REGARDLESS; CYSTIC NEOPLASMS; GASTRIC-CANCER; RESECTION; NUMBER; CLASSIFICATION; EXPERIENCE AB Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are being increasingly recognized, and often harbor cancer. Lymph node metastases are an important prognostic factor for patients with invasive intraductal papillary carcinoma (I-IPMC), but the role of lymph node ratio (LNR) in predicting survival after surgery for I-IPMC is unknown. Methods: The combined databases from the Surgical Department of Massachusetts General Hospital of Boston and the University of Verona were queried. We retrospectively reviewed clinical and pathologic data of all patients with resected, pathologically confirmed, I-IPMC between 1990 and 2007. Univariate and multivariate analysis were performed. Results: I-IPMCs were diagnosed in 104 patients (55 males and 49 females), median age was 69 years. Recurrent disease was identified in 49 patients (47.1%) and the median 5-year disease specific survival (DSS) was 60.1%. The median number of resected/ evaluated nodes was 15 (range, 5-60). There were 60 (57.7%) patients who had negative lymph nodes (N0), whereas 44 (42.3%) had lymph node metastases (N1). Patients with lymph node metastases had a shorter 5-year DSS (28.9%) compared with patients with negative lymph nodes (80.3%; P < 0.05) As the LNR increased, 5-year DSS decreased (LNR = 0, 86.5%; LNR >0 to 0.2, 34.4%; LNR >0.2, 11.1%; P < 0.05). On multivariate analysis, LNR, the presence of a family history of pancreatic cancer and a preoperative value of Ca 19.9 > 37 U/L were significant predictors of survival (P < 0.05). Conclusions: Lymph node ratio is a strong predictor of survival after resection for invasive intraductal papillary mucinous carcinoma. C1 [Partelli, Stefano; Bassi, Claudio; Crippa, Stefano; Falconi, Massimo; Pederzoli, Paolo; Salvia, Roberto] Univ Verona, Dept Surg, I-37100 Verona, Italy. [Fernandez-Del Castillo, Carlos; Thayer, Sarah P.; Ferrone, Cristina R.; Warshaw, Andrew L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. [Mantovani, William] Univ Verona, Dept Publ Hlth, I-37100 Verona, Italy. RP Salvia, R (reprint author), Policlin GB Rossi, Piazzale LA Scuro, I-37134 Verona, Italy. EM roberto.salvia@medicina.univr.it OI Falconi, Massimo/0000-0001-9654-7243 FU NCI NIH HHS [P01 CA117969, P01 CA117969-04, P01 CA117969-04S1, P01 CA117969-05, P50 CA127003, P50 CA127003-03, P50 CA127003-04]; NIDDK NIH HHS [K08 DK071329-04, K08 DK071329, K08 DK071329-05] NR 33 TC 26 Z9 28 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAR PY 2010 VL 251 IS 3 BP 477 EP 482 DI 10.1097/SLA.0b013e3181cf9155 PG 6 WC Surgery SC Surgery GA 562OD UT WOS:000275060800015 PM 20142730 ER PT J AU Raval, MV Bilimoria, KY Bentrem, DJ Stewart, AK Winchester, DP Ko, CY Reynolds, M AF Raval, Mehul V. Bilimoria, Karl Y. Bentrem, David J. Stewart, Andrew K. Winchester, David P. Ko, Clifford Y. Reynolds, Marleta TI Nodal Evaluation in Wilms' Tumors Analysis of the National Cancer Data Base SO ANNALS OF SURGERY LA English DT Article ID UNITED-STATES; QUALITY ASSESSMENT; COLON-CANCER; PROGNOSIS; CHILDREN; METASTASES; MANAGEMENT; SURVIVAL; STUDY-5; CARE AB Objective: We used a large US clinical cancer registry to assess nodal evaluation performance in children with Wilms' Tumors (WT), to determined factors associated with nodal evaluation, and to define the prognostic importance of nodal status. Summary Background Data: Lymph node assessment remains a part of accurate staging and helps determine therapy for patients with WT. Lack of nodal assessment has been noted but not well studied. Methods: Patients (0-18 years) with WT from the National Cancer Data Base (1985-2001) were assessed for nodal evaluation. Logistic regression was used to identify factors associated with the likelihood of lymph node evaluation. Survival was estimated using the Kaplan-Meier method. Cox regression was used to estimate the risk of mortality. Results: Of 3593 patients, 1510 (42%) had no lymph nodes evaluated by pathology and reported to the National Cancer Data Base. Of 2083 patients who had lymph nodes assessed, 535 (25.7%) had positive nodes. Patients age 2 years or younger, with larger tumor size, and treated at a higher volume center were more likely to have nodes assessed (P < 0.01). Patients who had nodes evaluated had a better 5-year survival compared with those who did not have nodes evaluated (92.2% vs. 88.1%, P < 0.001). In Cox regression, nodal metastases (P < 0.001; HR: 2.2, CI: 1.6-3.0) were associated with increased risk of death after adjusting for patient, tumor, and hospital characteristics. Conclusions: Many patients do not have lymph nodes evaluated during WT resection. Opportunities exist for improved staging and possibly survival in patients with WT through better nodal assessment. C1 [Raval, Mehul V.; Bilimoria, Karl Y.; Stewart, Andrew K.; Winchester, David P.; Ko, Clifford Y.] Amer Coll Surg, Canc Programs, Div Res & Optimal Patient Care, Chicago, IL USA. [Raval, Mehul V.; Reynolds, Marleta] Childrens Mem Hosp, Div Pediat Surg, Chicago, IL 60614 USA. [Raval, Mehul V.; Bilimoria, Karl Y.; Bentrem, David J.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Div Gastrointestinal & Oncol Surg, Chicago, IL 60611 USA. [Bentrem, David J.] Jesse Brown VA Med Ctr, Chicago, IL USA. [Winchester, David P.] N Shore Univ Hlth Syst, Dept Surg, Evanston, IL USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Raval, MV (reprint author), 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM m-raval@md.northwestern.edu OI Raval, Mehul/0000-0002-1527-2661 FU John Gray Research Fellowship; Daniel F. and Ada L. Rice Foundation; Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service; American College of Surgeons, Commission on Cancer; American Cancer Society FX Supported by the John Gray Research Fellowship and the Daniel F. and Ada L. Rice Foundation (to M. V. R.), a career development award from the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (D.J.B.). The National Cancer Data Base is supported by the American College of Surgeons, Commission on Cancer, and the American Cancer Society. NR 45 TC 13 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAR PY 2010 VL 251 IS 3 BP 559 EP 565 DI 10.1097/SLA.0b013e3181cc95d7 PG 7 WC Surgery SC Surgery GA 562OD UT WOS:000275060800028 PM 20083995 ER PT J AU Rauh-Hain, JA Olawaiye, AB Munro, EG Ko, E Alarcon, IA Del Carmen, MG Duska, L AF Rauh-Hain, J. Alejandro Olawaiye, Alexander B. Munro, Elizabeth G. Ko, Emily Alarcon, Irma A. Del Carmen, Marcela G. Duska, Linda TI Role of Computed Tomography in the Surgical Management of Patients with Bowel Obstruction Secondary to Recurrent Ovarian Carcinoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID INTESTINAL-OBSTRUCTION; PALLIATIVE SURGERY; PROGNOSTIC FACTORS; CANCER; CT; DIAGNOSIS AB The purpose of this study was to evaluate the potential role of preoperative computed tomography (CT) and clinical features for predicting the outcome of patients with bowel obstruction secondary to ovarian cancer. We identified a subpopulation of patients admitted to the Massachusetts General Hospital for bowel obstruction caused by recurrent ovarian cancer from January 1, 1995, to August 1, 2007. A retrospective review of 10 clinical features and 6 radiographic findings was performed. These findings were analyzed as variables with probable prognostic influence on survival and ability to predict successful palliation, defined as the ability to tolerate a regular or low-residue diet 60 days after discharge. Statistical significance was evaluated using the Fisher exact test. Univariate analysis was done by constructing probability curves according to the Kaplan-Meier method and comparing them by the log-rank test. The study population consisted of 55 patients. Absence of carcinomatosis on CT scan and albumin a parts per thousand yen3 g/dL were found to be able to predict successful palliation. Platinum resistance, albumin a parts per thousand yen3 g/dL, and peritoneal carcinomatosis on CT scan were identified as variables with prognostic influence on survival in the univariate analysis. In the Cox regression analysis, only the absence of CT findings of carcinomatosis (P = .009) and albumin a parts per thousand yen 3 g/dL (P = .05) were independently associated with survival. CT scan seems to be helpful in patients with a solitary site as the cause of bowel obstruction. All the patients in our study with this finding had a successful palliation. On the other hand, successful palliation is still feasible in the presence of peritoneal carcinomatosis on CT scan; therefore, this finding alone should not be the reason to avoid surgery in well-selected patients. C1 [Rauh-Hain, J. Alejandro; Munro, Elizabeth G.; Ko, Emily; Del Carmen, Marcela G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA 02115 USA. [Olawaiye, Alexander B.] Univ Pittsburgh, Med Ctr, Magee Womens Hosp, Div Gynecol Oncol, Pittsburgh, PA USA. [Alarcon, Irma A.] Tufts Univ, Sch Med, St Elizabeths Med Ctr, Dept Med, Boston, MA 02111 USA. [Duska, Linda] Univ Virginia, Div Gynecol Oncol, Charlottesville, VA USA. RP Rauh-Hain, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA 02115 USA. EM lrd5d@hscmail.mcc.virginia.edu NR 23 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD MAR PY 2010 VL 17 IS 3 BP 853 EP 860 DI 10.1245/s10434-009-0813-x PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 554ST UT WOS:000274455400027 PM 20183913 ER PT J AU Liberman, M Muzikansky, A Wright, CD Wain, JC Donahue, DM Allan, JS Gaissert, HA Morse, CR Mathisen, DJ Lanuti, M AF Liberman, Moishe Muzikansky, Alona Wright, Cameron D. Wain, John C. Donahue, Dean M. Allan, James S. Gaissert, Henning A. Morse, Christopher R. Mathisen, Douglas J. Lanuti, Michael TI Incidence and Risk Factors of Persistent Air Leak After Major Pulmonary Resection and Use of Chemical Pleurodesis SO ANNALS OF THORACIC SURGERY LA English DT Article ID AUTOLOGOUS BLOOD PATCH; WATER SEAL; REDUCTION SURGERY; RANDOMIZED-TRIAL; UPPER LOBECTOMY; LUNG RESECTION; CHEST TUBES; PREDICTORS; SUCTION; MANAGEMENT AB Background. Persistent air leak (PAL; defined as air leak > 5 days) after major pulmonary resection is prevalent and associated with significant morbidity. This study examines an incompletely characterized treatment for the management of PAL, chemical pleurodesis. Methods. A retrospective case-control study examining all isolated lobectomies and bilobectomies by thoracotomy was performed. The PALs (1997 to 2006) and controls (2002 to 2006) were identified from a prospective database. Incidence, risk factors, management, and outcome were defined. Results. Over 9 years, 78 PALs were identified in 1,393 patients (5.6%). Controls consisted of 700 consecutive patients. Propensity score analysis matching case and controls showed no predictive risk factors for air leak using a logistic regression model. Univariate analysis demonstrated that female gender, smoking history, and forced vital capacity were predictive risk factors. Treatment of PAL consisted of observation (n = 33, 42.3%), pleurodesis (n = 41, 52.6%), Heimlich valve (n = 3, 3.8%), and reoperation (n = 1, 1.3%). Seventy-three patients (93.6%) required no further intervention. One patient required a muscle flap, one readmission for pneumothorax, and one empyema resulting in death. Sclerosis was successful in 40 of 41 patients (97.6%). Mean time to treatment was 8.4 +/- 3.6 days, mean duration of air leak was 10.7 +/- 4.5, and mean duration of air leak postsclerotherapy was 2.8 +/- 2.2 days. Postoperative pneumonia occurred with increased frequency in PAL patients (6 of 45 [13.3%] vs 34 of 700 [4.9%], p = 0.014). PAL was associated with increased length of stay (14.2 vs 7.1 days, p < 0.001) and time with chest tube (11.5 vs 3.4 days, p < 0.001). Conclusions. Air leaks remain an important cause of morbidity. Pleurodesis is an effective option in management of PAL after major pulmonary resection. (Ann Thorac Surg 2010;89:891-8) (C) 2010 by The Society of Thoracic Surgeons C1 Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Biostat, Boston, MA 02114 USA. RP Lanuti, M (reprint author), 55 Fruit St,Blake 1570, Boston, MA 01748 USA. EM mlanuti@partners.org FU Division of Thoracic Surgery at the Massachusetts General Hospital FX Financial support for this study was provided by the Division of Thoracic Surgery at the Massachusetts General Hospital. We would like to acknowledge our data manager and research coordinator, Sheila Cann and Diane Davies, respectively, for their diligence and dedication toward compiling and maintaining the Thoracic Surgery Database. NR 40 TC 14 Z9 16 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD MAR PY 2010 VL 89 IS 3 BP 891 EP 898 DI 10.1016/j.athoracsur.2009.12.012 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 558JF UT WOS:000274736800032 PM 20172150 ER PT J AU Salm, TJV Toran, AJ AF Salm, Thomas J. Vander Toran, Ann J. TI An Aortic Cinch to Quell Suture Line Bleeding SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material AB Bleeding from an aortic suture line or cannula site may be difficult to control, especially in the patient with a fragile or dilated aorta. This method of wrapping a vascular graft around the aorta to relieve tension on the suture line and control bleeding is simple and effective, and it facilitates obtaining the proper tension of the wrapped graft. (Ann Thorac Surg 2010; 89: 990-1) (C) 2010 by The Society of Thoracic Surgeons C1 [Salm, Thomas J. Vander] N Shore Med Ctr, Dept Surg, Salem, MA 01970 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Salm, TJV (reprint author), N Shore Med Ctr, Dept Surg, 81 Highland Ave, Salem, MA 01970 USA. EM tvandersalm@partners.org NR 2 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 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD MAR PY 2010 VL 89 IS 3 BP 990 EP 991 DI 10.1016/j.athoracsur.2009.04.131 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 558JF UT WOS:000274736800064 ER PT J AU Wiederhold, NP Najvar, LK Bocanegra, R Graybill, JR Patterson, TF AF Wiederhold, Nathan P. Najvar, Laura K. Bocanegra, Rosie Graybill, John R. Patterson, Thomas F. TI Efficacy of Posaconazole as Treatment and Prophylaxis against Fusarium solani SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CELL TRANSPLANT RECIPIENTS; IN-VITRO ACTIVITIES; ORAL POSACONAZOLE; INVASIVE ASPERGILLOSIS; HEMATOLOGIC MALIGNANCY; AMPHOTERICIN-B; PHARMACOKINETICS; VORICONAZOLE; TRIAZOLES; INFECTION AB Invasive fusariosis is a highly aggressive fungal infection associated with high mortality in heavily immunocompromised patients. Although posaconazole is efficacious as salvage therapy against infections caused by Fusarium species, concerns remain regarding this agent in the setting of reduced potency. To evaluate the efficacy of posaconazole as treatment or prophylaxis against invasive fusariosis caused by Fusarium solani, we utilized a neutropenic murine model of disseminated disease. ICR mice were administered escalating doses of posaconazole (6.25, 12.5, 25, or 50 mg/kg of body weight twice daily [BID]) by oral gavage beginning 2 days prior to inoculation in the prophylaxis studies or beginning 12 h after inoculation as treatment. Therapy was continued until day 9 postinoculation, and animals were monitored off therapy until day 15 for survival. Fungal burden was assessed as CFU in the kidneys. A clear dose-response relationship was observed, as the highest dose of posaconazole (50 mg/kg) was the most effective in prolonging survival and reducing tissue fungal burden both as prophylaxis and as treatment. This dose response was associated with high posaconazole serum concentrations as measured by bioassay. However, the extent of efficacy was also dependent on the infecting inoculum, as greater increases in survival and reductions in fungal burden were observed with the lower inocula tested. In this model high dosages of posaconazole were effective as treatment and prophylaxis against disseminated fusariosis caused by F. solani. C1 [Wiederhold, Nathan P.; Najvar, Laura K.; Bocanegra, Rosie; Graybill, John R.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Wiederhold, Nathan P.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Najvar, Laura K.; Bocanegra, Rosie; Graybill, John R.; Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Wiederhold, NP (reprint author), Univ Texas Hlth Sci Ctr San Antonio, PERC 6220,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM wiederholdn@uthscsa.edu OI Wiederhold, Nathan/0000-0002-2225-5122 FU Schering-Plough, Inc.; Schering-Plough; Pfizer; Merck; Basilea; CyDex; Nektar Therapeutics FX This study was funded by Schering-Plough, Inc.; N. P. W. has received research support from Schering-Plough, Pfizer, Merck, Basilea, and CyDex. T. F. P. has received research support from Merck, Basilea, Pfizer, Schering-Plough, and Nektar Therapeutics; has received speaker fees from Merck and Pfizer; and has served as a consultant for Basilea, Merck, Pfizer, and Toyama. NR 22 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2010 VL 54 IS 3 BP 1055 EP 1059 DI 10.1128/AAC.01445-09 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 558HY UT WOS:000274733300012 PM 20065054 ER PT J AU Leuckfeld, I Paster, BJ Kristoffersen, AK Olsen, I AF Leuckfeld, Inga Paster, Bruce J. Kristoffersen, Anne K. Olsen, Ingar TI Diversity of Veillonella spp. from subgingival plaque by polyphasic approach SO APMIS LA English DT Article DE Cellular fatty acids; SDS-PAGE; RAPD; 16S rRNA gene; rpoB gene; sequencing ID OBSTRUCTIVE PULMONARY-DISEASE; 16S RIBOSOMAL-RNA; SP-NOV.; GENUS VEILLONELLA; CYSTIC-FIBROSIS; DENTAL PLAQUE; BACTERIA; TAXONOMY AB In a biofilm such as the subgingival microflora, strain-specific properties or factors induced by the host may impart a survival advantage to some bacterial strains. Periodontal disease has been associated with chronic obstructive pulmonary disease (COPD) and we previously found high amounts of Veillonella in the subgingival microflora of COPD subjects. Differentiation of Veillonella is difficult. The aims of this study were to identify subgingival Veillonella isolates by phenotypic, genetic typing and molecular genetic methods, and further, to assess if Veillonella strain properties or identity correlated with periodontal disease or COPD. From 22 subjects, 26 subgingival Veillonella isolates and one pulmonary isolate were analysed. The majority of the subgingival Veillonella isolates were identified as Veillonella parvula. Genotyping showed heterogeneity within strains of the same species. A subgingival and pulmonary isolate in one COPD subject was found to be genetically identical strains of V. parvula. Scanning electron microscopy of the lung biopsy confirmed single small cocci adhering or coaggregating with larger cocci on the airway epithelium. Apart from a variation in cellular fatty acid composition of six subgingival isolates from periodontitis subjects, no correlation between the subgingival Veillonella strains or genotypes and the presence of either periodontitis or COPD was found. In conclusion, V. parvula was the predominant subgingival Veillonella species with high genetic variability within strains of the same species. Subgingival V. parvula can translocate to the lungs; however, Veillonella identity or genotype did not correlate with periodontal disease or COPD. C1 [Leuckfeld, Inga] Natl Hosp Norway, Oslo Univ Hosp, Dept Resp Med, N-0027 Oslo, Norway. [Leuckfeld, Inga; Kristoffersen, Anne K.; Olsen, Ingar] Univ Oslo, Fac Dent, Inst Oral Biol, Oslo, Norway. [Paster, Bruce J.] Forsyth Inst, Dept Mol Genet, Boston, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Leuckfeld, I (reprint author), Natl Hosp Norway, Oslo Univ Hosp, Dept Resp Med, Sognsvannsveien 20, N-0027 Oslo, Norway. EM inga.leuckfeld@rikshospitalet.no FU Faculty of Dentistry, University of Oslo, Oslo, Norway; Departments of Thoracic and Cardiovascular Surgery and Respiratory Medicine, Rikshospitalet Medical Center, Oslo FX This work was supported by the Faculty of Dentistry, University of Oslo, Oslo, Norway, and the Departments of Thoracic and Cardiovascular Surgery and Respiratory Medicine, Rikshospitalet Medical Center, Oslo. We thank Drs. Odd Geiran and circle divide ystein Bj circle divide rtuft for their kind help with the patients and the lung material. Steinar St circle divide len and Dr. Yiqing Cai are thanked for their excellent technical assistance with SEM and TEM respectively, and Emnet Abesha-Belay and Dr. Emenike RK Eribe are acknowledged for their skilful laboratory assistance. Enevold Falsen, CCUG, Gothenburg, Sweden, is acknowledged for his help with long-chain cellular fatty acid analyses. We are grateful to Drs. W.E.C. Moore (deceased) and L.V.H. Moore for gifts from their culture collection. NR 31 TC 4 Z9 4 U1 1 U2 10 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0903-4641 J9 APMIS JI APMIS PD MAR PY 2010 VL 118 IS 3 BP 230 EP 242 DI 10.1111/j.1600-0463.2009.02584.x PG 13 WC Immunology; Microbiology; Pathology SC Immunology; Microbiology; Pathology GA 550RX UT WOS:000274147700008 PM 20132189 ER PT J AU Hussein, MRA Al Bshabshe, AA Dalati, T AF Hussein, Mahmoud Rezk A. Al Bshabshe, Ali A. Dalati, Taufik TI Leukemia Cutis: Case Report and Review of Literature SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Review DE leukemia; skin; myeloperoxidase ID SECTIONS AB Leukemias are neoplasms of hematolymphoid cells that predominantly involve the peripheral blood. Cutaneous involvement (leukemia cutis) occurs in chronic myeloid leukemia, chronic lymphocytic leukemia, and in monocytic leukemia. Here, we report a case of a 49-year-old female patient known to have chronic myeloid leukemia presented with multiple cutaneous lesions. The clinicopathologic features were presented and the relevant literature was discussed. C1 [Hussein, Mahmoud Rezk A.; Al Bshabshe, Ali A.; Dalati, Taufik] Asir Cent Hosp, Dept Pathol & Med, Abha, Saudi Arabia. [Hussein, Mahmoud Rezk A.] Univ Wisconsin, Sch Med, Madison, WI USA. [Hussein, Mahmoud Rezk A.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Hussein, MRA (reprint author), Assiut Univ, Fac Med, Dept Pathol, Assiut, Egypt. EM mrcpath17@gmail.com NR 5 TC 5 Z9 5 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-3345 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD MAR PY 2010 VL 18 IS 2 BP 190 EP 191 DI 10.1097/PAI.0b013e3181bfbcdc PG 2 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA 563UI UT WOS:000275160000014 PM 19956066 ER PT J AU Gerstner, ER Batchelor, TT AF Gerstner, Elizabeth R. Batchelor, Tracy T. TI Primary Central Nervous System Lymphoma SO ARCHIVES OF NEUROLOGY LA English DT Review ID PRIMARY CNS LYMPHOMA; HIGH-DOSE METHOTREXATE; NON-HODGKINS-LYMPHOMA; PHASE-II; DEFERRED RADIOTHERAPY; EUROPEAN ORGANIZATION; MALIGNANT-LYMPHOMA; FOLLOW-UP; CHEMOTHERAPY; BRAIN AB Primary central nervous system (CNS) lymphoma (PCNSL), an uncommon variant of extranodal non-Hodgkin lymphoma (NHL), can affect any part of the neuraxis including the eyes, brain, leptomeninges, or spinal cord. It accounts for approximately 3% of all the primary CNS tumors diagnosed each year in the United States. Congenital or acquired immunodeficiency is the only established risk factor for PCNSL, and individuals with human immunodeficiency virus (HIV) infection are at greater risk for developing this tumor. Infection with HIV likely accounted for the increased incidence in PCNSL observed from 1970 to 2000, but over the last decade the number of cases of PCNSL has stabilized or decreased to about 0.47 cases per 100 000 persons. Owing to the rarity of PCNSL, the disease has been challenging to study and an effective standard of care has been difficult to establish. Unfortunately, although durable remissions may be achieved for some patients with PCNSL, the tumor relapses in most cases. In this review, we will focus on PCNSL in the immunocompetent host. C1 [Gerstner, Elizabeth R.; Batchelor, Tracy T.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol & Oncol, Boston, MA 02114 USA. [Gerstner, Elizabeth R.; Batchelor, Tracy T.] Massachusetts Gen Hosp, Ctr Canc, Dept Neurol, Boston, MA 02114 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Gerstner, ER (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol & Oncol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM egerstner@partners.org NR 28 TC 63 Z9 70 U1 2 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAR PY 2010 VL 67 IS 3 BP 291 EP 297 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 565QG UT WOS:000275308600005 PM 20212226 ER PT J AU Walcott, BP Jaglowski, JR Curry, WT AF Walcott, Brian P. Jaglowski, Jeffrey R. Curry, William T., Jr. TI Spinal Epidural Metastasis SO ARCHIVES OF NEUROLOGY LA English DT Editorial Material ID CORD COMPRESSION C1 [Walcott, Brian P.; Curry, William T., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. [Jaglowski, Jeffrey R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Walcott, BP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, 55 Fruit St,White Bldg,Room 502, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu NR 4 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAR PY 2010 VL 67 IS 3 BP 358 EP 359 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 565QG UT WOS:000275308600016 PM 20212236 ER PT J AU Gupta, SR Agnani, S Tehrani, S Yeh, S Lauer, AK Suhler, EB AF Gupta, Seema R. Agnani, Shivali Tehrani, Shandiz Yeh, Steven Lauer, Andreas K. Suhler, Eric B. TI Endogenous Streptococcus agalactiae (Group B Streptococcus) Endophthalmitis as a Presenting Sign of Precursor T-Cell Lymphoblastic Leukemia SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID BACTERIAL ENDOPHTHALMITIS C1 [Gupta, Seema R.; Agnani, Shivali; Tehrani, Shandiz; Yeh, Steven; Lauer, Andreas K.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Casey Eye Inst, Dept Ophthalmol, Portland, OR 97239 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. RP Suhler, EB (reprint author), Oregon Hlth & Sci Univ, Casey Eye Inst, Dept Ophthalmol, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM suhlere@ohsu.edu NR 4 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAR PY 2010 VL 128 IS 3 BP 384 EP 385 PG 3 WC Ophthalmology SC Ophthalmology GA 565QC UT WOS:000275308100023 PM 20212217 ER PT J AU Eversole, GM Moriarty, AT Schwartz, MR Clayton, AC Souers, R Fatheree, LA Chmara, BA Tench, WD Henry, MR Wilbur, DC AF Eversole, Galen M. Moriarty, Ann T. Schwartz, Mary R. Clayton, Amy C. Souers, Rhona Fatheree, Lisa A. Chmara, Beth A. Tench, William D. Henry, Michael R. Wilbur, David C. TI Practices of Participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology, 2006 SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; CURRENT LABORATORY PRACTICES; UNDETERMINED SIGNIFICANCE; SPECIMEN ADEQUACY; GYNECOLOGIC CYTOLOGY; QUALITY-ASSURANCE; REPORTING RATES; TERMINOLOGY; MANAGEMENT; TESTS AB Context.-Liquid-based preparations (LBPs) and human papillomavirus testing have led to changes in cervical cytology practices. The College of American Pathologists attempts to track practice patterns using a supplemental questionnaire, which allows laboratories to report diagnostic practices. Objective.-To analyze the 2006 reporting practices and to compare the results with the 2003 survey data. Design.-Questionnaire was mailed to 1621 laboratories. Participants included laboratories enrolled in the 2006 College of American Pathologists Gynecologic Proficiency Testing Program or the educational Interlaboratory Comparison Program in Gynecologic Cytology. Results.-Of the 679 responding laboratories (response rate, 42%), most (97.8%; n = 664) had implemented the Bethesda 2001 terminology. The median rate for all preparations with low-grade squamous intraepithelial lesions was 2.5% (2.9% for LBPs) compared with a 2003 median rate of 2.1%; the increase was confined to LBPs. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little. High-grade squamous intraepithelial lesions and unsatisfactory rates varied at statistically significant levels between types of LBPs. Most atypical squamous cell cases were subclassified as undetermined significance (median, 4.3%). The median ratio of atypical squamous cells to squamous intraepithelial lesions and carcinomas for all specimen types combined was 1.5, similar to the 2003 median ratio of 1.4. The median rates for findings of squamous cell abnormalities for 2006 were significantly higher for LBPs than for conventional smears. Conclusions.-Most responding laboratories have implemented the Bethesda 2001 terminology. There is an increase in LBP low-grade squamous intraepithelial lesion rates when compared with 2003 data. Liquid-based preparations have higher median squamous intraepithelial lesion and atypical squamous cell rates. (Arch Pathol Lab Med. 2010; 134: 331-335) C1 [Eversole, Galen M.] Quest Diagnostics Inc, Dept Pathol, Las Vegas, NV 89119 USA. [Moriarty, Ann T.] AmeriPath Indiana, Dept Pathol, Indianapolis, IN USA. [Schwartz, Mary R.] Methodist Hosp, Dept Pathol, Houston, TX 77030 USA. [Clayton, Amy C.; Henry, Michael R.] Mayo Clin, Dept Anat Pathol, Rochester, MN USA. [Souers, Rhona] Coll Amer Pathologists, Dept Biostat, Northfield, IL USA. [Fatheree, Lisa A.; Chmara, Beth A.] Coll Amer Pathologists, Dept Cytol Surveys, Northfield, IL USA. [Tench, William D.] Palomar Med Ctr, Dept Lab Serv, Escondido, CA USA. [Wilbur, David C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Eversole, GM (reprint author), Quest Diagnostics Inc, Dept Pathol, 4320 Burnham Ave, Las Vegas, NV 89119 USA. EM gmeversole@mac.com FU College of American Pathologists (Northfield, Illinois) FX The College of American Pathologists (Northfield, Illinois) provided support for this study. NR 18 TC 27 Z9 34 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAR PY 2010 VL 134 IS 3 BP 331 EP 335 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 568NL UT WOS:000275529200002 PM 20196659 ER PT J AU McKenney, JK Amin, MB Epstein, JI Grignon, DJ Oliva, E Reuter, VE Srigley, JR Humphrey, PA AF McKenney, Jesse K. Amin, Mahul B. Epstein, Jonathan I. Grignon, David J. Oliva, Esther Reuter, Victor E. Srigley, John R. Humphrey, Peter A. CA Members Canc Comm Coll Amer Pathologists TI Protocol for the Examination of Specimens From Patients With Carcinoma of the Urethra SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID URINARY-BLADDER; INVASION C1 [Humphrey, Peter A.] Washington Univ, Med Ctr, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Humphrey, Peter A.] Barnes Jewish Hosp, St Louis, MO 63110 USA. [McKenney, Jesse K.] Stanford Univ, Med Ctr, Dept Pathol & Urol, Stanford, CA 94305 USA. [Amin, Mahul B.] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Epstein, Jonathan I.] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. [Grignon, David J.] Indiana Univ, Dept Pathol, Indianapolis, IN 46204 USA. [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Reuter, Victor E.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Srigley, John R.] Credit Valley Hosp, Dept Lab Med, Mississauga, ON, Canada. RP Humphrey, PA (reprint author), Washington Univ, Med Ctr, Sch Med, Dept Pathol & Immunol, 660 S Euclid Ave, St Louis, MO 63110 USA. EM humphrey@path.wustl.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAR PY 2010 VL 134 IS 3 BP 345 EP 350 PG 6 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 568NL UT WOS:000275529200005 PM 20196662 ER PT J AU Dussel, V Joffe, S Hilden, JM Watterson-Schaeffer, J Weeks, JC Wolfe, J AF Dussel, Veronica Joffe, Steven Hilden, Joanne M. Watterson-Schaeffer, Jan Weeks, Jane C. Wolfe, Joanne TI Considerations About Hastening Death Among Parents of Children Who Die of Cancer SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID PHYSICIAN-ASSISTED SUICIDE; PALLIATIVE SEDATION THERAPY; TERMINALLY-ILL PATIENTS; OF-LIFE DECISIONS; ADVANCED DISEASE; END; EUTHANASIA; CARE; ATTITUDES; DESIRE AB Objectives: To estimate the frequency of hastening death discussions, describe current parental endorsement of hastening death and intensive symptom management, and explore whether children's pain influences these views in a sample of parents whose child died of cancer. Design: Cross-sectional survey. Setting: Two tertiary-care US pediatric institutions. Participants: A total of 141 parents of children who died of cancer (response rate, 64%). Outcome Measures: Proportion of parents who (1) considered or (2) discussed hastening death during the child's end of life and who endorsed (3) hastening death or (4) intensive symptom management in vignettes portraying children with end-stage cancer. Results: A total of 19 of 141 (13%; 95% confidence interval [CI], 8%-19%) parents considered requesting hastened death for their child and 9% (95% CI, 4%-14%) discussed hastening death; consideration of hastening death tended to increase with an increase in the child's suffering from pain. In retrospect, 34% (95% CI, 26%42%) of parents reported that they would have considered hastening their child's death had the child been in uncontrollable pain, while 15% or less would consider hastening death for nonphysical suffering. In response to vignettes, 50% (95% CI, 42%-58%) of parents endorsed hastening death while 94% (95% CI, 90%-98%) endorsed intensive pain management. Parents were more likely to endorse hastening death if the vignette involved a child in pain compared with coma (odds ratio, 1.4; 95% CI, 1.1-1.8). Conclusions: More than 10% of parents considered hastening their child's death; this was more likely if the child was in pain. Attention to pain and suffering and education about intensive symptom management may mitigate consideration of hastening death among parents of children with cancer. C1 [Dussel, Veronica; Joffe, Steven; Weeks, Jane C.; Wolfe, Joanne] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Dussel, Veronica; Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dussel, Veronica; Joffe, Steven; Wolfe, Joanne] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Hilden, Joanne M.] Peyton Manning Childrens Hosp St Vincent, Indianapolis, IN USA. [Watterson-Schaeffer, Jan] Childrens Hosp & Clin, St Paul, MN USA. [Weeks, Jane C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, 44 Binney St, Boston, MA 02115 USA. EM joanne_wolfe@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 FU Agency for Health Research and Quality [T32HP10018]; National Cancer Institute [NCI 5 K07 CA096746]; Pine Tree Apple Tennis Classic Oncology Research Fund FX Funding/Support: This study was supported by fellowship T32HP10018 from the Agency for Health Research and Quality (Dr Dussel); and grant NCI 5 K07 CA096746 from the National Cancer Institute (Dr Wolfe); and partially supported by the Pine Tree Apple Tennis Classic Oncology Research Fund (Ms Watterson-Schaeffer). NR 41 TC 8 Z9 8 U1 0 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD MAR PY 2010 VL 164 IS 3 BP 231 EP 237 PG 7 WC Pediatrics SC Pediatrics GA 562IA UT WOS:000275042300004 PM 20194255 ER PT J AU Joffe, S AF Joffe, Steven TI Framing the Benefits of Cancer Clinical Trials SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Editorial Material ID PARTICIPATION; US C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Joffe, S (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM steven_joffe@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 NR 15 TC 1 Z9 1 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD MAR PY 2010 VL 164 IS 3 BP 293 EP 294 PG 2 WC Pediatrics SC Pediatrics GA 562IA UT WOS:000275042300015 PM 20194266 ER PT J AU Chen, SL Bih, LI Chen, GD Huang, YH You, YH Lew, HL AF Chen, Sung-Lang Bih, Liu-Ing Chen, Gin-Den Huang, Yu-Hui You, Ya-Hui Lew, Henry L. TI Transrectal Ultrasound-Guided Transperineal Botulinum Toxin A Injection to the External Urethral Sphincter for Treatment of Detrusor External Sphincter Dyssynergia in Patients With Spinal Cord Injury SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Autonomic dysreflexia; Botulinum toxins; Rehabilitation; Ultrasonography; Urinary bladder; Urodynamics ID FOLLOW-UP; DYSFUNCTION; DISEASE; MUSCLE; MEN AB Chen S-L, Bih L-T, Chen G-I), Huang Y-H, You Y-H, Lew HL. Transrectal ultrasound guided transperineal botulinum toxin A injection to the external urethral sphincter for treatment of detrusor external sphincter dyssynergia in patients with spinal cord injury. Arch Phys Med Rehabil 2010;91:340-4. Objective: To evaluate the effects of a single transrectal ultrasound (TRUS)-guided transperineal injection of botulinum toxin A (BTX-A) to the external urethral sphincter (EUS) for treating detrusor external sphincter dyssynergia (DESD). Design: Descriptive study. Setting: Rehabilitation hospital affiliated with a medical university. Participants: Patients (N=18) with suprasacral spinal cord injury who had DESD confirmed on video-urodynamic study. Interventions: A single dose of 100U BTX-A was applied into the EUS via TRUS-guided transperineal route injection. Main Outcome Measures: Maximal detrusor pressure, detrusor leak-point pressure, integrated electromyography (iEMG), maximal pressure on static urethral pressure profilometry, and postvoiding residuals. Results: There were significant reductions in iEMG (P=.008) and static (P=.012) and dynamic urethral pressure (P=.023), but not in detrusor pressure and detrusor leak-point pressure after treatment. Postvoiding residuals also significantly decreased in the first and second month after treatment (P<.012). Conclusions: TRUS-guided transperineal injection of BTX-A has beneficial effects in treating DESD. C1 [Bih, Liu-Ing; Huang, Yu-Hui] Chung Shan Med Univ, Dept Phys Med & Rehabil, Chung Shan Med Univ Hosp, Sch Med, Taichung 406, Taiwan. [Chen, Sung-Lang] Chung Shan Med Univ, Dept Urol, Chung Shan Med Univ Hosp, Sch Med, Taichung 406, Taiwan. [Chen, Gin-Den] Chung Shan Med Univ, Dept Obstet & Gynecol, Chung Shan Med Univ Hosp, Sch Med, Taichung 406, Taiwan. [You, Ya-Hui] Taipei City Hosp, Dept Nursing, Zhongxiao Branch, Taipei, Taiwan. [Lew, Henry L.] VA Boston Healthcare Syst, Phys Med & Rehabil Serv, Boston, MA USA. RP Huang, YH (reprint author), Chung Shan Med Univ, Dept Phys Med & Rehabil, 1142 Sect 3,Tay Yuan Rd, Taichung 406, Taiwan. EM yhhuang59@hotmail.com FU National Science Council of the Republic of China [NSC 972314B040003] FX Supported by the National Science Council of the Republic of China (grant no. NSC NSC 972314B040003). NR 34 TC 8 Z9 11 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAR PY 2010 VL 91 IS 3 BP 340 EP 344 DI 10.1016/j.apmr.2009.11.006 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 592YM UT WOS:000277417900002 PM 20298821 ER PT J AU Hula, WD Doyle, PJ Hula, SNA AF Hula, William D. Doyle, Patrick J. Hula, Shannon N. Austermann TI Patient-Reported Cognitive and Communicative Functioning: 1 Construct or 2? SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Communication disorders; Patient outcomes assessment; Rehabilitation; Stroke ID FIT STATISTICS; ITEM BANKS; SCALE; STROKE; RELIABILITY; VALIDITY; OUTCOMES; SCORE; UNIDIMENSIONALITY; DIMENSIONALITY AB Hula WD, Doyle PJ, Austermann Hula SN. Patient-reported cognitive and communicative functioning: 1 construct or 2? Arch Phys Med Rehabil 2010;91:400-6. Objectives: To examine the dimensionality of scales for measuring patient-reported cognitive and communicative functioning in a sample of stroke survivors and to evaluate the consequences for measurement of treating them as a single, undifferentiated construct. Design: Secondary analysis of existing cross-sectional data. Setting: Data were collected in outpatient rehabilitation clinics and in the community. Participants: Unilateral stroke survivors (N=316) 3 months or more postonset referred for participation in research. Interventions: Not applicable. Main Outcome Measures: The Burden of Stroke Scale cognition and communication domain scales were evaluated by using confirmatory factor analysis. Rasch analysis, and tests of differential item functioning (DIF). To evaluate the impact of multidimensionality on the measurement of individual patients, separately estimated cognition and communication scores were compared. Combined and separately estimated scores were also examined for responsiveness to group differences in the presence of cognitive and communicative impairment. Results: Factor analysis and Rasch model fit analyses equivocally supported the unidimensionality of the item pool. DIF analyses between participants with right versus left hemisphere stroke suggested multidimensionality. Scaling cognition and communication items separately resulted in different person scores for a significant number of patients and greater responsiveness to group differences. Conclusions: Patient-reported scales assessing communication along with more general cognitive activities may possess an internal structure that is inconsistent with a unidimensional measurement model with potential negative consequences for measurement. C1 [Hula, William D.; Doyle, Patrick J.; Hula, Shannon N. Austermann] VA Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA 15206 USA. [Hula, William D.; Doyle, Patrick J.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. RP Hula, WD (reprint author), VA Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, 7180 Highland Dr,132A-H, Pittsburgh, PA 15206 USA. EM William.Hula@va.gov FU Veterans Affairs Rehabilitation Research and Development (VA RRD); Veterans Affairs Rehabilitation Research and Development [C2386R]; [C6210M] FX Supported by the Veterans Affairs Rehabilitation Research and Development (VA RR&D) Career Development Award (grant no. C6210M) and the Veterans Affairs Rehabilitation Research and Development Merit Review Award (grant no. C2386R). NR 41 TC 3 Z9 3 U1 2 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAR PY 2010 VL 91 IS 3 BP 400 EP 406 DI 10.1016/j.apmr.2009.11.013 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 592YM UT WOS:000277417900012 PM 20298831 ER PT J AU Monach, PA Nigrovic, PA Chen, M Hock, H Lee, DM Benoist, C Mathis, D AF Monach, Paul A. Nigrovic, Peter A. Chen, Mei Hock, Hanno Lee, David M. Benoist, Christophe Mathis, Diane TI Neutrophils in a Mouse Model of Autoantibody-Mediated Arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; ANTIBODY-INDUCED ARTHRITIS; TUMOR-NECROSIS-FACTOR; II COLLAGEN ANTIBODY; TRANSCRIPTION FACTOR GFI-1; INFL AMMATORY ARTHRITIS; RECEPTOR GAMMA-CHAIN; MAST-CELLS; INFLAMMATORY ARTHRITIS; RHEUMATOID-ARTHRITIS AB Objective. Neutrophils represent a prominent component of inflammatory joint effusions and are required for synovial inflammation in mouse models, but the mechanisms are poorly understood. In this study, we developed a system with which to test the importance of the production of specific factors by neutrophils in a mouse model of arthritis. Methods. Neutrophil-deficient Gfi-1(-/-) mice were administered sublethal doses of radiation and were then engrafted with donor bone marrow cells (BMCs), which resulted in the production of mature neutrophils within 2 weeks. By reconstituting with BMCs from mice lacking selected proinflammatory factors, we generated mice that specifically lacked these factors on their neutrophils. Arthritis was initiated by transfer of K/BxN serum to identify the role of defined neutrophil factors on the incidence and severity of arthritis. Results. Neutrophils lacking the signaling chain of stimulatory Fc receptors (FcR gamma(-/-)) were unable to elicit arthritis, but neutrophils lacking Fc gamma RIII still did so. Neutrophils lacking the chemotactic or adhesion receptor C5a receptor (C5aR) or CD11a/lymphocyte function-associated antigen 1 (LFA-1) also failed to initiate arthritis but could enter joints in which inflammation had been initiated by wild-type neutrophils. Neutrophils unable to produce interleukin-1 alpha (IL-1 alpha) and IL-1 beta (IL-1 alpha/beta(-/-)) or leukotrienes (5-lipoxygenase [5-LOX(-/-)]) produced arthritis of intermediate severity. The inability of neutrophils to make tumor necrosis factor or to express receptors for tumor necrosis factor or IL-1 had no effect on arthritis. Conclusion. A novel transfer system was developed to identify neutrophil production of FcR gamma, C5aR, and CD11a/LFA-1 as critical components of autoantibody-mediated arthritis. Neutrophil production of IL-1 and leukotriene B(4) likely contributes to inflammation but is not essential. Molecular requirements for neutrophil influx into joints become more permissive after inflammation is initiated. C1 [Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Monach, Paul A.; Benoist, Christophe; Mathis, Diane] Brigham & Womens Hosp, Joslin Diabet Ctr, Boston, MA 02115 USA. [Nigrovic, Peter A.; Chen, Mei; Lee, David M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Hock, Hanno] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Benoist, C (reprint author), Harvard Univ, Sch Med, Dept Pathol, 77 Ave Louis Pasteur,NRB 1052, Boston, MA 02115 USA. EM cb@hms.harvard.edu; dm@hms.harvard.edu FU NIH [R01-AR-46580, R01-AR-055271, P01-AI-65858]; National Institute of Diabetes and Digestive and Kidney Diseases; Arthritis Foundation; Young Chair; Abbott Scholar award for Rheumatology Research FX Supported by the NIH (grants R01-AR-46580, R01-AR-055271, and P01-AI-65858) and by the Diabetes and Endocrinology Research Center at Joslin Diabetes Center, which is funded by a core facilities grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Monach's work was supported by an Abbott Scholar award for Rheumatology Research and by an Arthritis Investigator award from the Arthritis Foundation. Drs. Benoist and Mathis's work was supported by funding through the Young Chair. NR 65 TC 52 Z9 53 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD MAR PY 2010 VL 62 IS 3 BP 753 EP 764 DI 10.1002/art.27238 PG 12 WC Rheumatology SC Rheumatology GA 619LR UT WOS:000279432200015 PM 20191628 ER PT J AU Stone, JH Khosroshahi, A Deshpande, V Stone, JR AF Stone, John H. Khosroshahi, Arezou Deshpande, Vikram Stone, James R. TI IgG4-Related Systemic Disease Accounts for a Significant Proportion of Thoracic Lymphoplasmacytic Aortitis Cases SO ARTHRITIS CARE & RESEARCH LA English DT Article ID TERM-FOLLOW-UP; AUTOIMMUNE PANCREATITIS; SCLEROSING DISEASE; ANEURYSM; PERIAORTITIS; CLASSIFICATION; REGURGITATION; DISSECTION; PATHOLOGY; ARTERITIS AB Objective. IgG4-related systemic disease, a disorder recognized only recently, can cause lymphoplasmacytic inflammation in the thoracic aorta. The percentage of cases caused by IgG4-related systemic disease is not known. We aimed to determine the percentage of noninfectious thoracic aortitis cases that are associated with IgG4-related systemic disease and to establish pathologic criteria for identifying involvement of the thoracic aorta by this disorder. Methods. We searched our Pathology Service database to identify patients with noninfectious thoracic aortitis who underwent resection over a 5-year time span. The histologic features of these cases were reviewed. All cases of lymphoplasmacytic aortitis and representative cases of giant cell aortitis and atherosclerosis were stained by immunohistochemistry for IgG4 and for the plasma cell marker CD138. We determined the fraction of plasma cells that stained for IgG4. Results. Of 638 resected thoracic aortas, 33 (5.2%) contained noninfectious aortitis. Four of these cases (12% of all patients with noninfectious aortitis) had histologic features of lymphoplasmacytic aortitis. Three of those 4 cases (9% of the noninfectious aortitis cases) demonstrated pathologic involvement by IgG4-related systemic disease, with an elevated proportion of plasma cells staining for IgG4 (mean +/- SD 0.82 +/- 0.08) compared with cases of giant cell aortitis (0.18 +/- 0.13) and atherosclerosis (0.19 +/- 0.08; P < 0.00001). Conclusion. IgG4-related systemic disease accounted for 75% of lymphoplasmacytic aortitis cases and 9% of all cases of noninfectious thoracic aortitis in our institution during a 5-year period. Immunohistochemical assessment of the percentage of plasma cells that stained for IgG4 in resected aortas was helpful in identifying patients with IgG4-related systemic disease. C1 [Stone, James R.] Massachusetts Gen Hosp, Simches Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Stone, JR (reprint author), Massachusetts Gen Hosp, Simches Res Ctr, 185 Cambridge St,CPZN 8400, Boston, MA 02114 USA. EM jrstone@partners.org NR 39 TC 71 Z9 78 U1 0 U2 5 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 MAR PY 2010 VL 62 IS 3 BP 316 EP 322 DI 10.1002/acr.20095 PG 7 WC Rheumatology SC Rheumatology GA 639MP UT WOS:000280979200005 PM 20391477 ER PT J AU Emkey, GR Stone, JH AF Emkey, Gregory R. Stone, John H. TI A 46-Year-Old Woman With Chin Pain and a Fainting Spell SO ARTHRITIS CARE & RESEARCH LA English DT Article ID LYME-DISEASE; NUMB CHIN; TEMPORAL ARTERITIS; CELL ARTERITIS; CARDITIS C1 [Emkey, Gregory R.; Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Emkey, GR (reprint author), Massachusetts Gen Hosp, Bulfinch Bldg,Room 165,55 Fruit St, Boston, MA 02114 USA. EM gemkey@partners.org NR 23 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAR PY 2010 VL 62 IS 3 BP 434 EP 438 DI 10.1002/acr.20093 PG 5 WC Rheumatology SC Rheumatology GA 639MP UT WOS:000280979200020 PM 20391493 ER PT J AU Hodi, FS AF Hodi, F. Stephen TI Overcoming immunological tolerance to melanoma: Targeting CTLA-4 SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Review DE antibodies; combination therapy; CTLA-4; immunotherapy; melanoma ID CYTOTOXIC-T-LYMPHOCYTE; TUMOR-INFILTRATING LYMPHOCYTES; ANTIGEN-4 MONOCLONAL-ANTIBODY; PHASE-I TRIAL; METASTATIC MELANOMA; IMMUNE-RESPONSE; BLOCKADE; AUTOIMMUNITY; CANCER; IMMUNOTHERAPY AB The use of immunotherapeutics in melanoma has received much attention, and recent advances to further characterize the regulatory components of the immune system and the importance of co-stimulatory molecules have opened a new area for clinical investigation. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves as a negative regulator of immunity. Recent trials administering fully human anti-CTLA-4 monoclonal antibodies to melanoma patients have demonstrated clinically meaningful responses. Treatment with CTLA-4 blocking antibodies, however, is not without potential toxicities. Autoimmune side-effects, the most common being colitis-associated diarrhea, are frequently associated with clinical responses. In efforts to build upon prior vaccination efforts as well as attempt to offer patients clinically meaningful immune responses with a CTLA-4 blockade but without significant toxicities, we conducted a clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GVAX; Cell Genesys, South San Francisco, CA, USA) with periodic infusions of CTLA-4 blocking antibodies. This sequential treatment resulted in clinically significant anti-tumor immunity without grade 3 or 4 toxicity in most patients. Pathological analyses following treatment of pre-existing tumors revealed a linear correlation between tumor necrosis and the ratio of intra-tumoral CD8+ effector cells to FoxP3+ regulatory cells (T(regs)). Effective anti-tumor immunity and serious autoimmunity can be disassociated. Further targeting of anti-tumor T(regs)in combinatorial therapy approaches may be a rich avenue of future investigation. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM stephen_hodi@dfci.harvard.edu NR 38 TC 12 Z9 12 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1743-7555 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD MAR PY 2010 VL 6 SU 1 BP S16 EP S26 DI 10.1111/j.1743-7563.2010.01271.x PG 11 WC Oncology SC Oncology GA 563MO UT WOS:000275136800003 PM 20482528 ER PT J AU Betjemann, RS Johnson, EP Barnard, H Boada, R Filley, CM Filipek, PA Willcutt, EG DeFries, JC Pennington, BF AF Betjemann, Rebecca S. Johnson, Erin Phinney Barnard, Holly Boada, Richard Filley, Christopher M. Filipek, Pauline A. Willcutt, Erik G. DeFries, John C. Pennington, Bruce F. TI Genetic Covariation Between Brain Volumes and IQ, Reading Performance, and Processing Speed SO BEHAVIOR GENETICS LA English DT Article DE Twin design; MRI; Brain volume; Intelligence; Processing speed; Reading ID ENVIRONMENTAL-INFLUENCES; WORKING-MEMORY; PHONOLOGICAL AWARENESS; INSPECTION TIME; HUMAN NEOCORTEX; WHITE-MATTER; INTELLIGENCE; VARIABILITY; DISABILITY; MRI AB Although there has been much interest in the relation between brain size and cognition, few studies have investigated this relation within a genetic framework and fewer still in non-adult samples. We analyzed the genetic and environmental covariance between structural MRI data from four brain regions (total brain volume, neocortex, white matter, and prefrontal cortex), and four cognitive measures (verbal IQ (VIQ), performance IQ (PIQ), reading ability, and processing speed), in a sample of 41 MZ twin pairs and 30 same-sex DZ twin pairs (mean age at cognitive test = 11.4 years; mean age at scan = 15.4 years). Multivariate Cholesky decompositions were performed with each brain volume measure entered first, followed by the four cognitive measures. Consistent with previous research, each brain and cognitive measure was found to be significantly heritable. The novel finding was the significant genetic but not environmental covariance between brain volumes and cognitive measures. Specifically, PIQ shared significant common genetic variance with all four measures of brain volume (r (g) = .58-.82). In contrast, VIQ shared significant genetic influence with neocortex volume only (r (g) = .58). Processing speed was significant with total brain volume (r (g) = .79), neocortex (r (g) = .64), and white matter (r (g) = .89), but not prefrontal cortex. The only brain measure to share genetic influence with reading was total brain volume (r (g) = .32), which also shared genetic influences with processing speed. C1 [Betjemann, Rebecca S.] Regis Univ, Dept Psychol, Denver, CO 80221 USA. [Johnson, Erin Phinney; Barnard, Holly; Boada, Richard; Pennington, Bruce F.] Univ Denver, Denver, CO USA. [Boada, Richard; Filley, Christopher M.] Univ Colorado, Denver Sch Med, Denver, CO 80202 USA. [Filley, Christopher M.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Filipek, Pauline A.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Willcutt, Erik G.; DeFries, John C.] Univ Colorado, Boulder, CO 80309 USA. RP Betjemann, RS (reprint author), Regis Univ, Dept Psychol, D-12,3333 Regis Blvd, Denver, CO 80221 USA. EM rbetjema@regis.edu FU NIMH [T32 MH016880-25]; NIH [HD027802] FX Initial work on this paper was done when R. Betjemann was a postdoctoral trainee at the Institute for Behavioral Genetics, University of Colorado, Boulder, CO. This training was funded by NIMH training grant T32 MH016880-25. This project was also funded by NIH grant HD027802 to the Colorado Learning Disabilities Research Center, of which B. Pennington, J. DeFries, and E. Willcutt are Co-PIs. NR 61 TC 14 Z9 14 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD MAR PY 2010 VL 40 IS 2 SI SI BP 135 EP 145 DI 10.1007/s10519-009-9328-2 PG 11 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 561GM UT WOS:000274964000004 PM 20072853 ER PT J AU Saleh, FM Malin, HM Grudzinskas, AJ Vitacco, MJ AF Saleh, Fabian M. Malin, H. Martin Grudzinskas, Albert J., Jr. Vitacco, Michael J. TI Paraphilias with Co-Morbid Psychopathy: The Clinical and Legal Significance to Sex Offender Assessments SO BEHAVIORAL SCIENCES & THE LAW LA English DT Article ID PREDATOR CIVIL COMMITMENT; DIAGNOSTIC RELIABILITY; CHECKLIST; CONSTRUCT; AROUSAL; SADISM AB This article briefly discusses the historical development of the constructs of paraphilia and psychopathy. An overview of recent developments in the assessment of these constructs for legal purposes is also provided. The historical, clinical, legal, and ethical obligations of clinicians who work with persons suffering from paraphilias and comorbid psychopathy is then reviewed. An emphasis of the current article is integrating recent developments in the construct of psychopathy into a discussion of sex offender risk assessment and treatment. The co-morbidity of psychopathy and paraphilias as factors in predicting risk of recidivism is reviewed. The need for practitioners to remain cognizant of language requirements in both legal and clinical contexts is addressed. Finally, this article reviews the legal history of sex offender legislation and its evolution into current United States Supreme Court jurisprudence. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Saleh, Fabian M.] Harvard Univ, Sch Med, Law & Psychiat Serv, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Malin, H. Martin] Inst Adv Study Human Sexual, San Francisco, CA USA. [Malin, H. Martin] Natl Inst Study Prevent & Treatment Sexual Trauma, Baltimore, MD USA. [Grudzinskas, Albert J., Jr.] Univ Massachusetts, Sch Med, Dept Psychiat, Coordinator Legal Studies, Worcester, MA 01655 USA. [Vitacco, Michael J.] Mendota Mental Hlth Inst, Madison, WI USA. RP Saleh, FM (reprint author), Harvard Univ, Sch Med, Law & Psychiat Serv, Massachusetts Gen Hosp, WACC 812,15 Parkman St, Boston, MA 02114 USA. EM fsaleh@partners.org NR 53 TC 5 Z9 5 U1 2 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0735-3936 J9 BEHAV SCI LAW JI Behav. Sci. Law PD MAR-APR PY 2010 VL 28 IS 2 BP 211 EP 223 DI 10.1002/bsl.933 PG 13 WC Psychology, Applied; Law SC Psychology; Government & Law GA 597FU UT WOS:000277742700006 PM 20422646 ER PT J AU Beck, JC AF Beck, James C. TI Dangerous Severe Personality Disorder: The Controversy Continues SO BEHAVIORAL SCIENCES & THE LAW LA English DT Article ID MENTAL-HEALTH; PUBLIC PROTECTION; PSYCHIATRY; PROPOSALS; PEOPLE; ACT AB Following a high profile murder in 1996, the government in England moved to involuntarily contain individuals, almost all men, who were thought to be at risk of violence and to have a personality disorder. In 2008 the Dangerous Severe Personality Disorder program of assessment, commitment and treatment for this newly defined legal category of persons went into effect. The program was initially opposed by a majority of the forensic psychiatrists in England, but consistently supported by a minority. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Beck, James C.] Harvard Univ, Sch Med, Cambridge, MA 02140 USA. [Beck, James C.] Massachusetts Gen Hosp, Law & Psychiat Serv, Cambridge, MA 02140 USA. RP Beck, JC (reprint author), Harvard Univ, Sch Med, 34 Bates St, Cambridge, MA 02140 USA. EM jamesbeck56@gmail.com NR 17 TC 3 Z9 3 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0735-3936 J9 BEHAV SCI LAW JI Behav. Sci. Law PD MAR-APR PY 2010 VL 28 IS 2 BP 277 EP 288 DI 10.1002/bsl.931 PG 12 WC Psychology, Applied; Law SC Psychology; Government & Law GA 597FU UT WOS:000277742700010 PM 20422650 ER PT J AU Fabbro, D Manley, PW Jahnke, W Liebetanz, J Szyttenholm, A Fendrich, G Strauss, A Zhang, JM Gray, NS Adrian, F Warmuth, M Pelle, X Grotzfeld, R Berst, F Marzinzik, A Cowan-Jacob, SW Furet, P Mestan, J AF Fabbro, Doriano Manley, Paul W. Jahnke, Wolfgang Liebetanz, Janis Szyttenholm, Alexandra Fendrich, Gabriele Strauss, Andre Zhang, Jianming Gray, Nathanael S. Adrian, Francisco Warmuth, Markus Pelle, Xavier Grotzfeld, Robert Berst, Frederic Marzinzik, Andreas Cowan-Jacob, Sandra W. Furet, Pascal Mestan, Juergen TI Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article; Proceedings Paper CT 6th International Conference on Inhibitors of Protein Kinases ( IPK 2009) CY JUN 27-JUL 01, 2009 CL Warsaw, POLAND DE Abl; Imatinib resistance; Myristate binders; Kinase inhibitors; Abl structure ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL; PROTEIN-KINASES; C-ABL; STRUCTURAL BIOLOGY; TYROSINE KINASES; RESISTANCE; IMATINIB; MUTATION AB The ATP-competitive inhibitors dasatinib and nilotinib, which bind to catalytically different conformations of the Abl kinase domain, have recently been approved for the treatment of imatinib-resistant CML These two new drugs, albeit very efficient against most of the imatinib-resistant mutants of Bcr-Abl, fail to effectively suppress the Bcr-Abl activity of the T3151 (or gatekeeper) mutation. Generating new ATP site-binding drugs that target the T3151 in Abl has been hampered, amongst others, by target selectivity, which is frequently an issue when developing ATP-competitive inhibitors. Recently, using an unbiased cellular screening approach, GNF-2, a non-ATP-competitive inhibitor, has been identified that demonstrates cellular activity against Bcr-Abl transformed cells. The exquisite selectivity of GNF-2 is due to the finding that it targets the myristate binding site located near the C-terminus of the Abl kinase domain, as demonstrated by genetic approaches, solution NMR and X-ray crystallography. GNF-2, like myristate, is able to induce and/or stabilize the clamped inactive conformation of AN analogous to the SH2-Y527 interaction of Src. The molecular mechanism for allosteric inhibition by the GNF-2 inhibitor class, and the combined effects with ATP-competitive inhibitors such as nilotinib and imatinib on wild-type Abl and imatinib-resistant mutants, in particular the T3151 gatekeeper mutant, are reviewed. (C) 2010 Elsevier B.V. All rights reserved. C1 [Fabbro, Doriano; Manley, Paul W.; Jahnke, Wolfgang; Liebetanz, Janis; Szyttenholm, Alexandra; Fendrich, Gabriele; Strauss, Andre; Warmuth, Markus; Pelle, Xavier; Grotzfeld, Robert; Berst, Frederic; Marzinzik, Andreas; Cowan-Jacob, Sandra W.; Furet, Pascal; Mestan, Juergen] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland. [Adrian, Francisco] GNF, La Jolla, CA USA. [Zhang, Jianming; Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Fabbro, D (reprint author), Novartis Inst BioMed Res, CH-4002 Basel, Switzerland. EM doriano.fabbro@novartis.com NR 46 TC 30 Z9 30 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD MAR PY 2010 VL 1804 IS 3 SI SI BP 454 EP 462 DI 10.1016/j.bbapap.2009.12.009 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 559ZX UT WOS:000274872500006 PM 20152788 ER PT J AU Eck, MJ Yun, CH AF Eck, Michael J. Yun, Cai-Hong TI Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article; Proceedings Paper CT 6th International Conference on Inhibitors of Protein Kinases ( IPK 2009) CY JUN 27-JUL 01, 2009 CL Warsaw, POLAND DE Tyrosine kinase; Epidermal growth factor receptor; X-ray crystallography; Gefitinib; Lung cancer; Drug resistance ID GROWTH-FACTOR-RECEPTOR; TYROSINE KINASE INHIBITORS; CHRONIC MYELOID-LEUKEMIA; ACQUIRED-RESISTANCE; CLINICAL-RESPONSE; BCR-ABL; GEFITINIB; MUTANTS; DOMAIN; ACTIVATION AB EGFR and other ErbB-family tyrosine kinases are overexpressed in many human tumors, and their aberrant expression and mutational activation is associated with the development, progression and aggressiveness of a number of malignancies. Thus the EGFR kinase has long been recognized as a potential drug target in oncology, and small-molecule inhibitors have been under development for more than two decades. As a result of their effectiveness in treating non-small cell lung cancers (NSCLCs) driven by somatic mutations in the EGFR kinase, gefitinib and erlotinib were the first EGFR tyrosine kinase inhibitors (TKIs) approved for clinical use. Ironically, these drugs found their target against mutant forms of the EGFR kinase, which have altered enzyme active sites, and not against the wild type (WT) kinase against which their potency and selectivity was carefully honed. Here we review recent structural and enzymological studies that explore the exquisite sensitivity of a subset of these lung cancer mutants to gefitinib and erlotinib. We discuss available structural evidence for the mechanisms of activation of the EGFR kinase by these mutants, and compare it to physiologic activation of the kinase by ligand-induced dimerization. Finally, we consider the mechanisms by which the secondary T790M "gatekeeper" mutation confers resistance to gefitinib and erlotinib. (C) 2009 Elsevier B.V. All rights reserved. C1 [Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Eck, MJ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 44 Binney St, Boston, MA 02115 USA. EM eck@red.dfci.harvard.edu FU NCI NIH HHS [R01 CA080942, R01 CA116020-05, R01 CA080942-08, R01 CA080942-06A1, R01 CA116020, R01 CA080942-10, R01 CA080942-09, R01 CA116020-04, R01 CA080942-07, R01 CA116020-01A1, R01 CA116020-03, R01 CA116020-02]; NHLBI NIH HHS [P01 HL048675-170012, P01 HL048675-150012, P01 HL048675-160012, P01 HL048675-140012, P01 HL048675-130012, P01 HL048675] NR 40 TC 52 Z9 55 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 EI 0006-3002 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD MAR PY 2010 VL 1804 IS 3 SI SI BP 559 EP 566 DI 10.1016/j.bbapap.2009.12.010 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 559ZX UT WOS:000274872500019 PM 20026433 ER PT J AU Shoemaker, LD Arlotta, P AF Shoemaker, Lorelei D. Arlotta, Paola TI Untangling the cortex: Advances in understanding specification and differentiation of corticospinal motor neurons SO BIOESSAYS LA English DT Review DE Bhlhb5; Clim1; corticospinal motor neurons (CSMN); Crim1; Ctip2; Diap3; FACS; Fezf2; Mu-Crystallin; Satb2; Sox5; subcerebral projection neurons ID DEVELOPING CEREBRAL-CORTEX; TRANSLATIONAL PROFILING APPROACH; SUBCORTICAL PROJECTION NEURONS; SUBTYPE-SPECIFIC GENES; SPINAL-CORD-INJURY; PAX6 MUTANT MICE; CNS CELL-TYPES; MAMMALIAN TELENCEPHALON; INTERNEURON DIVERSITY; CORTICAL INTERNEURONS AB The mature cerebral cortex contains a staggering variety of projection neuron subtypes, and a number of complementary studies have recently begun to define their identity and embryonic origin. Among the different types of cortical projection neurons, subcerebral projection neurons, including corticospinal motor neurons (CSMN), have been extensively studied and some of the molecular controls over their differentiation have been elucidated. Here, we first provide an overview of the approaches used to purify and molecularly profile neuronal populations of the neocortex and, more broadly, of the central nervous system (CNS). Next, we specifically review recent progress in understanding the genes that define and control development of the CSMN population. Finally, we briefly discuss the relevance of this work to current questions regarding the mechanisms of the establishment of projection neuron subtype identity in the neocortex and its implications to direct the differentiation of CSMN for therapeutic benefit. C1 [Shoemaker, Lorelei D.; Arlotta, Paola] Harvard Univ, Ctr Regenerat Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Shoemaker, Lorelei D.; Arlotta, Paola] Harvard Univ, Dept Neurosurg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Arlotta, Paola] Harvard Univ, Dept Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Arlotta, Paola] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Arlotta, P (reprint author), Harvard Univ, Ctr Regenerat Med, Massachusetts Gen Hosp, Sch Med, Simches Res Bldg,Room 4238,185 Cambridge St, Boston, MA 02114 USA. EM paola_arlotta@hms.harvard.edu FU NIH [NS062849]; Harvard Stem Cell Institute; Spastic Paraplegia Foundation; William Randolph Hearst Fellowship FX We would like to thank Zachary Trayes-Gibson, Simona Lodato, Caroline Rouaux, and Eiman Azim for their Suggestions and critical reading. This work was partially supported by the NIH (NS062849), the Harvard Stem Cell Institute and the Spastic Paraplegia Foundation to P A.; L. D. S. was partially supported by a William Randolph Hearst Fellowship. NR 105 TC 15 Z9 15 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD MAR PY 2010 VL 32 IS 3 BP 197 EP 206 DI 10.1002/bies.200900114 PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 568FY UT WOS:000275508900003 PM 20108227 ER PT J AU Rimol, LM Panizzon, MS Fennema-Notestine, C Eyler, LT Fischl, B Franz, CE Hagler, DJ Lyons, MJ Neale, MC Pacheco, J Perry, ME Schmitt, JE Grant, MD Seidman, LJ Thermenos, HW Tsuang, MT Eisen, SA Kremen, WS Dale, AM AF Rimol, Lars M. Panizzon, Matthew S. Fennema-Notestine, Christine Eyler, Lisa T. Fischl, Bruce Franz, Carol E. Hagler, Donald J. Lyons, Michael J. Neale, Michael C. Pacheco, Jennifer Perry, Michele E. Schmitt, J. Eric Grant, Michael D. Seidman, Larry J. Thermenos, Heidi W. Tsuang, Ming T. Eisen, Seth A. Kremen, William S. Dale, Anders M. TI Cortical Thickness Is Influenced by Regionally Specific Genetic Factors SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cortical thickness; endophenotypes; genetic correlation; heritability; imaging genetics; MRI; twins ID POSTTRAUMATIC-STRESS-DISORDER; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; HUMAN BRAIN STRUCTURE; COORDINATE SYSTEM; MRI; TWIN; RELIABILITY; RECONSTRUCTION; SEGMENTATION AB Background: Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally specific sets of genes. Methods: We mapped the heritability of cortical thickness throughout the brain using three-dimensional structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface. Results: There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions. Conclusions: These results provide strong evidence of regionally specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders and normal and pathological cognitive aging. C1 [Panizzon, Matthew S.; Fennema-Notestine, Christine; Eyler, Lisa T.; Franz, Carol E.; Perry, Michele E.; Tsuang, Ming T.; Kremen, William S.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Rimol, Lars M.; Fennema-Notestine, Christine; Hagler, Donald J.; Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Rimol, Lars M.] Ulleval Univ, Div Psychiat, Oslo, Norway. Univ Oslo, Inst Psychiat, Oslo, Norway. [Eyler, Lisa T.; Tsuang, Ming T.; Kremen, William S.] Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA. [Fischl, Bruce; Pacheco, Jennifer] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyons, Michael J.; Grant, Michael D.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Psychiat & Human Genet, Richmond, VA 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. [Tsuang, Ming T.; Kremen, William S.] Univ Calif San Diego, Ctr Behav Genom, La Jolla, CA 92093 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 Neurosci, La Jolla, CA 92093 USA. RP Kremen, WS (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr,Mail Code 0738, La Jolla, CA 92093 USA. EM wkremen@ucsd.edu RI Lyons, Michael/B-6119-2011; OI Lyons, Michael/0000-0001-6516-9219; Rimol, Lars M./0000-0002-1243-0396; Fennema-Notestine, Christine/0000-0002-6527-6361 FU NCRR NIH HHS [R01 RR016594, S10 RR019307]; NIA NIH HHS [R01 AG031224, AG018384, AG018386, AG022381, AG022982, R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; NIBIB NIH HHS [R01 EB006758]; NINDS NIH HHS [R01 NS039581, R01 NS052585, R21 NS072652] NR 47 TC 63 Z9 63 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2010 VL 67 IS 5 BP 493 EP 499 DI 10.1016/j.biopsych.2009.09.032 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 563BL UT WOS:000275100300014 PM 19963208 ER PT J AU Ballen, KK Shrestha, S Sobocinski, KA Zhang, MJ Bashey, A Bolwell, BJ Cervantes, F Devine, SM Gale, RP Gupta, V Hahn, TE Hogan, WJ Kroger, N Litzow, MR Marks, DI Maziarz, RT McCarthy, PL Schiller, G Schouten, HC Roy, V Wiernik, PH Horowitz, MM Giralt, SA Arora, M AF Ballen, Karen K. Shrestha, Smriti Sobocinski, Kathleen A. Zhang, Mei-Jie Bashey, Asad Bolwell, Brian J. Cervantes, Francisco Devine, Steven M. Gale, Robert Peter Gupta, Vikas Hahn, Theresa E. Hogan, William J. Kroeger, Nicolaus Litzow, Mark R. Marks, David I. Maziarz, Richard T. McCarthy, Philip L. Schiller, Gary Schouten, Harry C. Roy, Vivek Wiernik, Peter H. Horowitz, Mary M. Giralt, Sergio A. Arora, Mukta TI Outcome of Transplantation for Myelofibrosis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Myelofibrosis; Allogeneic transplantation ID STEM-CELL TRANSPLANTATION; UNRELATED DONOR TRANSPLANTATION; AGNOGENIC MYELOID METAPLASIA; INTERNATIONAL-WORKING-GROUP; IDIOPATHIC MYELOFIBROSIS; ALLOGENEIC TRANSPLANTATION; MARROW-TRANSPLANTATION; PROGNOSTIC-FACTORS; GRUPPO-ITALIANO; SCORING SYSTEM AB Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients. Biol Blood Marrow Transplant 16: 358-367 (