FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Lindenhovious, ALC Helmerhorts, GTT Schnellen, AC Vrahas, M Ring, D Kloen, P AF Lindenhovious, Anneluuk L. C. Helmerhorts, Gijs T. T. Schnellen, Alexandra C. Vrahas, Mark Ring, David Kloen, Peter TI Differences in Prescription of Narcotic Pain Medication After Operative Treatment of Hip and Ankle Fractures in the United States and the Netherlands SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article DE Narcotics; Pain medication; Hip; Ankle; Fractures ID ADULT ATTACHMENT; ANALGESIA; SURGERY; DISABILITY; REPLACEMENT; PREDICTORS; DICLOFENAC; INTENSITY; KETOROLAC; DISTRESS AB Background: Interactions between American and Dutch surgeons suggested differences in prescription habits for pain medication after fracture treatment. Methods: The percentages of 190 American [100 after hip open reduction and interal fixation (ORIF) and 90 after ankle ORIF] and 116 Dutch patients (69 after hip ORIF and 47 after ankle ORIF) receiving inpatient and outpatient prescriptions for narcotics were retrospectively compared between countries, to test the hypothesis that narcotics are prescribed more frequently in the United States as compared with the Netherlands after operative fracture treatment. Results: Among patients with hip fractures, 85% of American and 58% of Dutch patients were prescribed narcotics during hospitalization (P < 0.001). After discharge, 77% of American and none of the Dutch patients were prescribed narcotics (p < 0.001). The multivariate model including country accounted for 11% of the variation in inpatient narcotic prescription (P < 0.001), and the model including country and surgeon accounted for 55% of the variation in outpatient narcotic prescription (p < 0.001). Among patients with ankle fracture, 98% of American and 64% of Dutch patients were prescribed narcotics during hospitalization (p < 0.001). After discharge, 82% of American patients and 6% of Dutch patients were prescribed narcotics (p < 0.001). Predictors included country and surgeon and they accounted for 20% of the variation in inpatient narcotics prescription (p < 0.001) and 49% of the variation in outpatient narcotic prescription (p < 0.001). Conclusions: American patients are prescribed significantly more inpatient and outpatient narcotic pain medication than Dutch patients after operative treatment of hip and ankle fractures. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. RP Ring, D (reprint author), Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 30 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD JUL PY 2009 VL 67 IS 1 BP 160 EP 164 DI 10.1097/TA.0b013e31818c12ee PG 5 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 470CZ UT WOS:000267953100029 PM 19590328 ER PT J AU Mimiaga, MJ Reisner, SL Cranston, K Isenberg, D Bright, D Daffin, G Bland, S Driscoll, MA VanDerwarker, R Vega, B Mayer, KH AF Mimiaga, Matthew J. Reisner, Sari L. Cranston, Kevin Isenberg, Deborah Bright, Donna Daffin, Gary Bland, Sean Driscoll, Maura A. VanDerwarker, Rodney Vega, Benny Mayer, Kenneth H. TI Sexual Mixing Patterns and Partner Characteristics of Black MSM in Massachusetts at Increased Risk for HIV Infection and Transmission SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE HIV/AIDS; STD; African American/Black; MSM; Prevention ID PERCEIVED SOCIAL SUPPORT; AFRICAN-AMERICAN MEN; UNITED-STATES; GAY MEN; CAGE QUESTIONNAIRE; PSYCHOMETRIC EVALUATION; MULTIDIMENSIONAL SCALE; TRANSMITTED-DISEASES; HIDDEN POPULATIONS; ANAL INTERCOURSE AB Black men who have sex with men (MSM) are at increased risk for HIV infection in the United States compared to other MSM. The aim of this study was to investigate Black MSM's sexual mixing patterns and partner characteristics in relation to sexual risk taking, as a possible explanation for this observed increase in HIV incidence. Between January and July 2008, 197 Black MSM were recruited via modified respondent-driven sampling and completed optional pretest and post-test HIV serological testing, counseling, and a demographic, behavioral, and psychosocial assessment battery. Bivariate and multivariable logistic regression procedures were used to examine predictors of risky sex across partner types. Overall, 18% of the sample was HIV-infected; 50% reported unprotected intercourse with men, 30% with women, and 5% with transgender partners. Fifty-three percent identified as bisexual or straight, although all reported oral or anal sex with another man in the prior 12 months. Significant predictors of engaging in at least one episode of: (1) serodiscordant unprotected anal sex (UAS) with a male partner in the past 12 months: individuals at risk for social isolation (AOR = 4.23; p = 0.03), those with unstable housing (AOR = 4.19; p = 0.03), and those who used poppers at least weekly during sex (AOR = 5.90; p = 0.05); (2) UAS and/or unprotected vaginal intercourse with a female partner in the past 12 months: those with unstable housing (AOR = 4.85; p = 0.04), those who used cocaine at least weekly during sex (AOR = 16.78; p = 0.006), being HIV-infected (AOR = 0.07; p = 0.02), and feeling social norms favor condom use (AOR = 0.60; p = 0.05); (3) UAS with the participants' most recent nonmain male sex partner: use of alcohol and drugs during last sex by participant (AOR = 4.04; p = 0.01), having sex with a Hispanic/Latino male (AOR = 2.71; p = 0.04) or a Black male (AOR = 0.50; p = 0.05) compared to a White male, and lower education (AOR = 1.31; p = 0.02). Findings suggest that sexual risk behaviors of Black MSM differ across partner type and by the characteristics of their sexual networks and that this subpopulation of MSM are at high risk for HIV acquisition and transmission. Effective prevention strategies need to address the distinct sexual and behavioral risk patterns presented by different sexual partnerships reported by Black MSM. C1 [Mimiaga, Matthew J.; Reisner, Sari L.; Bland, Sean; VanDerwarker, Rodney; Vega, Benny; Mayer, Kenneth H.] Fenway Community Hlth, Fenway Inst, Boston, MA 02215 USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Cranston, Kevin; Isenberg, Deborah; Driscoll, Maura A.] Massachusetts Dept Publ Hlth, Boston, MA USA. [Bright, Donna] Justice Resource Inst, Boston, MA USA. [Daffin, Gary] Multicultural AIDS Coalit, Boston, MA USA. [Mayer, Kenneth H.] Miriam Hosp, Brown Med Sch, Providence, RI 02906 USA. RP Mimiaga, MJ (reprint author), Fenway Community Hlth, Fenway Inst, 1340 Boylston St, Boston, MA 02215 USA. EM mmimiaga@fenwayhealth.org FU National Institute on Drug Abuse [R03DA023393] FX This work was funded by the HIV/AIDS Bureau, Massachusetts Department of Public Health. Some of the investigator time on this project was support by grant number R03DA023393 from the National Institute on Drug Abuse (PI: M. Mimiaga). The content is solely the responsibility of the authors and does not necessarily represent the of. cial views of the National Institutes of Health. NR 70 TC 53 Z9 55 U1 3 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD JUL PY 2009 VL 86 IS 4 BP 602 EP 623 DI 10.1007/s11524-009-9363-6 PG 22 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 465MW UT WOS:000267592500009 PM 19466554 ER PT J AU Olumi, AF AF Olumi, Aria F. TI Predictive Value of Combined Immunohistochemical Markers in Patients With pT1 Urothelial Carcinoma at Radical Cystectomy EDITORIAL COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Olumi, AF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2009 VL 182 IS 1 BP 84 EP 84 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 457RI UT WOS:000266949800025 ER PT J AU Rudolph, JL Marcantonio, ER Culley, DJ Silverstein, JH Rasmussen, LS Crosby, GJ Inouye, SK AF Rudolph, J. L. Marcantonio, E. R. Culley, D. J. Silverstein, J. H. Rasmussen, L. S. Crosby, G. J. Inouye, S. K. TI Delirium is Associated With Early Postoperative Cognitive Dysfunction Editorial Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Rudolph, J. L.; Marcantonio, E. R.; Culley, D. J.; Silverstein, J. H.; Rasmussen, L. S.; Crosby, G. J.; Inouye, S. K.] Harvard Univ, Brigham & Womens Hosp, Div Aging,Med Sch, VA Boston Healthcare Syst,Geriatr Educ & Clin Ctr, Boston, MA 02115 USA. RP Rudolph, JL (reprint author), Harvard Univ, Brigham & Womens Hosp, Div Aging,Med Sch, VA Boston Healthcare Syst,Geriatr Educ & Clin Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2009 VL 182 IS 1 BP 187 EP 187 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 457RI UT WOS:000266949800080 ER PT J AU Haynes, AB Weiser, TG Berry, WR Lipsitz, SR Breizat, AH Dellinger, EP Herbosa, T Joseph, S Kibatala, PL Lapitan, MC Merry, AF Moorthy, K Reznick, RK Taylor, B Gawande, AA AF Haynes, A. B. Weiser, T. G. Berry, W. R. Lipsitz, S. R. Breizat, A. H. Dellinger, E. P. Herbosa, T. Joseph, S. Kibatala, P. L. Lapitan, M. C. Merry, A. F. Moorthy, K. Reznick, R. K. Taylor, B. Gawande, A. A. CA Safe Surg Saves Lives Study Grp TI A Surgical Safety Checklist to Reduce Morbidity and Mortality in a Global Population Editorial Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Haynes, A. B.; Weiser, T. G.; Berry, W. R.; Lipsitz, S. R.; Breizat, A. H.; Dellinger, E. P.; Herbosa, T.; Joseph, S.; Kibatala, P. L.; Lapitan, M. C.; Merry, A. F.; Moorthy, K.; Reznick, R. K.; Taylor, B.; Gawande, A. A.; Safe Surg Saves Lives Study Grp] Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Haynes, AB (reprint author), Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, 665 Huntington Ave, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2009 VL 182 IS 1 BP 262 EP 262 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 457RI UT WOS:000266949800111 ER PT J AU Malloy, PC Grassi, CJ Kundu, S Gervais, DA Miller, DL Osnis, RB Postoak, DW Rajan, DK Sacks, D Schwartzberg, MS Zuckerman, DA Cardella, JF AF Malloy, Patrick C. Grassi, Clement J. Kundu, Sanjoy Gervais, Debra Ann Miller, Donald L. Osnis, Robert B. Postoak, Darren W. Rajan, Dheeraj K. Sacks, David Schwartzberg, Marc S. Zuckerman, Darryl A. Cardella, John F. CA Stand Practice Committee TI Consensus Guidelines for Periprocedural Management of Coagulation Status and Hemostasis Risk in Percutaneous Image-guided Interventions SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID CENTRAL VENOUS CATHETERS; LUMBAR PUNCTURE; LIVER-BIOPSY; THROMBOCYTOPENIC PATIENTS; PLATELET TRANSFUSION; SUBCUTANEOUS PHYTONADIONE; ANTITHROMBOTIC THERAPY; CANCER-PATIENT; ACUTE-LEUKEMIA; REVERSAL C1 [Malloy, Patrick C.] Hartford Hosp, Div Vasc & Intervent Radiol, Hartford, CT 06106 USA. [Grassi, Clement J.] VAMC Boston, Boston Healthcare Syst, Dept Radiol, Boston, MA USA. [Kundu, Sanjoy] Scarborough Gen Hosp, Dept Med Imaging, Richmond Hill, ON, Canada. [Gervais, Debra Ann] Massachusetts Gen Hosp, GI GU Div, Dept Radiol, Boston, MA 02114 USA. [Miller, Donald L.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. [Miller, Donald L.] Natl Naval Med Ctr, Dept Radiol, Bethesda, MD USA. [Osnis, Robert B.] RADIA, Everett, WA USA. [Postoak, Darren W.] Univ Florida, Dept Radiol, Gainesville, FL 32610 USA. [Rajan, Dheeraj K.] Univ Toronto, Univ Hlth Network, Div Vasc & Intervent Radiol, Dept Med Imaging, Toronto, ON, Canada. [Sacks, David] Reading Hosp Med Ctr, Dept Intervent Radiol, W Reading, PA USA. [Schwartzberg, Marc S.] Radiol Associates Cent Florida, Mt Dora, FL USA. [Zuckerman, Darryl A.] Edward Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Cardella, John F.] Geisinger Hlth Syst, Geisinger Syst Radiol, Danville, PA USA. RP Malloy, PC (reprint author), Hartford Hosp, Div Vasc & Intervent Radiol, 85 Seymour St,Ste 200, Hartford, CT 06106 USA. EM pmalloy@jeffersonradiology.com NR 57 TC 55 Z9 57 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUL PY 2009 VL 20 IS 7 BP S240 EP S249 DI 10.1016/j.jvir.2008.11.027 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 465UK UT WOS:000267613200007 PM 19394868 ER PT J AU Rose, SC Dupuy, DE Gervais, DA Millward, SF Brown, DB Cardella, JF Wallace, MJ AF Rose, Steven C. Dupuy, Damian E. Gervais, Debra A. Millward, Steven F. Brown, Daniel B. Cardella, John F. Wallace, Michael J. CA Technology Assessment Comm Soc Int TI Research Reporting Standards for Percutaneous Thermal Ablation of Lung Neoplasms SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID GUIDED RADIOFREQUENCY ABLATION; PULMONARY MALIGNANT-TUMORS; COLORECTAL-CARCINOMA; NONSURGICAL CANDIDATES; MICROWAVE ABLATION; HELICAL CT; FOLLOW-UP; CANCER; METASTASES; PNEUMOTHORAX C1 [Rose, Steven C.] Univ Calif San Diego, Med Ctr, Dept Radiol, Sect Intervent Oncol, San Diego, CA 92103 USA. [Dupuy, Damian E.] Rhode Isl Hosp, Brown Med Sch, Dept Diagnost Imaging, Providence, RI USA. [Gervais, Debra A.] Massachusetts Gen Hosp, Dept Radiol, Gastrointestinal Genitourinary Div, Boston, MA 02114 USA. [Millward, Steven F.] Univ Western Ontario, Dept Radiol, London, ON, Canada. [Millward, Steven F.] Peterborough Reg Hlth Ctr, Dept Radiol, Peterborough, ON, Canada. [Brown, Daniel B.] Thomas Jefferson Univ Hosp, Dept Radiol, Div Intervent Radiol, Philadelphia, PA 19107 USA. [Cardella, John F.] Geisinger Hlth Syst, Dept Radiol, Danville, PA USA. [Wallace, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Intervent Radiol, Houston, TX 77030 USA. RP Rose, SC (reprint author), Care of McClenny T, Soc Intervent Radiol, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM mcclenny@sirweb.org OI Dupuy, Damian/0000-0003-0524-5982 NR 56 TC 15 Z9 15 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUL PY 2009 VL 20 IS 7 BP S474 EP S485 DI 10.1016/j.jvir.2009.01.016 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 465UK UT WOS:000267613200037 PM 19246213 ER PT J AU Patel, R Conrad, MF Paruchuri, V Kwolek, CJ Chung, TK Cambria, RP AF Patel, Rajendra Conrad, Mark F. Paruchuri, Vikram Kwolek, Christopher J. Chung, Thomas K. Cambria, Richard P. TI Thoracoabdominal aneurysm repair: Hybrid versus open repair SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID THORACIC AORTIC-ANEURYSMS; OPEN-SURGICAL REPAIR; HIGH-RISK PATIENTS; ENDOVASCULAR TREATMENT; STENT-GRAFT; TRIAL; OUTCOMES; IV; REVASCULARIZATION; EXPERIENCE AB Objective: Hybrid repair of thoracoabdominal aortic aneurysms (TAAA) may reduce morbidity and mortality in high-risk candidates for open repair. This study reviews the outcomes of hybrid TAAA repair for Crawford extent I-III TAAA in high-risk patients in comparison to patients who underwent concurrent open TAAA repair. Methods. During the interval from June 2005 to December 2007, a total of 23 high-risk patients with TAAA (type 1: 9 [39%], 11: 5 [22%], and 111: 9 [39%]) underwent renal and/or mesenteric debranching (11 [48%] with four vessel debranching) with subsequent placement of a thoracic stent graft; 77 patients underwent open TAAA repair (type 1: 13 [17%], 11: 11 [14%], 111: 27 [35%], and IV: 26 [34%]) during the same interval. The primary high-risk criteria for hybrid TAAA included advanced age/poor functional status (n = 14), major pulmonary dysfunction (n = 8), and technical consideration (prior thoracic aortic aneurysm repair [n = 4] or prior thoracoabdominal aneurysm repair [n = 21 and obesity [n = 21) with 6 patients having overlapping high-risk criteria. Composite (30-day) mortality and/or permanent paraplegia (PP) were the major study endpoints. Results: The hybrid and open TAAA groups had (respectively) no statistical difference in mean age (76.6 vs 72.7 years), aneurysm size (6.51 vs 6.52 cm), and non-elective operation (30.4% vs 26.0%). The hybrid group had a higher mean Society for Vascular Surgery (SVS) risk score (9.1 vs 6.0; P <= .001), incidence of oxygen-dependent chronic obstructive pulmonary disease (COPD) (34.8% vs 2.6%; P <= .001), and prior thoracic (n = 4) or thoracoabdominal (n = 2) repair (26.1% vs 1.3%; P <= .001). Composite mortality and/or PP was doubled in the hybrid group (21.7% vs 11.7%; P = .33). The rate of any type of reoperation was higher in hybrid TAAA repair (39.1% vs 20.8%; P = .03). One year actuarial survival for both groups was comparable (hybrid, 68 +/- 12%; open, 73 +/- 6%). A total of 5/23 (22%) hybrid TAAA patients developed an endoleak (type I: 3/23 and type II : 2/23) with 3 requiring endovascular re-intervention. A total of 7/70 (10%) visceral/renal bypass grafts were noted to be occluded during follow-up (I superior inesenteric artery, 1 celiac, and 5 renal). Examination of patients with an SVS risk score :58 (mean SVS risk score in hybrid 6.2 [n = 10] vs 5.5 [n = 68] in open; P = .27) revealed the hybrid group had a higher incidence of composite mortality and/or PP (40% vs 10.3%; P = .03). Conclusion: Hybrid TAAA repair in high-risk patients has significant morbidity and mortality suggesting a non-interventional approach may be appropriate in many such patients. The morbidity and mortality of the hybrid TAAA repair was substantial even in lower risk patients (SVS risk score <= 8), albeit patient numbers were small. Prospective study in comparable patient risk cohorts is required to define the role of hybrid TAAA repair. (J Vasc Surg 2009;50: 15-22.) C1 [Cambria, Richard P.] Massachusetts Gen Hosp, Dept Vasc & Endovasc Surg, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, Dept Vasc & Endovasc Surg, Div Vasc & Endovasc Surg, 15 Parkman St,WAC 440, Boston, MA 02114 USA. OI Chung, Thomas/0000-0001-6148-1184 NR 38 TC 56 Z9 58 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUL PY 2009 VL 50 IS 1 BP 15 EP 22 DI 10.1016/j.jvs.2008.12.051 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 464IL UT WOS:000267498500003 PM 19563950 ER PT J AU Alter, G Rihn, S Walter, K Nolting, A Martin, M Rosenberg, ES Miller, JS Carrington, M Altfeld, M AF Alter, Galit Rihn, Suzannah Walter, Katharine Nolting, Anne Martin, Maureen Rosenberg, Eric S. Miller, Jeffrey S. Carrington, Mary Altfeld, Marcus TI HLA Class I Subtype-Dependent Expansion of KIR3DS1(+) and KIR3DL1(+) NK Cells during Acute Human Immunodeficiency Virus Type 1 Infection SO JOURNAL OF VIROLOGY LA English DT Article ID NATURAL-KILLER-CELLS; IMMUNOGLOBULIN-LIKE RECEPTOR; ACUTE HIV-1 INFECTION; INHIBITORY RECEPTORS; PERIPHERAL-BLOOD; SELF-MHC; INNATE; CYTOMEGALOVIRUS; ACTIVATION; RESISTANCE AB NK cells are critical in the early containment of viral infections. Epidemiological and functional studies have shown an important role of NK cells expressing specific killer immunoglobulin-like receptors (KIRs) in the control of human immunodeficiency virus type 1 (HIV-1) infection, but little is known about the mechanisms that determine the expansion of these antiviral NK cell populations during acute HIV-1 infection. Here we demonstrate that NK cells expressing the activating receptor KIR3DS1(+) and, to a lesser extent, the inhibitory receptor KIR3DL1(+) specifically expand in acute HIV-1 infection in the presence of HLA-B Bw480I, the putative HLA class I ligand for KIR3DL1/3DS1. These data demonstrate for the first time the HLA class I subtype-dependent expansion of specific KIR+ NK cells during an acute viral infection in humans. C1 [Alter, Galit; Rihn, Suzannah; Walter, Katharine; Nolting, Anne; Rosenberg, Eric S.; Altfeld, Marcus] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA 02129 USA. [Alter, Galit; Rihn, Suzannah; Walter, Katharine; Nolting, Anne; Rosenberg, Eric S.; Altfeld, Marcus] Harvard Univ, Ragon Inst MGH MIT & Harvard, Sch Med, Boston, MA 02129 USA. [Alter, Galit; Rihn, Suzannah; Walter, Katharine; Nolting, Anne; Rosenberg, Eric S.; Altfeld, Marcus] Harvard Univ, Div AIDS, Sch Med, Boston, MA 02129 USA. [Martin, Maureen; Carrington, Mary] SAIC Frederick Inc, Basic Res Program, Lab Genom Div, Frederick, MD USA. [Miller, Jeffrey S.] Univ Minnesota, Ctr Canc, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. RP Alter, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA 02129 USA. EM galter@partners.org OI Miller, Jeffrey S/0000-0002-0339-4944 FU NIH [R01-AI067031, PO1-AI074415]; National Cancer Institute, National Institutes of Health [N01-C0-12400]; Susan Ragon Foundation FX This work was supported by NIH grants R01-AI067031 and PO1-AI074415. The project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-C0-12400. CHAVI (Center for HIV/AIDS Vaccine Immunology) provided support for the development of the quantitative RT-PCR. We thank the Philip T. and Susan Ragon Foundation for support. NR 37 TC 105 Z9 112 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2009 VL 83 IS 13 BP 6798 EP 6805 DI 10.1128/JVI.00256-09 PG 8 WC Virology SC Virology GA 462LM UT WOS:000267354100046 PM 19386717 ER PT J AU Solberg, LI Asche, SE Anderson, LH Sepucha, K Thygeson, NM Madden, JE Morrissey, L Kraemer, KK AF Solberg, Leif I. Asche, Stephen E. Anderson, Louise H. Sepucha, Karen Thygeson, N. Marcus Madden, Joan E. Morrissey, Larry Kraemer, Karen K. TI Evaluating Preference-Sensitive Care for Uterine Fibroids: It's Not So Simple SO JOURNAL OF WOMENS HEALTH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; DECISION-MAKING; REGIONAL-VARIATIONS; PATIENT DECISION; HEALTH OUTCOMES; MEDICAL-CARE; NEW-HAVEN; QUALITY; AIDS; SUPPORT AB Background: Preference-sensitive care decisions should reflect an informed patient's preferences. This retrospective survey of women with fibroids, a benign condition with multiple treatment options, sought to evaluate the extent to which this was measurable and true. Methods: All 260 women in one medical group with visit codes for uterine fibroids during a 9-month period in 2006 were mailed surveys constructed through focus groups with physicians and interviews with patients. Correlations tested associations among their preferences, knowledge, and treatment decisions. Results: The adjusted response rate was 82%, but only 100 respondents fit all criteria for analysis. Nearly all wanted to either share or control the decision, and 86% felt informed, satisfied, and that the decision was consistent with their values. However, only 55% of patients could answer at least five of seven fibroid questions correctly. Hysterectomy use was significantly correlated with desire to relieve symptoms, have a permanent treatment, and do something right away (r = 0.36, 0.37, and 0.30, respectively). Those deciding not to treat were significantly less likely to have these preferences (r = -0.65, -0.40, and -0.58). These relationships were not affected by patient knowledge level, but patients with high knowledge scores were significantly more likely to believe their decision was concordant with their preferences (94.9% vs. 74.4%, p<0.01). Conclusions: There were knowledge gaps but unclear associations between knowledge and decision-preference relationships for this condition, which has many different treatment alternatives. A prospective intervention trial is needed to determine if better information and counseling would produce stronger concordance between treatment selected and patient preferences. C1 [Solberg, Leif I.; Asche, Stephen E.; Anderson, Louise H.; Thygeson, N. Marcus; Madden, Joan E.; Kraemer, Karen K.] HealthPartners Res Fdn, Minneapolis, MN 55440 USA. [Solberg, Leif I.; Asche, Stephen E.; Anderson, Louise H.; Thygeson, N. Marcus; Madden, Joan E.; Kraemer, Karen K.] HealthPartners, HealthPartners Med Grp, Minneapolis, MN USA. [Sepucha, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Morrissey, Larry] Stillwater Med Grp, Stillwater, MN USA. RP Solberg, LI (reprint author), HealthPartners Res Fdn, POB 1524,MS 21111R, Minneapolis, MN 55440 USA. EM leif.i.solberg@healthpartners.com FU HealthPartners Research Foundation FX We are very grateful to the obstetrics/gynecology physicians and patients who helped so much in creating and modifying the questions used to measure knowledge and decision quality. The physician collaboration was greatly facilitated by the department chair (J.M.). This work was supported by a Partnership grant from HealthPartners Research Foundation. NR 36 TC 4 Z9 4 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD JUL PY 2009 VL 18 IS 7 BP 1071 EP 1079 DI 10.1089/jwh.2008.0948 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 469FS UT WOS:000267881900018 PM 19580366 ER PT J AU Lu, TC Wang, ZH Feng, XB Chuang, PY Fang, W Shen, YH Levy, DE Xiong, HB Chen, N He, JC AF Lu, Ting-Chi Wang, Zhao-Hui Feng, Xiaobei Chuang, Peter Y. Fang, Wei Shen, Yuhong Levy, David E. Xiong, Huabao Chen, Nan He, John Cijiang TI Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy SO KIDNEY INTERNATIONAL LA English DT Article DE collagen IV; diabetic nephropathy; glomerulosclerosis; mesangial cells; Stat3 ID JAK/STAT-SIGNALING PATHWAY; FACTOR-KAPPA-B; LOW-GRADE INFLAMMATION; MESANGIAL CELLS; HIGH GLUCOSE; INDUCED ACTIVATION; KIDNEY GLOMERULI; DB/DB MICE; NEPHROPATHY; GROWTH AB Recent studies suggest that Stat3, a transcription factor that mediates cytokine signaling, plays a critical role in the pathogenesis of diabetic nephropathy. Complete Stat3 gene knockout is embryonic lethal; therefore, we crossed Stat3+/- mice with Stat3 mutant mice (SA/SA) that lack full Stat3 activity. This strategy generated Stat3SA/- mice (25% activity) and Stat3SA/+ mice (75% activity), which were made diabetic using streptozotocin in order to define the role of Stat3 in diabetic kidney disease. While the glomerular number was not different between these two groups of mice, the diabetic SA/- mice had significantly less proteinuria, mesangial expansion, glomerular cell proliferation, and macrophage infiltration than the diabetic SA/+ mice. The reduction in Stat3 activity did not affect glomerular hyperfiltration seen after the induction of diabetes, as it was increased to the same degree in both groups of mice. Phosphorylation of Stat3 was markedly increased in the glomeruli of diabetic SA/+ mice compared to diabetic SA/- mice. The expression of inflammatory markers, IL-6, MCP-1, and activated NF-kappa B; type IV collagen, TGF-beta, and ICAM-1 mRNA; or type IV collagen and TGF-beta protein, were all found to be significantly less in glomeruli isolated from diabetic SA/- mice, as compared with diabetic SA/+ mice. Our study shows that Stat3 plays a critical role in the regulation of inflammation and abnormal matrix synthesis at an early stage of DN. C1 [He, John Cijiang] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. [Lu, Ting-Chi; He, John Cijiang] James J Peters VA Med Ctr, Bronx, NY USA. [Wang, Zhao-Hui; Feng, Xiaobei; Chen, Nan] Shanghai Jiao Tong Univ, Sch Med, RuiJin Hosp, Dept Nephrol, Shanghai 200030, Peoples R China. [Shen, Yuhong] Rockefeller Univ, Mol Cell Biol Lab, New York, NY 10021 USA. [Levy, David E.] NYU, Dept Pathol, New York, NY 10016 USA. [Xiong, Huabao] Mt Sinai Sch Med, Immunobiol Ctr, New York, NY USA. [He, John Cijiang] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY USA. RP He, JC (reprint author), Mt Sinai Sch Med, Dept Med, Div Nephrol, Box 1243,1 Gustave L Levy Pl, New York, NY 10029 USA. EM cijiang.he@mssm.edu OI Levy, David/0000-0002-7320-7788 FU NIH [R01 DK078897, K08 KD082760] FX JC He was supported by NIH R01 DK078897. PY Chuang was supported by NIH K08 KD082760. NR 43 TC 29 Z9 37 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2009 VL 76 IS 1 BP 63 EP 71 DI 10.1038/ki.2009.98 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 461KR UT WOS:000267266200011 PM 19357722 ER PT J AU Eisner, BH Tanrikut, C Dahl, DM AF Eisner, Brian H. Tanrikut, Cigdem Dahl, Douglas M. TI Chyluria secondary to lymphorenal fistula SO KIDNEY INTERNATIONAL LA English DT Editorial Material C1 [Eisner, Brian H.; Tanrikut, Cigdem; Dahl, Douglas M.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Eisner, BH (reprint author), Massachusetts Gen Hosp, Dept Urol, GRB 1102,55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org NR 0 TC 3 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2009 VL 76 IS 1 BP 126 EP 126 DI 10.1038/ki.2009.64 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 461KR UT WOS:000267266200020 PM 19528993 ER PT J AU Kiernan, TJ Yan, BP Gupta, V Garasic, JM AF Kiernan, Thomas J. Yan, Bryan P. Gupta, Vishal Garasic, Joseph M. TI Unusual case of recurrent renal artery stenosis: lessons to learn SO KIDNEY INTERNATIONAL LA English DT Article ID PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; PEDIATRIC RENOVASCULAR HYPERTENSION; BALLOON ANGIOPLASTY; NEONATAL HYPERTENSION; RANDOMIZED-TRIAL; STENT PLACEMENT; RISK-FACTORS; FOLLOW-UP; CHILDREN; MANAGEMENT AB A 39 year old male chef with previous right aorto-renal artery surgical reimplantation at age 8 for reported congenital renal artery stenosis presented to an outside hospital with gastroenteritis including symptoms of abdominal pain, nausea, diarrhea and vomiting. Past medical history apart from previous surgery for congenital renal artery stenosis was unremarkable. He was an active tobacco user of one pack per day for the previous 20 years. There was no family history of premature coronary disease. Examination revealed a blood pressure of 210/100 mmHg, heart rate of 88 beats per minute and respiratory rate of 16 per minute. Blood pressure recordings were equal in both upper limbs. The radial, brachial, femoral and distal lower limb pulses were symmetrical and of normal volume. No bruits were audible over the carotid, subclavian or femoral arteries. The remainders of the cardiac, respiratory and abdominal examinations were unremarkable apart from a surgical scar as a result of previous renal artery surgery. Medications included nifedipine 90 mg and enalapril 20 mg had been started one month earlier for worsening hypertension. Laboratory profile on admission is shown in (Table 1). C1 [Kiernan, Thomas J.; Yan, Bryan P.; Gupta, Vishal; Garasic, Joseph M.] Massachusetts Gen Hosp, Dept Intervent Cardiol & Vasc Med, Boston, MA 02114 USA. RP Kiernan, TJ (reprint author), Massachusetts Gen Hosp, Dept Intervent Cardiol & Vasc Med, 55 Fruit St, Boston, MA 02114 USA. EM tom_kiernan@hotmail.com RI Yan, Bryan/P-5928-2015 NR 41 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2009 VL 76 IS 2 BP 224 EP 228 DI 10.1038/ki.2008.353 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 464HV UT WOS:000267496900015 PM 18633338 ER PT J AU Deschler, DG Bunting, GW Lin, DT Emerick, K Rocco, J AF Deschler, Daniel G. Bunting, Glenn W. Lin, Derrick T. Emerick, Kevin Rocco, James TI Evaluation of Voice Prosthesis Placement at the Time of Primary Tracheoesophageal Puncture with Total Laryngectomy SO LARYNGOSCOPE LA English DT Article DE Tracheoesophageal voice restoration; total laryngectomy ID VOCAL REHABILITATION; SPEAKING PROFICIENCY; BLOM-SINGER; RESTORATION; EXPERIENCE; SPEECH AB Objectives/Hypothesis: Primary tracheoesophageal puncture (TEP) is a well-described and accepted method of surgical voice restoration and is standardly completed with a catheter placement intraoperatively, which is replaced with a prosthesis at a later date. This study evaluates the intraoperative placement of the voice prosthesis at the time of the primary TEP in an effort to understand the potential advantages and disadvantages of voice prosthesis placement at the time of primary TEP completed in conjunction with total laryngectomy. Study Design: Retrospective chart review within an academic medical center. Methods: After approval by the institutional review board of the Massachusetts Eye and Ear Infirmary, a retrospective chart review was completed of all cases of primary tracheoesophageal prosthesis placement completed in conjunction with primary tracheoesophageal puncture performed at the time of total laryngectomy. Results: Thirty patients were identified, 29 of whom underwent laryngectomy for advanced laryngeal carcinoma. Twenty-eight of 29 patients received preoperative full-dose radiation therapy. Twenty-nine of 30 patients had a 20F classic Indwelling Blom-Singer prosthesis (InHealth Technologies, Carpinteria, CA) placed. One had placement of 16F Indwelling Blom-Singer prosthesis. No complications were noted with intraoperative prosthesis placement. No prostheses were dislodged in the postoperative period. Twenty-nine of 30 subjects had initial success with tracheoesophageal voice production. At 1-year follow-up, 23/30 subjects (77%) had successful voice restoration. Five failed because of recurrent disease, one subject never achieved successful voice, and one subject wanted the prosthesis removed although successful voice was achieved. Twenty-three of 25 (92%) disease-free subjects had functional voice restoration at 1-year post-total laryngectomy and primary prosthesis placement. Conclusions: This study demonstrates that the voice prosthesis can be safely and effectively placed intraoperatively at the time of primary TEP and laryngectomy. Initial voice acquisition rates were high and long-term success was well within the acceptable range. C1 [Deschler, Daniel G.; Bunting, Glenn W.; Lin, Derrick T.; Emerick, Kevin; Rocco, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Head & Neck Surg,Dept Otol & Laryngol, Boston, MA USA. RP Deschler, DG (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Div Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM daniel_deschler@meei.harvard.edu NR 22 TC 15 Z9 15 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD JUL PY 2009 VL 119 IS 7 BP 1353 EP 1357 DI 10.1002/lary.20490 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 467KO UT WOS:000267737800016 PM 19507224 ER PT J AU Lembo, AJ Ganz, RA Sheth, S Cave, D Kelly, C Levin, P Kazlas, PT Baldwin, PC Lindmark, WR McGrath, JR Hamblin, MR AF Lembo, Anthony J. Ganz, Robert A. Sheth, Sunil Cave, David Kelly, Ciaran Levin, Philip Kazlas, Peter T. Baldwin, Paul C., III Lindmark, William R. McGrath, Jonathan R. Hamblin, Michael R. TI Treatment of Helicobacter pylori Infection With Intra-Gastric Violet Light Phototherapy: A Pilot Clinical Trial SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE Helicobacter pylori; gastroenterology; laser phototherapy; porphyrins; endoscopy ID PHOTODYNAMIC THERAPY; PROPIONIBACTERIUM-ACNES; VISIBLE-LIGHT; ERADICATION; PORPHYRINS; QUADRUPLE; BACTERIA AB Background and Objective: Helicobacter pylori infects the mucus layer of the human stomach and causes peptic ulcers and adenocarcinoma. We have previously shown that H. pylori accumulates photoactive porphyrins making the organism susceptible to inactivation by light, and that small spot endoscopic illumination with violet light reduced bacterial load in human stomachs. This study assessed the feasibility and safety of whole-stomach intra-gastric violet phototherapy for the treatment of H. pylori infection. Study Design/Materials and Methods: A controlled, prospective pilot trial was conducted using a novel light source consisting of laser diodes and diffusing fibers to deliver 408-nm illumination at escalating total fluences to the whole stomach. Eighteen adults (10 female) with H. pylori infection were treated at three U.S. academic endoscopy centers. Quantitative bacterial counts were obtained from biopsies taken from the antrum, body, and fundus, and serial urea breath tests. Results: The largest reduction in bacterial load was in the antrum (>97%), followed by body (>95%) and fundus (>86%). There was a correlation between log reduction and initial bacterial load in the antrum. There was no dose-response seen with increasing illumination times. The urea breath test results indicated that the bacteria repopulated in days following illumination. Conclusion: Intra-gastric violet light phototherapy is feasible and safe and may represent a novel approach to eradication of H. pylori, particularly in patients who have failed standard antibiotic treatment. This was a pilot study involving a small number of patients. Further research is needed to determine if phototherapy can be effective for eradicating H. pylori. Lasers Surg. Med. 41:337-344, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Baldwin, Paul C., III; Lindmark, William R.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Lembo, Anthony J.; Sheth, Sunil; Kelly, Ciaran] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ganz, Robert A.] Abbott NW Hosp, Dept Gastroenterol, Minneapolis, MN 55407 USA. [Cave, David] UMASS Med Ctr, Worcester, MA USA. [Levin, Philip; Kazlas, Peter T.; Baldwin, Paul C., III; Lindmark, William R.; McGrath, Jonathan R.] LumeRx Inc, Marlborough, MA USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed BAR414, 40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Cave, David/0000-0003-3391-7299; Hamblin, Michael/0000-0001-6431-4605 FU LumeRx, Inc; NIH [R01AI050875] FX Contract grant sponsor: LumeRx, Inc.; Contract grant sponsor: NIH; Contract grant number: R01AI050875. NR 22 TC 32 Z9 36 U1 1 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD JUL PY 2009 VL 41 IS 5 BP 337 EP 344 DI 10.1002/lsm.20770 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA 464RS UT WOS:000267524400002 PM 19533762 ER PT J AU Akilov, OE Yousaf, W Lukjan, SX Verma, S Hasan, T AF Akilov, Oleg E. Yousaf, Wajeeha Lukjan, Sebastian X. Verma, Sarika Hasan, Tayyaba TI Optimization of Topical Photodynamic Therapy With 3,7-bis(di-n-butylamino)Phenothiazin-5-ium Bromide for Cutaneous Leishmaniasis SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE Leishmania; topical application; light; antiparasitic therapy ID VISCERAL LEISHMANIASIS; RESISTANCE; MILTEFOSINE; PROMASTIGOTES; PAROMOMYCIN; PARASITES; EFFICACY; AGENTS AB Background and Objective: Photodynamic therapy (PDT) has evolved as a promising therapeutic measure for the treatment of cutaneous leishmaniasis (CL). In particular, phenothiazine compounds have demonstrated efficacy for PDT of CL. The objective of our present study is to define the use of a new specific phenothiazine photosensitizer, 3,7-bis(di-n-butylamino)phenothiazin-5-ium bromide (PPA904) applied topically as a cream to treat CL. Materials and Methods: To establish the optimal conditions for this treatment, we compared two different ways to improve current regimens of PDT with PPA904 cream (500 mu M of PPA904 in Unguentum M) by changing the duration of topical application, and by administration of several consecutive PDT procedures. An initial regimen recommended by the manufacturer (Photopharmica Co. Ltd., Leeds, UK) was maintained as a control: the cream was applied topically for 30 minutes at a final concentration of PPA904 at 500 mu M, and the designated treatment area was irradiated with a broad band light source of 665 +/- 15 nm at a fluence of 50 J/cm(2) (50 MW/cm(2)). Results: The best curative PPA904-PDT regimen was achieved under the conditions of a longer duration of topical application time (90 minutes) and several (three) consecutive treatments with 4-day intervals between treatments. The mechanisms responsible for such improvements (kinetics of drug penetration, depth of necrosis of the CL lesions after PDT, and daily changes in the parasitic load after PDT) are discussed in the present study. Conclusion: Topical PPA904-PDT, implemented as described above, is a promising treatment for CL, and clinical studies will be initiated to establish efficacy in humans. Lasers Surg. Med. 41:358-365, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Akilov, Oleg E.] Harvard Univ, Dept Dermatol, Sch Med, Massachusetts Gen Hosp,Wellman Ctr Photomed, Boston, MA 02114 USA. [Yousaf, Wajeeha] Aga Khan Univ, Coll Med, Karachi, Pakistan. [Akilov, Oleg E.; Verma, Sarika; Hasan, Tayyaba] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Lukjan, Sebastian X.] MIT, Cambridge, MA 02139 USA. RP Hasan, T (reprint author), Harvard Univ, Dept Dermatol, Sch Med, Massachusetts Gen Hosp,Wellman Ctr Photomed, 40 Blossom St,BAR 314, Boston, MA 02114 USA. EM thasan@partners.org FU Department of Defense Medical Free Electron Laser Program [FA9550-04-1-0079] FX Biological Science, University of Notre Dame, Notre Dame, IN, USA) for providing us with the L. major strain V1. We are appreciative of the assistance of Carol Winkelman and Elizabeth Davis with the manuscript preparation. This work was supported by the Department of Defense Medical Free Electron Laser Program Grant No. FA9550-04-1-0079 (to T. Hasan). NR 34 TC 13 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD JUL PY 2009 VL 41 IS 5 BP 358 EP 365 DI 10.1002/lsm.20775 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA 464RS UT WOS:000267524400005 PM 19533767 ER PT J AU Stegmaier, K AF Stegmaier, K. TI Genomic approaches to small molecule discovery SO LEUKEMIA LA English DT Review DE small molecule screening; gene expression; genomics; drug discovery ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; B-CELL LYMPHOMA; GENE-EXPRESSION SIGNATURE; TYROSINE KINASE INHIBITOR; SET ENRICHMENT ANALYSIS; PROSTATE-CANCER; MYELODYSPLASTIC SYNDROME; MEMORY DIFFERENTIATION AB With the sequencing of the human genome and the development of new genomic technologies, biomedical discovery has been transformed. The applications of these new approaches are ever-expanding from disease classification, to identification of new targets, to outcome prediction. A logical next step is the integration of genomic approaches into small molecule discovery. This review will focus on the application of genomics to compound discovery, with an emphasis on the hematological malignancies. It will focus on the use of genomic tools to discover cancer targets and the development and application of both cell-based and in silico gene expression-based approaches to small molecule discovery. Leukemia (2009) 23, 1226-1235; doi: 10.1038/leu.2009.29; published online 5 March 2009 C1 [Stegmaier, K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Childrens Hosp Boston, Boston, MA 02115 USA. [Stegmaier, K.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Stegmaier, K.] MIT, Cambridge, MA 02139 USA. RP Stegmaier, K (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Childrens Hosp Boston, D640C,44 Binney St, Boston, MA 02115 USA. EM kimberly_stegmaier@dfci.harvard.edu FU US National Institutes of Health; Howard Hughes Medical Institute Physician Scientist Early Career Award; Leukemia and Lymphoma Society; Sidney Kimmel Foundation for Cancer Research; Smith Family New Investigator Awards Program (Richard Allan Barry Fund at the Boston Foundation); SynCure Cancer Research Foundation; William Lawrence Pediatric Foundation FX The Stegmaier laboratory is supported by the US National Institutes of Health, the Howard Hughes Medical Institute Physician Scientist Early Career Award, the Leukemia and Lymphoma Society, the Sidney Kimmel Foundation for Cancer Research, the Smith Family New Investigator Awards Program (Richard Allan Barry Fund at the Boston Foundation), the SynCure Cancer Research Foundation and the William Lawrence Pediatric Foundation. NR 70 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 2009 VL 23 IS 7 BP 1226 EP 1235 DI 10.1038/leu.2009.29 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 470KB UT WOS:000267972500005 PM 19262600 ER PT J AU Neff, T Armstrong, SA AF Neff, T. Armstrong, S. A. TI Chromatin maps, histone modifications and leukemia SO LEUKEMIA LA English DT Review DE epigenetics; chromatin; histones; methyltransferases; methylation ID EMBRYONIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; MIXED-LINEAGE LEUKEMIA; GENOME-WIDE MAPS; DNA METHYLATION; GENE-EXPRESSION; GROUP PROTEINS; SACCHAROMYCES-CEREVISIAE; SET DOMAIN; TRANSCRIPTIONAL ELONGATION AB Recent years have seen great advances in the understanding of epigenetic gene regulation. Many of the molecular players involved have recently been identified and are rapidly being characterized in detail. Genome scale studies, using chromatin immunoprecipitation followed by expression arrays ('ChIP-Chip') or next generation sequencing ('ChIP-Seq'), have been applied to the study of transcription factor binding, DNA methylation, alternative histone use, and covalent histone modifications such as acetylation, ubiquitination and methylation. Initial studies focused on yeast, and embryonic stem cells. Genome-wide studies are now also being employed to characterize cancer and specifically leukemia genomes, with the prospect of improved diagnostic accuracy and discovery of novel therapeutic strategies. Here, we review some of the epigenetic modifications and their relevance for leukemia. Leukemia (2009) 23, 1243-1251; doi: 10.1038/leu.2009.40; published online 26 March 2009 C1 [Armstrong, S. A.] Childrens Hosp Boston, Div Hematol Oncol, Karp Family Res Labs, Boston, MA 02215 USA. [Neff, T.; Armstrong, S. A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Armstrong, S. A.] Harvard Stem Cell Inst, Boston, MA USA. RP Armstrong, SA (reprint author), Childrens Hosp Boston, Div Hematol Oncol, Karp Family Res Labs, 1 Blackfan Circle, Boston, MA 02215 USA. EM Scott.Armstrong@childrens.harvard.edu OI Neff, Tobias/0000-0002-0188-8393 NR 126 TC 37 Z9 38 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 2009 VL 23 IS 7 BP 1243 EP 1251 DI 10.1038/leu.2009.40 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 470KB UT WOS:000267972500007 PM 19322211 ER PT J AU Stone, ME AF Stone, Martha E. TI Routine Miracles: Restoring Faith and Hope in Medicine. SO LIBRARY JOURNAL LA English DT Book Review C1 [Stone, Martha E.] Massachusetts Gen Hosp Lib, Boston, MA 02114 USA. RP Stone, ME (reprint author), Massachusetts Gen Hosp Lib, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU REED BUSINESS INFORMATION PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD JUL PY 2009 VL 134 IS 12 BP 117 EP 118 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 469AG UT WOS:000267866400246 ER PT J AU Li, W Meng, ZH Liu, YL Reyes, JD Lang, JD AF Li, Wei Meng, Zihui Liu, Yuliang Reyes, Jorge D. Lang, John D. TI THE PROTECTIVE EFFECT OF NITRITE ON LIVER COLD ISCHEMIA REPERFUSION INJURY SO LIVER TRANSPLANTATION LA English DT Meeting Abstract CT 15th Annual Congress of the International-Liver-Transplantation-Society CY JUL 08-11, 2009 CL New York, NY SP Int Liver Transplantat Soc C1 [Li, Wei; Meng, Zihui; Liu, Yuliang; Reyes, Jorge D.; Lang, John D.] Univ Washington, Seattle, WA 98195 USA. [Liu, Yuliang; Lang, John D.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Reyes, Jorge D.] Childrens Hosp & Reg Med Ctr, Seattle, WA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD JUL PY 2009 VL 15 IS 7 BP S236 EP S236 PG 1 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 468CV UT WOS:000267792300547 ER PT J AU Rosen, AK Loveland, SA Romano, PS Itani, KMF Silber, JH Even-Shoshan, OO Halenar, MJ Teng, Y Zhu, JS Volpp, KG AF Rosen, Amy K. Loveland, Susan A. Romano, Patrick S. Itani, Kamal M. F. Silber, Jeffrey H. Even-Shoshan, Orit O. Halenar, Michael J. Teng, Yun Zhu, Jingsan Volpp, Kevin G. TI Effects of Resident Duty Hour Reform on Surgical and Procedural Patient Safety Indicators Among Hospitalized Veterans Health Administration and Medicare Patients SO MEDICAL CARE LA English DT Article DE patient safety; hospital quality; resident duty hour reform; administrative data ID WORK HOURS; ADVERSE EVENTS; CARE; MORTALITY; QUALITY; REGULATIONS; PERFORMANCE; LIMITS; IMPACT; ERRORS AB Objective: Improving patient safety was a strong motivation behind duty hour regulations implemented by Accreditation Council for Graduate Medical Education on July 1, 2003. We investigated whether rates of patient safety indicators (PSIs) changed after these reforms. Research Design: Observational study of patients admitted to Veterans Health Administration (VA) (N = 826,047) and Medicare (N = 13,367,273) acute-care hospitals from July 1, 2000 to June 30, 2005. We examined changes in patient safety events in more versus less teaching-intensive hospitals before (2000-2003) and after (2003-2005) duty hour reform, using conditional logistic regression, adjusting for patient age, gender, comorbidities, secular trends, baseline severity, and hospital site. Measures: Ten PSIs were aggregated into 3 composite measures based on factor analyses: "Continuity of Care," "Technical Care," and "Other" composites. Results: Continuity of Care composite rates showed no significant changes postreform in hospitals of different teaching intensity in either VA or Medicare. In the VA, there were no significant changes postreform for the technical care composite. In Medicare, the odds of a Technical Care PSI event in more versus less teaching-intensive hospitals in postreform year 1 were 1.12 (95% CI; 1.01-1.25), there were no significant relative changes in postreform year 2. Other composite rates increased in VA in postreform year 2 in more versus less teaching-intensive hospitals (odds ratio, 1.63; 95% CI; 1.10-2.41), but not in Medicare in either postreform year. Conclusions: Duty hour reform had no systematic impact on PSI rates. In the few cases where there were statistically significant increases in the relative odds of developing a PSI, the magnitude of the absolute increases were too small to be clinically meaningful. C1 [Rosen, Amy K.; Loveland, Susan A.] VA Ctr Excellence, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA 01730 USA. [Rosen, Amy K.; Loveland, Susan A.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Romano, Patrick S.] Univ Calif Davis, Sch Med, Div Gen Med, Sacramento, CA 95817 USA. [Romano, Patrick S.] Univ Calif Davis, Sch Med, Ctr Healthcare Policy & Res, Sacramento, CA 95817 USA. [Itani, Kamal M. F.] Boston VA Healthcare Syst, Dept Surg, Boston, MA USA. [Itani, Kamal M. F.] Boston Univ, Dept Surg, Boston, MA 02215 USA. [Silber, Jeffrey H.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.; Even-Shoshan, Orit O.; Halenar, Michael J.; Zhu, Jingsan; Volpp, Kevin G.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.; Even-Shoshan, Orit O.; Teng, Yun; Volpp, Kevin G.] Childrens Hosp Philadelphia, Ctr Outcomes Res, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.; Volpp, Kevin G.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Halenar, Michael J.; Volpp, Kevin G.] VA Ctr Excellence, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Rosen, AK (reprint author), VA Ctr Excellence, Ctr Hlth Qual Outcomes & Econ Res, 200 Springs Rd 152, Bedford, MA 01730 USA. EM akrosen@bu.edu RI Romano, Patrick/N-4225-2014 OI Romano, Patrick/0000-0001-6749-3979 FU VA [IIR 04.202.1]; NHLBI RO1 HL082637; National Science Foundation [SES-06-0646002] FX Supported by VA grant HSR&D IIR 04.202.1 and NHLBI RO1 HL082637, with additional support from National Science Foundation grant SES-06-0646002. NR 47 TC 53 Z9 53 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP 723 EP 731 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463VZ UT WOS:000267462400003 PM 19536029 ER PT J AU Keating, NL Kouri, E He, YL Weeks, JC Winer, EP AF Keating, Nancy L. Kouri, Elena He, Yulei Weeks, Jane C. Winer, Eric P. TI Racial Differences in Definitive Breast Cancer Therapy in Older Women Are They Explained by the Hospitals where Patients Undergo Surgery? SO MEDICAL CARE LA English DT Article DE breast cancer; surgery; quality; racial disparities ID ACUTE MYOCARDIAL-INFARCTION; HEALTH-SERVICES RESEARCH; BLACK-AND-WHITE; COMORBIDITY INDEX; LINKED MEDICARE; LUNG-CANCER; DISPARITIES; VOLUME; SURVIVAL; CARE AB Background: Prior research has documented racial disparities in patterns of care and outcomes for women with breast cancer. Objectives: To assess whether black women receive care from lower-quality or lower-volume hospitals and if such differences explain disparities in receipt of definitive primary breast cancer therapy. Research Design: Observational study of a population-based sample of breast cancer patients included in the SEER-Medicare database. Subjects: Fifty five thousand four hundred seventy white or black women aged >65 diagnosed with stage I/II breast cancer during 1992-2002. Measures: Surgery at a high-quality hospital (top quartile rates of radiation after breast-conserving Surgery) or high volume (top quartile) hospital and receipt of definitive primary therapy (mastectomy or breast-conserving surgery with radiation). Results: Black women were significantly less likely than white women to be treated at high-quality hospitals (adjusted odds ratio [OR] 0.60; 95% confidence interval [Cl]: 0.40-0.87) but not high-volume hospitals (adjusted OR 0.85; 95% Cl: 0.54-1.34). Black women were less likely than white women to receive definitive primary therapy, a finding partially explained by having surgery at a high-quality hospital but not by having surgery at a high-volume hospital. Conclusions: Older black women were more likely than white women to undergo breast cancer surgery at hospitals with lower rates of radiation following breast-conserving surgery, and this explains some of the reported racial disparities previously observed in receipt of definitive therapy for early-stage breast cancer. Interventions to help hospitals treating large numbers of black women improve rates of radiation after breast-conserving surgery may help to decrease racial disparities in care. C1 [Keating, Nancy L.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02115 USA. [Keating, Nancy L.; Kouri, Elena; He, Yulei] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Weeks, Jane C.; Winer, Eric P.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu FU Cure Foundation FX Supported by the Susan G. Komen for the Cure Foundation. NR 44 TC 43 Z9 43 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP 765 EP 773 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463VZ UT WOS:000267462400008 PM 19536008 ER PT J AU Shugarman, LR Mack, K Sorbero, MES Tian, HJ Jain, AK Ashwood, JS Asch, SM AF Shugarman, Lisa R. Mack, Katherine Sorbero, Melony E. S. Tian, Haijun Jain, Arvind K. Ashwood, J. Scott Asch, Steven M. TI Race and Sex Differences in the Receipt of Timely and Appropriate Lung Cancer Treatment SO MEDICAL CARE LA English DT Article DE Medicare; lung cancer; SEER program; treatment; sex differences; race differences; disparities ID AFRICAN-AMERICAN PATIENTS; SEER-MEDICARE DATA; LEUKEMIA GROUP-B; QUALITY-OF-LIFE; SURGICAL RESECTION; SURVIVAL; DISPARITIES; GENDER; CARE; CHEMOTHERAPY AB Background: Previous research suggests that disparities in non-small-cell lung cancer (NSCLC) survival can be explained in part by disparities in the receipt of cancer treatment. Few studies, however, have considered race and sex disparities in the timing and appropriateness of treatment across stages of diagnosis. Objective: To evaluate the relationship of sex and race with the receipt of timely and clinically appropriate NSCLC treatment for each stage of diagnosis. Method: Surveillance Epidemiology and End Result data linked to Medicare claims for beneficiaries diagnosed with NSCLC between 1995 and 1999 were used to evaluate the relationship between race and sex with timely and appropriate NSCLC treatment while controlling for other demographic characteristics, comorbidities, socioeconomic status, and provider supply (N = 22,145). Results: Overall adjusted rates of timely and appropriate treatment are 37.2%, 58.1%, and 29.2% for Medicare beneficiaries diagnosed with stage I or 11, 111, and IV NSCLC, respectively. Among stage I or 11 patients, women were 25% less likely to receive timely Surgical resection relative to men, and blacks were 66% less likely to receive timely and appropriate treatment than whites. Black men were least likely to receive resection (22.2% compared with 43.7% for white men). Blacks were 34% less likely to receive timely surgery, chemotherapy, or radiation for stage III disease and were 51% less likely to receive chemotherapy in a timely fashion for stage IV disease relative to whites. Conclusion: Significant variations in appropriate timely treatment were found within and across stages of diagnosis, confirming that sex and race differences in NSCLC treatment exist. C1 [Shugarman, Lisa R.; Mack, Katherine] RAND Corp, Santa Monica, CA 90407 USA. [Sorbero, Melony E. S.; Ashwood, J. Scott] RAND Corp, Pittsburgh, PA USA. [Tian, Haijun] MS Hlth, Woodland Hills, CA USA. [Jain, Arvind K.] RAND Corp, Arlington, VA USA. [Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, RAND Corp, Vet Adm Greater Los Angeles Healthcare Syst, Santa Monica, CA USA. RP Shugarman, LR (reprint author), RAND Corp, 1776 Main St,POB 2138, Santa Monica, CA 90407 USA. EM lisas@rand.org FU Health Resources and Services Administration (HRSA) Office of Rural Health Policy [R04-RH03596-01-00] FX Supported by the Health Resources and Services Administration (HRSA) Office of Rural Health Policy (R04-RH03596-01-00). NR 47 TC 41 Z9 41 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP 774 EP 781 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463VZ UT WOS:000267462400009 PM 19536007 ER PT J AU Iwashyna, TJ Christie, JD Moody, J Kahn, JM Asch, DA AF Iwashyna, Theodore J. Christie, Jason D. Moody, James Kahn, Jeremy M. Asch, David A. TI The Structure of Critical Care Transfer Networks SO MEDICAL CARE LA English DT Article DE networks; critical care; regionalization; Medicare ID ACUTE MYOCARDIAL-INFARCTION; PERCUTANEOUS CORONARY INTERVENTIONS; UNITED-STATES; INTENSIVE-CARE; PRIMARY ANGIOPLASTY; HOSPITAL VOLUME; SOCIAL NETWORK; OUTCOMES; MORTALITY; CENTRALITY AB Rationale: Moving patients from low-performing hospitals to high-performing hospitals may improve patient outcomes. These transfers may be particularly important in critical care, where small relative improvements can yield substantial absolute changes in survival. Objective: To characterize the existing critical care network in terms of the pattern of transfers. Methods: In a retrospective cohort study, the nationwide 2005 Medicare fee-for-service claims were used to identify the interhospital transfer of critically ill patients, defined as instances where patients used critical care services in 2 temporally adjacent hospitalizations. Measurements: We Measured the characteristics of the interhospital transfer network and the extent to which intensive care unit patients are referred to each hospital in that network-a continuous quantitative measure at the hospital-level known as centrality. We evaluated associations between hospital centrality and organizational, medical, surgical, and radiologic capabilities. Results: There were 47,820 transfers of critically ill patients among 3308 hospitals. 4.5% of all critical care stays of any length involved an interhospital critical care transfer. Hospitals transferred out to a mean of 4.4 other hospitals. More central hospital positions were associated with multiple indicators of increased capability. Hospital characteristics explained 40.7% of the variance in hospitals' centrality. Conclusions: Critical care transfers are common, and traverse an informal but structured network. The centrality of a hospital is associated with increased capability in delivery of services, suggesting that existing transfers generally direct patients toward better resourced hospitals. Studies of this network promise further improvements in patient outcomes and efficiency of care. C1 [Iwashyna, Theodore J.] Univ Michigan, Dept Med, Div Pulm & Crit Care, Ann Arbor, MI 48109 USA. [Iwashyna, Theodore J.; Kahn, Jeremy M.; Asch, David A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Christie, Jason D.; Kahn, Jeremy M.] Hosp Univ Penn, Dept Med, Div Pulm Allergy & Crit Care, Philadelphia, PA 19104 USA. [Christie, Jason D.; Kahn, Jeremy M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Moody, James] Duke Univ, Dept Sociol, Durham, NC 27706 USA. [Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Iwashyna, TJ (reprint author), 3A23 300 NIB,SPC 5419,300 N Ingalls Bldg, Ann Arbor, MI 48109 USA. EM tiwashyna@umich.edu OI Iwashyna, Theodore/0000-0002-4226-9310 FU NIH [HL07891-09, K08 HL09 1249]; ATS Fellows Career Development Award FX Supported in part by NIH grants HL07891-09 and K08 HL09 1249 and an ATS Fellows Career Development Award. NR 49 TC 64 Z9 64 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP 787 EP 793 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463VZ UT WOS:000267462400011 PM 19536030 ER PT J AU Barnett, PG AF Barnett, Paul G. TI An Improved Set of Standards for Finding Cost for Cost-Effectiveness Analysis SO MEDICAL CARE LA English DT Article DE cost-benefit analysis; costs and cost analysis/methods; hospital costs; hospital charges; research design ID ECONOMIC EVALUATIONS; HEALTH-CARE; METHODOLOGIC EVALUATION; CLINICAL-TRIALS; TASK-FORCE; QUALITY; HOSPITALS; CHARGES AB Background: Guidelines have helped standardize methods of cost-effectiveness analysis, allowing different interventions to be compared and enhancing the generalizability of study findings. There is agreement that all relevant services be valued from the societal perspective using a long-term time horizon and that more exact methods be used to cost services most affected by the Study intervention. Guidelines are not specific enough with respect to costing methods, however. Method: The literature was reviewed to identify the problems associated with the 4 principal methods of cost determination. Findings: Microcosting requires direct measurement and is ordinarily reserved to cost novel interventions. Analysts should include nonwage labor cost, person-level and institutional overhead, and the cost of development, set-up activities, supplies, space, and screening. Activity-based cost systems have promise of finding accurate costs of all services provided, but are not widely adopted. Quality must be evaluated and the generalizability of cost estimates to other settings must be considered. Administrative cost estimates, chiefly cost-adjusted charges, are widely used, but the analyst must consider items excluded from the available system. Gross costing methods determine quantity of services used and employ a unit cost. If the intervention will affect the characteristics of a service, the method should not assume that the service is homogeneous. Conclusions: Questions are posed for future reviews of the quality of costing methods. The analyst must avoid inappropriate assumptions, especially those that bias the analysis by exclusion of costs that are affected by the intervention under study. C1 [Barnett, Paul G.] US Dept Vet Affairs, Hlth Econ Resource Ctr, Stanford, CA USA. [Barnett, Paul G.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Barnett, PG (reprint author), Hlth Econ Resource Ctr, 795 Willow Rd 152,Menlo Pk, Menlo Pk, CA 94025 USA. EM paul.barnett@va.gov FU US Department of Veterans Affairs Health Services Research and Development Service [ECN-99-017]; VA Cooperative Studies Program FX Supported by the US Department of Veterans Affairs Health Services Research and Development Service (ECN-99-017) and the VA Cooperative Studies Program. NR 41 TC 32 Z9 34 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S82 EP S88 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500014 PM 19536018 ER PT J AU Yabroff, KR Warren, JL Schrag, D Mariotto, A Meekins, A Topor, M Brown, ML AF Yabroff, K. Robin Warren, Joan L. Schrag, Deborah Mariotto, Angela Meekins, Angela Topor, Marie Brown, Martin L. TI Comparison of Approaches for Estimating Incidence Costs of Care for Colorectal Cancer Patients SO MEDICAL CARE LA English DT Article DE health care costs; health services research; cost and cost analysis; neoplasms; medicare; SEER program ID STAGE BREAST-CANCER; SEER-MEDICARE DATA; UNITED-STATES; ENROLLEES; DIAGNOSIS; WOMEN AB Background: Estimates of the costs of medical care vary across patient populations, data sources, and methods. The objective of this study was to compare 3 approaches for estimating the incidence costs of colorectal cancer (CRC) care using similar patient populations, but different data sources and methods. Methods: We used 2 data sources, linked SEER-Medicare and Medicare claims alone, to identify newly diagnosed CRC patients aged 65 and older and estimated their healthcare costs during the observation period, 1998 to 2002. Controls were matched by sex, age-group, and geographic location. We compared mean net costs, measured as the difference in total cost between cases and controls, for: (1) a SEER-Medicare cohort, (2) a Medicare claims alone cohort, and (3) a modeled phase of care approach using linked SEER-Medicare data. The SEER-Medicare cohort approach was considered the reference. Results: We found considerable variability across approaches for estimating net costs of care in CRC patients. In the first year after diagnosis, mean net costs were $32,648 (95% CI: $31,826 and $33,470) in the SEER-Medicare cohort. The other approaches understated mean net costs in year 1 by about 16%. Mean net 5-year costs of care were $37,227 (95% CI: $35,711 and $38,744) in the SEER-Medicare cohort, and $30,310 (95% CI: $25,894 and $34,726) in the claims only approach, with the largest difference in the 65 to 69 age group. Mean net 5-year costs of care were more similar to the reference in the modeled phase of care approach ($37,701 [range: $36,972 and $38,4461]). Differences from the SEER-Medicare cohort estimates reflect misclassification of prevalent cancer patients as newly diagnosed patients in the Medicare claims only approach, and differences in years of data and assumptions about comparison groups in the modeled phase of care approach. Conclusions: CRC incidence cost estimates vary substantially depending on the strategy and data source for identifying newly diagnosed cancer patients and methods for estimating longitudinal costs. Our findings may inform estimation of costs for other cancers as well as other diseases. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schrag, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Meekins, Angela; Topor, Marie] Informat Management Serv Inc, Rockville, MD USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov NR 27 TC 31 Z9 32 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S56 EP S63 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500010 PM 19536010 ER PT J AU Yabroff, KR Warren, JL Banthin, J Schrag, D Mariotto, A Lawrence, W Meekins, A Topor, M Brown, ML AF Yabroff, K. Robin Warren, Joan L. Banthin, Jessica Schrag, Deborah Mariotto, Angela Lawrence, William Meekins, Angela Topor, Marie Brown, Martin L. TI Comparison of Approaches for Estimating Prevalence Costs of Care for Cancer Patients What Is the Impact of Data Source? SO MEDICAL CARE LA English DT Article DE health care costs; health services research; cost and cost analysis; colorectal neoplasms; Medicare; SEER program; MEPS ID SEER-MEDICARE DATA; UNITED-STATES; LIFE AB Background: National prevalence costs of medical care can be key inputs in health policy decisions. Cost estimates vary across data sources, patient populations, and methods, however, the objective of this study was to compare 3 approaches for estimating the prevalence costs of colorectal cancer (CRC) care using different data sources, but similar patient populations and methods. Methods: We identified prevalent CRC patients aged 65 and older from: (1) linked Surveillance Epidemiology and End Results (SEER) registry-Medicare data, (2) Medicare claims only, and (3) the Medical Expenditure Panel Survey (MEPS). Controls were matched by sex, age-group, and geographic location. Mean per person total and net costs, measured as the difference between patients and controls, were compared for each approach during a similar observation period. The SEER-Medicare approach was our reference, and we evaluated the impact of patient selection criteria with sensitivity analyses. Aggregate prevalence estimates were also compared. Results: We found considerable variability across the different approaches to estimating prevalence costs of CRC. Mean net annual per person estimates in the SEER-Medicare reference were $5341 (95% CI: $5243, $5439), compared with $8736 (95% CI: $8203, $9269) for the Medicare claims only and $11,614 (95% CI: $7566, $15,663) for the MEPS. Aggregate national estimates of net prevalence costs of CRC in 2004 ranged from $4524 million, using the SEER-Medicare approach, to $9629 million, using the MEPS approach. Estimates varied by data source based on the payors included and identification of prevalent CRC patients. Conclusions: CRC prevalence cost estimates vary substantially depending on the data sources. Our findings have implications for estimating prevalence costs for other cancers and other diseases without registry systems that can be used to identify newly diagnosed individuals as well as those diagnosed less recently. C1 [Yabroff, K. Robin; Warren, Joan L.; Mariotto, Angela; Brown, Martin L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Banthin, Jessica; Lawrence, William] Agcy Healthcare Res & Qual, Rockville, MD USA. [Schrag, Deborah] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Schrag, Deborah] Harvard Univ, Sch Med, Boston, MA USA. [Meekins, Angela; Topor, Marie] Informat Management Serv Inc, Rockville, MD USA. RP Yabroff, KR (reprint author), Appl Res Program, Hlth Serv & Econ Branch, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 20 TC 35 Z9 36 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S64 EP S69 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500011 PM 19536016 ER PT J AU Sepucha, KR Ozanne, EM Partridge, AH Moy, B AF Sepucha, Karen R. Ozanne, Elissa M. Partridge, Ann H. Moy, Beverly TI Is There a Role for Decision Aids in Advanced Breast Cancer? SO MEDICAL DECISION MAKING LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-Medical-Decision-Making CY OCT 20-24, 2007 CL Pittsburgh, PA SP Soc Med Decis Making DE decision making; metastatic breast cancer; decision aids ID CELL LUNG-CANCER; TERM-FOLLOW-UP; 1ST-LINE CHEMOTHERAPY; MULTICENTER TRIAL; PREFERENCES; DOXORUBICIN; CRITERIA; WOMEN; CARE; CYCLOPHOSPHAMIDE AB Background. A diagnosis of metastatic breast cancer (BC) forces patients and providers to make difficult treatment decisions. Objective. To pilot test a decision aid (DA) for advanced BC. Design. Pretest, posttest study. Setting. Two academic cancer centers in Boston, Massachusetts. Patients. Fifty patients diagnosed with advanced BC. Intervention. A patient DA that consisted of a 30-minute DVD and booklet. Measurements. Patients were surveyed at baseline, after the intervention, and at 3 months. Measures included use and acceptability of DA, distress, treatment goals, and preference for and actual participation in decisions. Physicians were surveyed at baseline and 3 months. Measures included treatment goals, assessment of patients' experience with treatments, and patients' preference for and actual participation in decisions. Results. Thirty-two patients (64%) enrolled and completed the baseline survey, 30 completed the postvideo survey, and 25 completed the 3-month survey. The DA was acceptable and did not increase distress. The majority desired to share decision making with their doctor. Only 38% achieved their desired level of participation. At baseline, agreement between patients and providers on the main goal of treatment (lengthen life v. relieve symptoms) was 50% (kappa = -0.045, P = 0.71), and at 3 months it was 74% (kappa = 0.125, P = 0.48). Conclusions. It is feasible to perform a clinical trial of a DA with advanced BC patients. Most participants wanted to participate in decisions about their care and found the DA acceptable. This study highlights several issues in developing and implementing DAs in this vulnerable population facing complex decisions. C1 [Sepucha, Karen R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hlth Decis Res Unit, Boston, MA 02114 USA. [Ozanne, Elissa M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA 02114 USA. [Partridge, Ann H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02114 USA. [Moy, Beverly] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. RP Sepucha, KR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hlth Decis Res Unit, 50 Staniford St,Suite 936, Boston, MA 02114 USA. EM ksepucha@partners.org NR 38 TC 15 Z9 15 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL PY 2009 VL 29 IS 4 BP 475 EP 482 DI 10.1177/0272989X09333124 PG 8 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 474NP UT WOS:000268291200008 PM 19329775 ER PT J AU Daartz, J Engelsman, M Paganetti, H Bussiere, MR AF Daartz, J. Engelsman, M. Paganetti, Harald Bussiere, M. R. TI Field size dependence of the output factor in passively scattered proton therapy: Influence of range, modulation, air gap, and machine settings SO MEDICAL PHYSICS LA English DT Article DE biomedical measurement; dosimetry; phantoms; radiation therapy ID COLLIMATOR SCATTER; BEAMS AB At the Francis H. Burr Proton Therapy Center field specific output factors (i.e., dose per monitor unit) for patient treatments were modeled for all beamlines (two gantries, fixed stereotactic, and fixed eye beamline). The authors evaluated the accuracy of dose calculation and output model for small fields. Measurements in a water phantom were performed in three of our beamlines quantifying the dependency of the output factor on the field size for a variety of proton ranges. The influence of snout size, air gap, modulation, and second scatterer was investigated. The impact of field size on output depends strongly on the depth of interest. The air gap has a notable influence on small field outputs. A field size specific correction factor to the output is necessary if the latter was modeled or measured without the custom hardware in place. The output was shown to be field size dependent even for large fields, indicating an effect beyond charged particle disequilibrium caused by lateral scatter. C1 [Daartz, J.; Engelsman, M.; Paganetti, Harald; Bussiere, M. R.] Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. [Daartz, J.] German Canc Res Ctr, Dept Med Phys Radiat Oncol, D-69120 Heidelberg, Germany. RP Daartz, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. EM jdaartz@partners.org NR 8 TC 15 Z9 15 U1 2 U2 8 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2009 VL 36 IS 7 BP 3205 EP 3210 DI 10.1118/1.3152111 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 463KW UT WOS:000267431800037 PM 19673219 ER PT J AU Keane, MM Martin, E Verfaellie, M AF Keane, Margaret M. Martin, Elizabeth Verfaellie, Mieke TI Performance benefits and costs in forced choice perceptual identification in amnesia: Effects of prior exposure and word frequency SO MEMORY & COGNITION LA English DT Article ID IMPLICIT MEMORY TASKS; COUNTER MODEL; ENHANCED DISCRIMINABILITY; EXPLICIT MEMORY; BIAS; REPETITION; SYSTEMS AB Accuracy in identifying a perceptually degraded word (e.g., stake) can be either enhanced by recent exposure to the same stimulus or reduced by recent exposure to a similar stimulus (e.g., stare). In the present study, we explored the mechanisms underlying these benefits and costs by examining the performance of amnesic and control groups in a forced choice perceptual identification (FCPI) task in which briefly flashed words (that were identical to studied words, similar to studied words, or new) had to be identified, and two response choices were provided that differed from each other by one letter. Control participants showed a performance benefit and cost in FCPI with both high- and low-frequency words. Amnesic participants showed a benefit (but no cost) with high-frequency words and a benefit and a cost with low-frequency words. The benefit/cost pattern with low-frequency words in amnesia was obtained even when the to-be-identified stimulus in the FCPI task was eliminated (Experiment 2), suggesting that this effect was driven by processes operating at the level of the response choices. Our findings suggest that implicit memory effects in FCPI reflect the operation of multiple mechanisms, the relative contributions of which may vary with the frequency of the test stimuli. The results also highlight the need for caution in interpreting results from normal participants in the FCPI task, since those findings may reflect a contribution of explicit memory processes. C1 [Keane, Margaret M.] Wellesley Coll, Dept Psychol, Wellesley, MA 02481 USA. [Keane, Margaret M.; Martin, Elizabeth; Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02118 USA. [Keane, Margaret M.; Martin, Elizabeth; Verfaellie, Mieke] Boston VA Healthcare Syst, Boston, MA USA. RP Keane, MM (reprint author), Wellesley Coll, Dept Psychol, Wellesley, MA 02481 USA. EM mkeane@wellesley.edu OI Verfaellie, Mieke/0000-0001-5535-4584 FU NIMH NIH HHS [R01 MH057681, R01 MH070830, R01 MH070830-04, MH70830, MH57681] NR 33 TC 1 Z9 1 U1 0 U2 0 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0090-502X J9 MEM COGNITION JI Mem. Cogn. PD JUL PY 2009 VL 37 IS 5 BP 655 EP 666 DI 10.3758/MC.37.5.655 PG 12 WC Psychology, Experimental SC Psychology GA 457VO UT WOS:000266962600012 PM 19487757 ER PT J AU Price, MD Herndon, JH AF Price, Mark D. Herndon, James H. TI Gender differences in osteoarthritis SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID KNEE CARTILAGE DEFECTS; PATELLOFEMORAL JOINT; ARTICULAR-CARTILAGE; HIP OSTEOARTHRITIS; RISK-FACTORS; PREVALENCE; WOMEN; PATTERNS; INJURY; MEN C1 [Price, Mark D.; Herndon, James H.] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. RP Price, MD (reprint author), Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. NR 23 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 624 EP 625 DI 10.1097/gme.0b013e3181a5c9e6 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 468RJ UT WOS:000267837300003 PM 19384254 ER PT J AU Burnett-Bowie, SAM AF Burnett-Bowie, Sherri-Ann M. TI Vitamin D and fat: the chicken versus the egg SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID D DEFICIENCY; 25-HYDROXYVITAMIN-D; POPULATION; COMPONENTS; WOMEN; RISK C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Burnett-Bowie, SAM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. OI Burnett-Bowie, Sherri-Ann/0000-0002-0064-096X NR 13 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 637 EP 638 DI 10.1097/gme.0b013e3181aeebef PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 468RJ UT WOS:000267837300008 PM 19546823 ER PT J AU Huang, AJ Sawaya, GF Vittinghoff, E Lin, F Grady, D AF Huang, Alison J. Sawaya, George F. Vittinghoff, Eric Lin, Feng Grady, Deborah TI Hot flushes, coronary heart disease, and hormone therapy in postmenopausal women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Hot flushes; Coronary heart disease; Hormone therapy; Menopause; Estrogen ID ESTROGEN PLUS PROGESTIN; CARDIOVASCULAR-DISEASE; MENOPAUSAL COMPLAINTS; REPLACEMENT THERAPY; FLASHES; ASSOCIATION; HEALTH; RISK; POLYMORPHISMS; SYMPTOMS AB Objective: The aim of this study was to examine interactions between hot flushes, estrogen plus progestogen therapy (EPT), and coronary heart disease (CHD) events in postmenopausal women with CHD. Methods: We analyzed data from the Heart and Estrogen/Progestin Replacement Study, a randomized, placebo-controlled trial of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate in 2,763 postmenopausal women with CHD. Hot flushes were assessed at baseline using self-administered questionnaires; women reporting bothersome hot flushes "some" to "all" of the time were considered to have clinically significant flushing. Cox regression models were used to examine the effect of EPT on risk of CHD events among women with and without significant flushing at baseline. Results: The mean age of participants was 66.7 +/- 6.8 years, and 89% (n = 2,448) were white. Sixteen percent (n = 434) of participants reported clinically significant hot flushes at baseline. Among women with baseline flushing, EPT increased risk of CHD events nine-fold in the first year compared with placebo (hazard ratio = 9.01; 95% CI, 1.15-70.35); among women without baseline flushing, treatment did not significantly affect CHD event risk in the first year (hazard ratio = 1.32; 95% CI, 0.86-2.03; P = 0.07 for interaction of hot flushes with treatment). The trend toward differential effects of EPT on risk for CHD among women with and without baseline flushing did not persist after the first year of treatment. Conclusions: Among older postmenopausal women with CHD, EPT may increase risk of CHD events substantially in the first year of treatment among women with clinically significant hot flushes but not among those without hot flushes. C1 [Huang, Alison J.; Grady, Deborah] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Sawaya, George F.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Sawaya, George F.; Vittinghoff, Eric; Lin, Feng; Grady, Deborah] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Grady, Deborah] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. RP Huang, AJ (reprint author), 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM ahuang@ucsfmed.org FU Wyeth-Ayerst Research; National Institutes of Health (NIH); National Center for Research Resources [KL2RR024130] FX The Heart and Estrogen/Progestin Replacement Study was funded by Wyeth-Ayerst Research, but Wyeth-Ayerst Research had no role in the research described in this manuscript, including management, analysis, or interpretation of the data, or preparation or revision of this manuscript. This research was supported by National Institutes of Health (NIH) and the National Center for Research Resources Grant KL2RR024130 to the University of California San Francisco Clinical and Translational Science Institute. NR 24 TC 46 Z9 46 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 639 EP 643 DI 10.1097/gme.0b013e31819c11c4 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 468RJ UT WOS:000267837300009 PM 19325499 ER PT J AU Joffe, H Soares, CN Thurston, RC White, DP Cohen, LS Hall, JE AF Joffe, Hadine Soares, Claudio N. Thurston, Rebecca C. White, David P. Cohen, Lee S. Hall, Janet E. TI Depression is associated with worse objectively and subjectively measured sleep, but not more frequent awakenings, in women with vasomotor symptoms SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Vasomotor symptoms; Hot flashes; Sleep; Insomnia; Depression; Mood ID MENOPAUSAL HOT FLASHES; DATA-ANALYSIS SOFTWARE; PERIMENOPAUSAL WOMEN; POSTMENOPAUSAL WOMEN; WAKE ACTIVITY; PRIMARY-CARE; TRANSITION; INSOMNIA; DISTURBANCE; ACTIGRAPHY AB Objective: Depression occurs more commonly during the menopausal transition in women with vasomotor symptoms (VMS) than in those without, but most women with VMS do not develop depression. It has been hypothesized that VMS are associated with depression because VMS lead to repeated awakenings, which impair daytime well-being. We aimed to determine if objectively measured sleep and perceived sleep quality are worse in depressed women with VMS than in nondepressed women with VMS. Methods: Objectively and subjectively measured sleep parameters were compared between 52 depressed women with VMS and 51 nondepressed controls with VMS. Actigraphic measures of objective sleep conducted in the home environment and subjective measures of sleep quality (Pittsburgh Sleep Questionnaire Index) were compared using linear regression models. Results: On objective assessments, depressed women with VMS spent less time in bed (by 64.8 min; P < 0.001) and had shorter total sleep time (by 47.7 min; P = 0.008), longer sleep-onset latency (by 13.8 min; P = 0.03), and lower sleep efficiency (by 3.2 percentage points; P = 0.09), but did not awaken more or spend more time awake after sleep onset than nondepressed controls with VMS. Depressed women also reported worse sleep quality (mean Pittsburgh Sleep Questionnaire Index 12.0 vs 8.3; P < 0.001). Adjustment for VMS frequency and important demographic characteristics did not alter these associations. Conclusions: Sleep quality and selected parameters of objectively measured sleep, but not sleep interruption, are worse in depressed than in nondepressed women with VMS. The type of sleep disturbance seen in depressed participants was not consistent with the etiology of depression secondary to VMS-associated awakenings. C1 [Joffe, Hadine; Soares, Claudio N.; Cohen, Lee S.] Harvard Univ, Perinatal & Reprod Psychiat Program, Dept Psychiat, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. [Thurston, Rebecca C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [White, David P.] Brigham & Womens Hosp, Dept Med, Sleep Disorders Program, Boston, MA 02115 USA. [Hall, Janet E.] Harvard Univ, Dept Med, Massachusetts Gen Hosp, Reprod Endocrine Unit,Med Sch, Boston, MA 02114 USA. RP Joffe, H (reprint author), Harvard Univ, Perinatal & Reprod Psychiat Program, Dept Psychiat, Massachusetts Gen Hosp,Med Sch, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM hjoffe@partners.org FU National Institute of Mental Health [K23 MH066978]; Susan G. Komen Breast Cancer Foundation Award; GlaxoSmithKline FX This work was supported in part by National Institute of Mental Health grant K23 MH066978, a Susan G. Komen Breast Cancer Foundation Award, and GlaxoSmithKline. NR 55 TC 40 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 671 EP 679 DI 10.1097/gme.0b013e3181957377 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 468RJ UT WOS:000267837300014 PM 19197217 ER PT J AU Nagrath, D Xu, HZ Tanimura, Y Zuo, RJ Berthiaume, F Avila, M Yarmush, R Yarmush, ML AF Nagrath, Deepak Xu, Hongzhi Tanimura, Yoko Zuo, Rongjun Berthiaume, Francois Avila, Marco Yarmush, Rubin Yarmush, Martin L. TI Metabolic preconditioning of donor organs: Defatting fatty livers by normothermic perfusion ex vivo SO METABOLIC ENGINEERING LA English DT Article DE Nuclear receptors; Normothermic perfusion; Hepatocytes; Steatosis; Liver transplantation ID ISCHEMIA-REPERFUSION INJURY; PPAR-DELTA AGONIST; GENE-EXPRESSION; RAT-LIVER; TRIACYLGLYCEROL HYDROLASE; LIPID-METABOLISM; WARM ISCHEMIA; MUSCLE-CELLS; IN-VIVO; TRANSPLANTATION AB Fatty liver is a significant risk factor for liver transplantation, and accounts for nearly half of the livers rejected from the donor pool. We hypothesized that metabolic preconditioning via ex vivo perfusion of the liver graft can reduce fat content and increase post-transplant survival to an acceptable range. We describe a perfusate medium containing agents that promote the defatting of hepatocytes and explanted livers. Defatting agents were screened on cultured hepatocytes made fatty by pre-incubation with fatty acids. The most effective agents were then used on fatty livers. Fatty livers were isolated from obese Zucker rats and normothermically perfused with medium containing a combination of defatting agents. This combination decreased the intracellular lipid content of cultured hepatocytes by 35% over 24h, and of perfused livers by 50% over 3h. Metabolite analysis suggests that the defatting cocktail upregulated both lipid oxidation and export. Furthermore, gene expression analysis for several enzymes and transcription factors involved in fatty acid oxidation and triglyceride clearance were elevated. We conclude that a cocktail of defatting agents can be used to rapidly clear excess lipid storage in fatty livers, thus providing a new means to recondition donor livers deemed unacceptable or marginally acceptable for transplantation. (C) 2009 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med Surg Serv, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA 02114 USA. RP Yarmush, ML (reprint author), Rice Univ, Houston, TX 77251 USA. EM ireis@sbi.org OI Nagrath, Deepak/0000-0002-8999-2282 FU National Institutes of Health [R01DK059766, R01DK43371, P41EB002503]; Shriners Hospitals for Children FX Financial support: This work was partially supported by the National Institutes of Health Grant nos. R01DK059766, R01DK43371, P41EB002503, and the Shriners Hospitals for Children. NR 52 TC 27 Z9 30 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 1096-7176 J9 METAB ENG JI Metab. Eng. PD JUL-SEP PY 2009 VL 11 IS 4-5 BP 274 EP 283 DI 10.1016/j.ymben.2009.05.005 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 487JY UT WOS:000269270700007 PM 19508897 ER PT J AU Nosho, K Shima, K Irahara, N Kure, S Firestein, R Baba, Y Toyoda, S Chen, L Hazra, A Giovannucci, EL Fuchs, CS Ogino, S AF Nosho, Katsuhiko Shima, Kaori Irahara, Natsumi Kure, Shoko Firestein, Ron Baba, Yoshifumi Toyoda, Saori Chen, Li Hazra, Aditi Giovannucci, Edward L. Fuchs, Charles S. Ogino, Shuji TI SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer SO MODERN PATHOLOGY LA English DT Article DE colon cancer; epigenetics; sir2; HDAC; sirtuin; acetylation ID POPULATION-BASED SAMPLE; COLON-CANCER; LINE-1 HYPOMETHYLATION; CALORIE RESTRICTION; REGULATES SIRT1; BRAF MUTATION; CELL-SURVIVAL; CIMP; COHORT; P53 AB The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37%) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (>= 6 of 8 methylated CIMP-specific promoters, P = 0.002) and microsatellite instability (MSI)-high phenotype (P<0.0001). In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35-7.59; P = 0.008). In addition, mucinous component (P = 0.01), high tumor grade (P = 0.02), and fatty acid synthase overexpression (P = 0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, beta-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype. Modern Pathology (2009) 22, 922-932; doi: 10.1038/modpathol.2009.49; published online 8 May 2009 C1 [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol,Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Nosho, Katsuhiko; Shima, Kaori; Irahara, Natsumi; Kure, Shoko; Firestein, Ron; Baba, Yoshifumi; Toyoda, Saori; Chen, Li; Hazra, Aditi; Giovannucci, Edward L.; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hazra, Aditi; Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hazra, Aditi; Giovannucci, Edward L.; Ogino, Shuji] Harvard Univ, Sch Med, Dept Epidemiol, Boston, MA 02115 USA. [Nosho, Katsuhiko; Shima, Kaori; Irahara, Natsumi; Kure, Shoko; Firestein, Ron; Baba, Yoshifumi; Toyoda, Saori; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol,Ctr Mol Oncol Pathol, 75 Francis St,44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU US National Institute of Health (NIH) [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; Bennett Family Fund; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance (NCCRA); Japan Society for Promotion of Science FX We thank the Nurses' Health Study and Health Professionals Follow-up Study cohort participants who generously agreed to provide us with biological specimens and information through responses to questionnaires. We also thank Frank Speizer, Walter Willett, Susan Hankinson, Graham Colditz, Meir Stampfer, and many other staff members who implemented and have maintained the cohort studies. This work was supported by US National Institute of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003 (to CSF) and K07 CA122826 (to SO), and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance (NCCRA). KN was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. NR 58 TC 59 Z9 61 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD JUL PY 2009 VL 22 IS 7 BP 922 EP 932 DI 10.1038/modpathol.2009.49 PG 11 WC Pathology SC Pathology GA 465ID UT WOS:000267575400009 PM 19430421 ER PT J AU Erickson, LA Letts, GA Shahy, SM Shackelton, JB Duncan, LM AF Erickson, Lori A. Letts, Gary A. Shahy, Sonali M. Shackelton, Jeffrey B. Duncan, Lyn M. TI TRPM1 (Melastatin-1/MLSN1) mRNA expression in Spitz nevi and nodular melanomas SO MODERN PATHOLOGY LA English DT Article DE Spitz nevi; melanoma; TRPM1; melastatin; prognosis ID CUTANEOUS MALIGNANT-MELANOMA; AMERICAN JOINT COMMITTEE; MELANOCYTIC TUMORS; PROGNOSTIC MARKER; GENE; DIFFERENTIATION; MDA-7; PRODUCT; MART-1 AB The transient receptor potential cation channel, subfamily M, member 1 (TRPM1/Melastatin-1/MLSN-1) expression has been shown to have prognostic utility in the evaluation of primary cutaneous melanoma. We analyzed a series of spindled and epithelioid cell nevi (Spitz) and primary cutaneous nodular melanomas to determine whether the expression of TRPM1 mRNA may be useful in distinguishing between Spitz nevi and nodular melanomas and to further examine the patterns of TRPM1 mRNA expression in cutaneous melanocytic proliferations. Formalin-fixed, paraffin-embedded tissues from 95 Spitz nevi and 33 nodular melanomas were analyzed for the expression of TRPM1 mRNA by in situ hybridization using (35)S-labeled riboprobes. Ubiquitous melanocytic expression of TRPM1 mRNA was observed in 56 of 95 (59%) Spitz nevi and 4 of 33 (12%) nodular melanomas. Diffusely scattered loss of TRPM1 mRNA was identified in 38 of 95 (40%) Spitz nevi and 2 of 33 (6%) nodular melanomas. Regional loss of the TRPM1 mRNA expression by a significant subset of dermal tumor cells or a complete absence of TRPM1 expression by the dermal tumor was identified in 27 of 33 (82%) nodular melanomas, but only 1 of 95 (1%) Spitz nevi. These findings suggest that the pattern of TRPM1 mRNA expression may be helpful in the differentiation of Spitz nevi and nodular melanomas. Of the 16 patients who experienced metastasis, 15 (94%) had primary tumors that displayed reduced MLSN mRNA expression by all or a part of the dermal tumor. Modern Pathology (2009) 22, 969-976; doi: 10.1038/modpathol.2009.56; published online 24 April 2009 C1 [Duncan, Lyn M.] Massachusetts Gen Hosp, Dept Dermatopathol Unit, Dermatopathol Unit, Pathol Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Duncan, LM (reprint author), Massachusetts Gen Hosp, Dept Dermatopathol Unit, Dermatopathol Unit, Pathol Serv, WRN827,55 Fruit St, Boston, MA 02114 USA. EM duncan@helix.mgh.harvard.edu NR 26 TC 13 Z9 13 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD JUL PY 2009 VL 22 IS 7 BP 969 EP 976 DI 10.1038/modpathol.2009.56 PG 8 WC Pathology SC Pathology GA 465ID UT WOS:000267575400014 PM 19396153 ER PT J AU Lisovsky, M Dresser, K Baker, S Fisher, A Woda, B Banner, B Lauwers, GY AF Lisovsky, Mikhail Dresser, Karen Baker, Stephen Fisher, Andrew Woda, Bruce Banner, Barbara Lauwers, Gregory Y. TI Cell polarity protein Lgl2 is lost or aberrantly localized in gastric dysplasia and adenocarcinoma: an immunohistochemical study SO MODERN PATHOLOGY LA English DT Article DE gastric; dysplasia; Lgl2; cell polarity; adenocarcinoma ID LETHAL GIANT LARVAE; EPITHELIAL DYSPLASIA; TUMOR SUPPRESSORS; DROSOPHILA; CANCER; COMPLEX; APKC; CLASSIFICATION; ACTIVATION; HUGL-1 AB The diagnosis of gastric epithelial dysplasia, a precursor lesion of gastric adenocarcinoma, is hindered by interobserver variability and by its resemblance to regenerative changes. Loss of cell polarity, a histological feature of gastric epithelial dysplasia, may be difficult to ascertain, especially in the setting of inflammation or injury. A biomarker of cell polarity could be useful in diagnosis of dysplasia, but has not been reported. The Lethal giant larvae (lgl) gene controls apical-basal polarity of epithelial cells in Drosophila, and has properties of a tumor-suppressor gene. Two homologs, lgl1 and lgl2, are present in mammals and lgl2 mRNA is highly expressed in the stomach. The goal of our study was to test the hypothesis that Lgl2 protein expression and/or localization are disrupted in gastric epithelial dysplasia and adenocarcinoma. Routinely processed pathology specimens including 94 benign mucosae of digestive organs, in addition to 36 reactive gastropathy, 57 gastric epithelial dysplasia, and 77 gastric adenocarcinomas, were immunostained for Lgl2 protein. All normal, reactive, and chronically inflamed gastric epithelia showed basolateral Lgl2 staining. Normal esophageal, duodenal, colonic, biliary, and pancreatic duct mucosae, as well as gastric intestinal metaplasia, did not express Lgl2. All but one case each of gastric epithelial dysplasia and adenocarcinoma showed either complete loss of anti-Lgl2 immunoreactivity or diffuse, mostly weak, cytoplasmic staining. Complete loss of immunoreactivity was significantly more often observed in diffuse-type than in intestinal-type adenocarcinomas (79 vs 48%, respectively). Our data suggest that Lgl2 expression is either aberrantly localized or lost in gastric epithelial dysplasia and adenocarcinoma, whereas it is maintained in reactive gastric mucosa. We propose that Lgl2 may be a potential marker to rule out gastric epithelial dysplasia and adenocarcinoma in diagnostic specimens. However, the consistently negative anti-Lgl2 immunoreactivity seen in intestinal metaplasia does not allow differentiation of dysplasia from intestinal metaplasia with reactive change. Modern Pathology (2009) 22, 977-984; doi: 10.1038/modpathol.2009.68; published online 1 May 2009 C1 [Lisovsky, Mikhail; Lauwers, Gregory Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Lisovsky, Mikhail; Dresser, Karen; Fisher, Andrew; Woda, Bruce; Banner, Barbara] Univ Massachusetts, Sch Med, Dept Pathol, UMass Mem Med Ctr, Worcester, MA 01605 USA. [Baker, Stephen] Univ Massachusetts, Sch Med, Biostat Unit, UMass Mem Med Ctr, Worcester, MA 01605 USA. RP Lisovsky, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, 55 Fruit St,WRN 219, Boston, MA 02114 USA. EM mlisovsky@partners.org NR 28 TC 26 Z9 26 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD JUL PY 2009 VL 22 IS 7 BP 977 EP 984 DI 10.1038/modpathol.2009.68 PG 8 WC Pathology SC Pathology GA 465ID UT WOS:000267575400015 PM 19407852 ER PT J AU Dovey, M Patton, EE Bowman, T North, T Goessling, W Zhou, Y Zon, LI AF Dovey, Michael Patton, E. Elizabeth Bowman, Teresa North, Trista Goessling, Wolfram Zhou, Yi Zon, Leonard I. TI Topoisomerase II alpha Is Required for Embryonic Development and Liver Regeneration in Zebrafish SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; CELL-CYCLE; CHROMATIN TEMPLATES; DNA TOPOISOMERASES; NIH-3T3 CELLS; IN-VITRO; EXPRESSION; MUTANT; DECATENATION; INHIBITION AB Topoisomerases solve the topological problems encountered by DNA throughout the lifetime of a cell. Topoisomerase II alpha, which is highly conserved among eukaryotes, untangles replicated chromosomes during mitosis and is absolutely required for cell viability. A homozygous lethal mutant, can4, was identified in a screen to identify genes important for cell proliferation in zebrafish by utilizing an antibody against a mitosis-specific marker, phospho-histone H3. Mutant embryos have a decrease in the number of proliferating cells and display increases in DNA content and apoptosis, as well as mitotic spindle defects. Positional cloning revealed that the genetic defect underlying these phenotypes was the result of a mutation in the zebrafish topoisomerase II alpha (top2a) gene. top2a was found to be required for decatenation but not for condensation in embryonic mitoses. In addition to being required for development, top2a was found to be a haploinsufficient regulator of adult liver regrowth in zebrafish. Regeneration analysis of other adult tissues, including fins, revealed no heterozygous phenotype. Our results confirm a conserved role for TOP2A in vertebrates as well as a dose-sensitive requirement for top2a in adults. C1 [Zon, Leonard I.] Childrens Hosp Boston, Stem Cell Program & Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Harvard Stem Cell Inst, Howard Hughes Med Inst,Dana Farber Canc Inst, Boston, MA USA. RP Zon, LI (reprint author), Childrens Hosp Boston, Stem Cell Program & Hematol Oncol, Karp Family Res Bldg Room 7211,1 Blackfan Circle, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu OI Goessling, Wolfram/0000-0001-9972-1569 FU NIH [5 R01 CA103846-04]; Howard Hughes Medical Institute FX This work was supported by NIH 5 R01 CA103846-04. L.I.Z. is an Investigator of the Howard Hughes Medical Institute. NR 41 TC 16 Z9 17 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL 1 PY 2009 VL 29 IS 13 BP 3746 EP 3753 DI 10.1128/MCB.01684-08 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 457ZK UT WOS:000266978000025 PM 19380487 ER PT J AU Bodempudi, V Yamoutpoor, F Pan, WH Dudek, AZ Esfandyari, T Piedra, M Babovick-Vuksanovic, D Woo, RA Mautner, VF Kluwe, L Clapp, DW DeVries, GH Thomas, SL Kurtz, A Parada, LF Farassati, F AF Bodempudi, Vidya Yamoutpoor, Farnaz Pan, Weihong Dudek, Arkadiusz Z. Esfandyari, Tuba Piedra, Mark Babovick-Vuksanovic, Dusica Woo, Richard A. Mautner, Victor F. Kluwe, Lan Clapp, D. Wade DeVries, George H. Thomas, Stacey L. Kurtz, Andreas Parada, Luis F. Farassati, Faris TI Ral Overactivation in Malignant Peripheral Nerve Sheath Tumors SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR RECEPTOR; NEUROFIBROMATOSIS TYPE-1; ONCOGENIC RAS; NF1 GENE; SIGNALING PATHWAY; SCHWANN-CELLS; PROTEIN; CANCER; METASTASIS AB Ras leads an important signaling pathway that is deregulated in neurofibromatosis type 1 and malignant peripheral nerve sheath tumor (MPNST). In this study, we show that overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines. RalA, however, was overactivated in all MPNST cells and tumor samples compared to nontransformed Schwann cells. Silencing Ral or inhibiting it with a dominant-negative Ral (Ral S28N) caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells. Silencing Ral also reduced the expression of epithelial mesenchymal transition markers. Expression of the NF1-GTPase-related domain (NF1-GRD) diminished the levels of Ral activation, implicating a role for neurofibromin in regulating RalA activation. NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, but cell death increased. We propose Ral overactivation as a novel cell signaling abnormality in MPNST that leads to important biological outcomes with translational ramifications. C1 [Esfandyari, Tuba; Farassati, Faris] Univ Kansas, Mol Med Lab, Sch Med, Dept Med, Kansas City, KS USA. [Bodempudi, Vidya; Yamoutpoor, Farnaz; Pan, Weihong; Dudek, Arkadiusz Z.] Univ Minnesota, Minneapolis, MN USA. [Piedra, Mark; Babovick-Vuksanovic, Dusica] Mayo Clin, Rochester, MN USA. [Woo, Richard A.] So Illinois Univ, Springfield, IL USA. [Mautner, Victor F.; Kluwe, Lan] Univ Hosp Eppendorf, Hamburg, Germany. [Clapp, D. Wade] Indiana Univ, Sch Med, Indianapolis, IN USA. [DeVries, George H.; Thomas, Stacey L.] VA Hosp, Res Serv, Hines, IL USA. [Kurtz, Andreas] Massachusetts Gen Hosp, Charlestown, MA USA. [Parada, Luis F.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Farassati, F (reprint author), KUMC Mol Med Lab, 1000 Hixon,Mail Stop 4037,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM ffarassati@kumc.edu RI Parada, luis/B-9400-2014 FU Department of Defense-NF [NF050014] FX This study was supported in part by Department of Defense-NF research program grant NF050014 to F. F. We acknowledge the thoughtful advice and analysis by R. L. Martuza and S. D. Rabkin. We appreciate the editorial assistance of Michael J. Franklin, Martha Montello, and Amanda Wise. NR 72 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2009 VL 29 IS 14 BP 3964 EP 3974 DI 10.1128/MCB.01153-08 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 469ZA UT WOS:000267939300013 PM 19414599 ER PT J AU Hoang, B Benavides, A Shi, YJ Frost, P Lichtenstein, A AF Hoang, Bao Benavides, Angelica Shi, Yijiang Frost, Patrick Lichtenstein, Alan TI Effect of autophagy on multiple myeloma cell viability SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; PROTEASOME INHIBITOR PS-341; OVERCOMES DRUG-RESISTANCE; ISOLATED RAT HEPATOCYTES; MOLECULAR-MECHANISMS; ANTIMYELOMA ACTIVITY; MAMMALIAN TARGET; DEGRADATION; BORTEZOMIB AB Because accumulation of potentially toxic malfolded protein may be extensive in immunoglobulin-producing multiple myeloma (MM) cells, we investigated the phenomenon of autophagy in myeloma, a physiologic process that can protect against malfolded protein under some circumstances. Autophagy in MM cell lines that express and secrete immunoglobulin and primary specimens was significantly increased by treatment with the endoplasmic reticulum stress-inducing agent thapsigargin, the mammalian target of rapamycin inhibitor rapamycin, and the proteasome inhibitor bortezomib. Inhibition of basal autophagy in these cell lines and primary cells by use of the inhibitors 3-methyladenine and chloroquine resulted in a cytotoxic effect that was associated with enhanced apoptosis. Use of small interfering RNA to knock down expression of beclin-1, a key protein required for autophagy, also inhibited viable recovery of MM cells. Because the data suggested that autophagy protected MM cell viability, we predicted that autophagy inhibitors would synergize with bortezomib for enhanced antimyeloma effects. However, the combination of these drugs resulted in an antagonistic response. In contrast, the autophagy inhibitor 3-methyladenine did synergize with thapsigargin for an enhanced cytotoxic response. These data suggest that autophagy inhibitors have therapeutic potential in myeloma but caution against combining such drugs with bortezomib. [Mol Cancer Ther 2009;8(7):1974-84] C1 Univ Calif Los Angeles, Sch Med, Div Hematol Oncol, Dept Med,Greater Los Angeles Vet Affairs Healthca, Los Angeles, CA 90024 USA. Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. RP Lichtenstein, A (reprint author), W Los Angeles Vet Affairs Hosp, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM alan.lichtenstein@med.va.gov OI Frost, Patrick/0000-0003-3348-5983 FU NIH [RO1CA111448, KO1CA111623]; Multiple Myeloma Research Foundation; Veteran's Administration FX NIH grants RO1CA111448 and KO1CA111623, Multiple Myeloma Research Foundation, and research funds of the Veteran's Administration. NR 46 TC 67 Z9 70 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2009 VL 8 IS 7 BP 1974 EP 1984 DI 10.1158/1535-7163.MCT-08-1177 PG 11 WC Oncology SC Oncology GA 470UG UT WOS:000268005700026 PM 19509276 ER PT J AU Sleat, DE Ding, L Wang, S Zhao, CF Wang, YH Xin, WN Zheng, HY Moore, DF Sims, KB Lobel, P AF Sleat, David E. Ding, Lin Wang, Shudan Zhao, Caifeng Wang, Yanhong Xin, Winnie Zheng, Haiyan Moore, Dirk F. Sims, Katherine B. Lobel, Peter TI Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; SANFILIPPO-A-SYNDROME; SULFAMIDASE GENE; SHOTGUN PROTEOMICS; MOLECULAR DEFECTS; IIIA SANFILIPPO; CLN5 MUTATION; IDENTIFICATION; ONSET; GLYCOPROTEINS AB Diagnosis of lysosomal storage diseases (LSDs) can be problematic in atypical cases where clinical phenotype may overlap with other genetically distinct disorders. In addition, LSDs may result from mutations in genes not yet implicated in disease. Thus, there are individuals that are diagnosed with apparent LSD based upon clinical criteria where the gene defect remains elusive. The objective of this study was to determine whether comparative proteomics approaches could provide useful insights into such cases. Most LSDs arise from mutations in genes encoding lysosomal proteins that contain mannose 6-phosphate, a carbohydrate modification that acts as a signal for intracellular targeting to the lysosome. We purified mannose 6-phosphorylated proteins by affinity chromatography and estimated relative abundance of individual proteins in the mixture by spectral counting of peptides detected by tandem mass spectrometry. Our rationale was that proteins that are decreased or absent in patients compared with controls could represent candidates for the primary defect, directing biochemical or genetics studies. On a survey of brain autopsy specimens from 23 patients with either confirmed or possible lysosomal disease, this approach identified or validated the genetic basis for disease in eight cases. These results indicate that this protein expression approach is useful for identifying defects in cases of undiagnosed lysosomal disease, and we demonstrated that it can be used with more accessible patient samples, e. g. cultured cells. Furthermore this approach was instrumental in the identification or validation of mutations in two lysosomal proteins, CLN5 and sulfamidase, in the adult form of neuronal ceroid lipofuscinosis. Molecular & Cellular Proteomics 8: 1708-1718, 2009. C1 [Sleat, David E.; Ding, Lin; Zhao, Caifeng; Wang, Yanhong; Zheng, Haiyan; Lobel, Peter] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Sleat, David E.; Ding, Lin; Lobel, Peter] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. [Moore, Dirk F.] Univ Med & Dent New Jersey, Sch Publ Hlth, Dept Biostat, Piscataway, NJ 08854 USA. [Wang, Shudan] McGill Univ, Montreal, PQ H3A 2T5, Canada. [Xin, Winnie; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Sleat, DE (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol & Med, 679 Hoes Lane, Piscataway, NJ 08854 USA. EM sleat@cabm.rutgers.edu FU National Institutes of Health [DK054317, S10RR017992]; Batten Disease Support and Research Association FX This work was supported, in whole or in part, by National Institutes of Health Grants DK054317 and S10RR017992 (to P. L.). This work was also supported by a grant from the Batten Disease Support and Research Association (to D. E. S.). NR 39 TC 24 Z9 25 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JUL PY 2009 VL 8 IS 7 BP 1708 EP 1718 DI 10.1074/mcp.M900122-MCP200 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 470FJ UT WOS:000267960300020 PM 19383612 ER PT J AU Tilly, JL Telfer, EE AF Tilly, Jonathan L. Telfer, Evelyn E. TI Purification of germline stem cells from adult mammalian ovaries: a step closer towards control of the female biological clock? SO MOLECULAR HUMAN REPRODUCTION LA English DT Editorial Material DE germline stem cell; oogenesis; oocyte; ovary; menopause ID BONE-MARROW; MENOPAUSAL TRANSITION; POSTNATAL OOGENESIS; MICE; CHEMOTHERAPY; FERTILITY; FOLLICLES; OOCYTES; PROTEIN; EXPRESSION AB For decades it was believed that a non-renewable pool of oocyte-containing follicles is established in female mammals at birth. This cornerstone of reproductive biology was challenged 5 years ago by a study reporting on the presence of mitotically-active germ cells in juvenile and adult mouse ovaries. Additional findings presented in this study and others that followed further suggested that mammals retain the capacity to generate oocytes during adulthood; however, isolation of oocyte-producing germline stem cells (GSC) as unequivocal proof of their existence remained elusive. This piece of information now appears to have been provided by Ji Wu and colleagues. In addition to showing that proliferative germ cells resembling male spermatogonial stem cells can be purified from neonatal or adult mouse ovaries and maintained in vitro for months, transplantation studies demonstrated that these cells generate oocytes in ovaries of chemotherapy-sterilized recipients that fertilize and produce viable offspring. Although these findings do not establish that oogenesis occurs in adult females under physiological conditions, they strongly support the existence of GSC in adult mouse ovaries. If equivalent cells can be found in human ovaries, stem cell-based rejuvenation of the oocyte reserve in ovaries on the verge of failure may one day be realized. C1 [Tilly, Jonathan L.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Tilly, Jonathan L.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. [Telfer, Evelyn E.] Univ Edinburgh, Inst Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. RP Tilly, JL (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. EM jtilly@partners.org; evelyn.telfer@ed.ac.uk FU NIA NIH HHS [R01-AG024999, R37-AG012279] NR 54 TC 43 Z9 44 U1 1 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1360-9947 J9 MOL HUM REPROD JI Mol. Hum. Reprod. PD JUL PY 2009 VL 15 IS 7 BP 393 EP 398 DI 10.1093/molehr/gap036 PG 6 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 460XM UT WOS:000267225600001 PM 19509111 ER PT J AU Warren, HS Elson, CM Hayden, DL Schoenfeld, DA Cobb, JP Maier, RV Moldawer, LL Moore, EE Harbrecht, BG Pelak, K Cuschieri, J Herndon, DN Jeschke, MG Finnerty, CC Brownstein, BH Hennessy, L Mason, PH Tompkins, RG AF Warren, H. Shaw Elson, Constance M. Hayden, Douglas L. Schoenfeld, David A. Cobb, J. Perren Maier, Ronald V. Moldawer, Lyle L. Moore, Ernest E. Harbrecht, Brian G. Pelak, Kimberly Cuschieri, Joseph Herndon, David N. Jeschke, Marc G. Finnerty, Celeste C. Brownstein, Bernard H. Hennessy, Laura Mason, Philip H. Tompkins, Ronald G. CA Inflammation Host Response Injury TI A Genomic Score Prognostic of Outcome in Trauma Patients SO MOLECULAR MEDICINE LA English DT Article ID MULTIPLE ORGAN FAILURE; INJURY SEVERITY SCORE; APACHE-II; VARIABILITY; PREDICTORS; DISEASE; SYSTEM; CARE AB Traumatic injuries frequently lead to infection, organ failure, and death. Health care providers rely on several injury scoring systems to quantify the extent of injury and to help predict clinical outcome. Physiological, anatomical, and clinical laboratory analytic scoring systems (Acute Physiology and Chronic Health Evaluation (APACHE), Injury Severity Score (ISS)) are utilized, with limited success, to predict outcome following injury. The recent development of techniques for measuring the expression level of all of a person's genes simultaneously may make it possible to develop an injury scoring system based on the degree of gene activation. We hypothesized that a peripheral blood leukocyte gene expression score could predict outcome, including multiple organ failure, following severe blunt trauma. To test such a scoring system, we measured gene expression of peripheral blood leukocytes from patients within 12 h of traumatic injury. cRNA derived from whole blood leukocytes obtained within 12 h of injury provided gene expression data for the entire genome that were used to create a composite gene expression score for each patient. Total blood leukocytes were chosen because they are active during inflammation, which is reflective of poor outcome. The gene expression score combines the activation levels of all the genes into a single number which compares the patient's gene expression to the average gene expression in uninjured volunteers. Expression profiles from healthy volunteers were averaged to create a reference gene expression profile which was used to compute a difference from reference (DFR) score for each patient. This score described the overall genomic response of patients within the first 12 h following severe blunt trauma. Regression models were used to compare the association of the DFR, APACHE, and ISS scores with outcome. We hypothesized that patients with a total gene response more different from uninjured volunteers would tend to have poorer outcome than those more similar. Our data show that for measures of poor outcome, such as infections, organ failures, and length of hospital stay, this is correct. DFR scores were associated significantly with adverse outcome, including multiple organ failure, duration of ventilation, length of hospital stay, and infection rate. The association remained significant after adjustment for injury severity as measured by APACHE or ISS. A single score representing changes in gene expression in peripheral blood leukocytes within hours of severe blunt injury is associated with adverse clinical outcomes that develop later in the hospital course. Assessment of genome-wide gene expression provides useful clinical information that is different from that provided by currently utilized anatomic or physiologic scores. (C) 2009 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2009.00027 C1 [Warren, H. Shaw] Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA USA. [Elson, Constance M.; Hayden, Douglas L.; Schoenfeld, David A.; Pelak, Kimberly] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Cobb, J. Perren; Brownstein, Bernard H.] Washington Univ, Dept Surg, St Louis, MO USA. [Maier, Ronald V.; Cuschieri, Joseph; Hennessy, Laura] Univ Washington, Harborview Med Ctr, Dept Surg, Seattle, WA 98104 USA. [Moldawer, Lyle L.] Univ Florida, Coll Med, Dept Surg, Gainesville, FL USA. [Moore, Ernest E.] Univ Colorado, Dept Surg, Denver Hlth Med Ctr, Denver, CO 80202 USA. [Harbrecht, Brian G.] Univ Louisville, Dept Surg, Louisville, KY 40292 USA. [Mason, Philip H.; Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Herndon, David N.; Jeschke, Marc G.; Finnerty, Celeste C.] Univ Texas Med Branch, Shriners Burn Hosp, Dept Surg, Galveston, TX USA. RP Hayden, DL (reprint author), MGH Biostat Ctr, 50 Staniford St 560, Boston, MA 02114 USA. EM swarren1@partners.org; dhayden@partners.org FU NIGMS NIH HHS [2 U54 GM062119, U54 GM062119] NR 25 TC 38 Z9 39 U1 0 U2 3 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD JUL-AUG PY 2009 VL 15 IS 7-8 BP 220 EP 227 DI 10.2119/molmed.2009.00027 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 575CV UT WOS:000276043800003 PM 19593405 ER PT J AU Benoff, S Hauser, R Marmar, JL Hurley, IR Napolitano, B Centola, GM AF Benoff, Susan Hauser, Russ Marmar, Joel L. Hurley, Ian R. Napolitano, Barbara Centola, Grace M. TI Cadmium Concentrations in Blood and Seminal Plasma: Correlations with Sperm Number and Motility in Three Male Populations (Infertility Patients, Artificial Insemination Donors, and Unselected Volunteers) SO MOLECULAR MEDICINE LA English DT Article ID REPRODUCTIVE ENDOCRINE FUNCTION; INDUCED TESTICULAR DAMAGE; RESISTANT MURINE STRAINS; IN-VITRO FERTILIZATION; SEMEN QUALITY; GENERAL-POPULATION; RAT TESTIS; INTRAUTERINE INSEMINATION; GENDER-DIFFERENCES; ACROSOME-REACTION AB To investigate a possible common environmental exposure that may partially explain the observed decrease in human semen quality, we correlated seminal plasma and blood cadmium levels with sperm concentration and sperm motility. We studied three separate human populations: group 1, infertility patients (Long Island, NY, USA); group 2, artificial insemination donors (AID) (Rochester, NY, USA); and group 3, general population volunteers (Rochester, NY, USA). Information about confounding factors was collected by questionnaire. Seminal plasma cadmium did not correlate with blood cadmium (Spearman correlation, n = 91, r = -0.092, P = 0.386, NS). Both blood and seminal plasma cadmium were significantly higher among infertility patients than the other subjects studied (for example, median seminal plasma cadmium was 0.282 mu g/L in infertility patients versus 0.091 mu g/L in AID and 0.092 mu g/L in general population volunteers; Kruskal-Wallis test, P < 0.001). The percentage of motile sperm and sperm concentration correlated inversely with seminal plasma cadmium among the infertility patients (r = -0.201, P < 0.036 and r = -0.189, Pc 0.05, respectively), but not in the other two groups. Age (among infertility patients) was the only positive confounder correlating with seminal plasma cadmium. To validate our human findings in an animal model, we chronically exposed adolescent male Wistar rats to low-moderate cadmium in drinking water. Though otherwise healthy the rats exhibited decreases in epididymal sperm count and sperm motility associated with cadmium dose and time of exposure. Our human and rat study results are consistent with the hypothesis that environmental cadmium exposures may contribute significantly to reduced human male sperm concentration and sperm motility. (C) 2009 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.moimed.org doi: 10.2119/molmed.2008.00104 C1 [Benoff, Susan; Hurley, Ian R.] Feinstein Inst Med Res, Fertil Res Labs, Manhasset, NY 11030 USA. [Benoff, Susan] N Shore Univ Hosp, Dept Obstet & Gynecol, Manhasset, NY USA. [Benoff, Susan] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Benoff, Susan] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Androl Lab, Boston, MA 02114 USA. [Hauser, Russ] Massachusetts Gen Hosp, In Vitro Fertilizat Unit, Boston, MA 02114 USA. [Marmar, Joel L.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Surg, Div Urol, Camden, NJ 08103 USA. [Napolitano, Barbara] Feinstein Inst Med Res, Biostat Unit, Manhasset, NY 11030 USA. [Centola, Grace M.] Univ Rochester, Med Ctr, Dept Obstet & Gynecol, Rochester, NY 14642 USA. [Centola, Grace M.] New England Cryogen Ctr, Newton, MA USA. RP Benoff, S (reprint author), Feinstein Inst Med Res, Fertil Res Labs, 350 Community Dr, Manhasset, NY 11030 USA. EM Sbenoff@optonline.net FU NIEHS NIH HHS [ES06100, R01 ES010496, ES10496, R01 ES006100]; NIOSH CDC HHS [R21 OH007330, OH07330] NR 145 TC 49 Z9 52 U1 2 U2 11 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD JUL-AUG PY 2009 VL 15 IS 7-8 BP 248 EP 262 DI 10.2119/molmed.2008.00104 PG 15 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 575CV UT WOS:000276043800007 PM 19593409 ER PT J AU Ginsburg, G Forde, R Martyn, JAJ Eikermann, M AF Ginsburg, Greg Forde, Ryan Martyn, Jeevendra A. J. Eikermann, Matthias TI INCREASED SENSITIVITY TO A NONDEPOLARIZING MUSCLE RELAXANT IN A PATIENT WITH ACQUIRED NEUROMYOTONIA SO MUSCLE & NERVE LA English DT Article DE acquired neuromyotonia; Isaacs syndrome; voltage-gated potassium-channels; nondepolarizing muscle relaxants; rocuronium sensitivity ID ISAACS SYNDROME; VECURONIUM AB Neuromyotonia is a disorder of hyperexcitability of the peripheral nerve. It has electromyographic features of spontaneous, continuous, irregularly occurring doublets, or multiplets of motor unit potential discharges. Neuromyotonia is characterized by both myokymic and neuromyotonic discharges. To our knowledge, this is the first report in the literature to assess the sensitivity of skeletal muscle to a nondepolarizing muscle relaxant drug, rocuronium, in a woman with acquired neuromyotonia. She had a past medical history notable for prolonged postoperative paralysis following anesthesia. The patient showed increased sensitivity to the neuromuscular effects of rocuronium. This increase in sensitivity may be explained by downregulation of acetylcholine receptors in response to chronic high agonist (acetylcholine) concentrations. If patients with neuromyotonia receive anesthesia, we recommend that smaller doses of a nondepolarizing muscle relaxant be administered, accompanied by monitoring of neuromuscular function, so as to provide optimal muscle relaxation while avoiding overdose and prolonged postoperative recovery. Muscle Nerve 40: 139-142, 2009 C1 [Eikermann, Matthias] Massachusetts Gen Hosp, Shriners Hosp Children, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Shriners Hosp Children, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org FU NIGMS NIH HHS [R01 GM055082] NR 23 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD JUL PY 2009 VL 40 IS 1 BP 139 EP 142 DI 10.1002/mus.21322 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 494WD UT WOS:000269849200024 PM 19533664 ER PT J AU Addona, TA Abbatiello, SE Schilling, B Skates, SJ Mani, DR Bunk, DM Spiegelman, CH Zimmerman, LJ Ham, AJL Keshishian, H Hall, SC Allen, S Blackman, RK Borchers, CH Buck, C Cardasis, HL Cusack, MP Dodder, NG Gibson, BW Held, JM Hiltke, T Jackson, A Johansen, EB Kinsinger, CR Li, J Mesri, M Neubert, TA Niles, RK Pulsipher, TC Ransohoff, D Rodriguez, H Rudnick, PA Smith, D Tabb, DL Tegeler, TJ Variyath, AM Vega-Montoto, LJ Wahlander, A Waldemarson, S Wang, M Whiteaker, JR Zhao, L Anderson, NL Fisher, SJ Liebler, DC Paulovich, AG Regnier, FE Tempst, P Carr, SA AF Addona, Terri A. Abbatiello, Susan E. Schilling, Birgit Skates, Steven J. Mani, D. R. Bunk, David M. Spiegelman, Clifford H. Zimmerman, Lisa J. Ham, Amy-Joan L. Keshishian, Hasmik Hall, Steven C. Allen, Simon Blackman, Ronald K. Borchers, Christoph H. Buck, Charles Cardasis, Helene L. Cusack, Michael P. Dodder, Nathan G. Gibson, Bradford W. Held, Jason M. Hiltke, Tara Jackson, Angela Johansen, Eric B. Kinsinger, Christopher R. Li, Jing Mesri, Mehdi Neubert, Thomas A. Niles, Richard K. Pulsipher, Trenton C. Ransohoff, David Rodriguez, Henry Rudnick, Paul A. Smith, Derek Tabb, David L. Tegeler, Tony J. Variyath, Asokan M. Vega-Montoto, Lorenzo J. Wahlander, Asa Waldemarson, Sofia Wang, Mu Whiteaker, Jeffrey R. Zhao, Lei Anderson, N. Leigh Fisher, Susan J. Liebler, Daniel C. Paulovich, Amanda G. Regnier, Fred E. Tempst, Paul Carr, Steven A. TI Multi-site assessment of the precision and reproducibility of multiple reaction monitoring-based measurements of proteins in plasma SO NATURE BIOTECHNOLOGY LA English DT Article ID MASS-SPECTROMETRIC QUANTITATION; ABSOLUTE QUANTIFICATION; ISOTOPE-DILUTION; BIOMARKER DISCOVERY; PEPTIDE STANDARDS; SERUM; ASSAYS; LC/MS/MS; PROTEOME; LIMITS AB Verification of candidate biomarkers relies upon specific, quantitative assays optimized for selective detection of target proteins, and is increasingly viewed as a critical step in the discovery pipeline that bridges unbiased biomarker discovery to preclinical validation. Although individual laboratories have demonstrated that multiple reaction monitoring (MRM) coupled with isotope dilution mass spectrometry can quantify candidate protein biomarkers in plasma, reproducibility and transferability of these assays between laboratories have not been demonstrated. We describe a multilaboratory study to assess reproducibility, recovery, linear dynamic range and limits of detection and quantification of multiplexed, MRM-based assays, conducted by NCI-CPTAC. Using common materials and standardized protocols, we demonstrate that these assays can be highly reproducible within and across laboratories and instrument platforms, and are sensitive to low lg/ml protein concentrations in unfractionated plasma. We provide data and benchmarks against which individual laboratories can compare their performance and evaluate new technologies for biomarker verification in plasma. C1 [Addona, Terri A.; Abbatiello, Susan E.; Mani, D. R.; Keshishian, Hasmik; Blackman, Ronald K.; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Schilling, Birgit; Cusack, Michael P.; Gibson, Bradford W.; Held, Jason M.] Buck Inst Age Res, Novato, CA USA. [Skates, Steven J.; Pulsipher, Trenton C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Bunk, David M.; Dodder, Nathan G.; Rudnick, Paul A.] Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Spiegelman, Clifford H.; Variyath, Asokan M.; Vega-Montoto, Lorenzo J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Zimmerman, Lisa J.; Ham, Amy-Joan L.; Li, Jing; Tabb, David L.; Liebler, Daniel C.] Vanderbilt Univ, Nashville, TN USA. [Hall, Steven C.; Allen, Simon; Johansen, Eric B.; Niles, Richard K.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Borchers, Christoph H.; Jackson, Angela; Smith, Derek] Univ Victoria, Genome BC Prote Ctr, Victoria, BC, Canada. [Buck, Charles; Regnier, Fred E.] Purdue Univ, W Lafayette, IN 47907 USA. [Cardasis, Helene L.; Neubert, Thomas A.; Wahlander, Asa] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY USA. [Cardasis, Helene L.; Neubert, Thomas A.; Wahlander, Asa] NYU, Sch Med, Dept Pharmacol, New York, NY USA. [Hiltke, Tara; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry] NCI, NIH, Bethesda, MD 20892 USA. [Ransohoff, David] Univ N Carolina, Chapel Hill, NC USA. [Tegeler, Tony J.; Wang, Mu] Monarch Life Sci, Indianapolis, IN USA. [Wang, Mu] Indiana Univ, Sch Med, Indianapolis, IN USA. [Whiteaker, Jeffrey R.; Zhao, Lei; Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Anderson, N. Leigh] Plasma Proteome Inst, Washington, DC USA. [Tempst, Paul] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Carr, SA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA. EM scarr@broad.mit.edu RI Held, Jason/B-1319-2010; Waldemarson, Sofia/C-6377-2012; Dodder, Nathan/C-7971-2015; Vega-Montoto, Lorenzo/B-9035-2017; OI Dodder, Nathan/0000-0001-5913-1767; Vega-Montoto, Lorenzo/0000-0002-4096-1100; Tempst, Paul/0000-0002-6680-3987; Held, Jason/0000-0001-8024-2736; Liebler, Daniel/0000-0002-7873-3031 FU NCI NIH HHS [U24 CA126480-01, U24 CA126476, U24 CA126476-03, U24 CA126480, U24 CA126485]; PHS HHS [U24 126477, U24 126479, U24 126480] NR 38 TC 588 Z9 595 U1 9 U2 102 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2009 VL 27 IS 7 BP 633 EP U85 DI 10.1038/nbt.1546 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 469OF UT WOS:000267908500020 PM 19561596 ER PT J AU De Jager, PL Jia, XM Wang, J de Bakker, PIW Ottoboni, L Aggarwal, NT Piccio, L Raychaudhuri, S Tran, D Aubin, C Briskin, R Romano, S Baranzini, SE McCauley, JL Pericak-Vance, MA Haines, JL Gibson, RA Naeglin, Y Uitdehaag, B Matthews, PM Kappos, L Polman, C McArdle, WL Strachan, DP Evans, D Cross, AH Daly, MJ Compston, A Sawcer, SJ Weiner, HL Hauser, SL Hafler, DA Oksenberg, JR AF De Jager, Philip L. Jia, Xiaoming Wang, Joanne de Bakker, Paul I. W. Ottoboni, Linda Aggarwal, Neelum T. Piccio, Laura Raychaudhuri, Soumya Tran, Dong Aubin, Cristin Briskin, Rebeccah Romano, Susan Baranzini, Sergio E. McCauley, Jacob L. Pericak-Vance, Margaret A. Haines, Jonathan L. Gibson, Rachel A. Naeglin, Yvonne Uitdehaag, Bernard Matthews, Paul M. Kappos, Ludwig Polman, Chris McArdle, Wendy L. Strachan, David P. Evans, Denis Cross, Anne H. Daly, Mark J. Compston, Alastair Sawcer, Stephen J. Weiner, Howard L. Hauser, Stephen L. Hafler, David A. Oksenberg, Jorge R. CA Int MS Genetics Consortium TI Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci SO NATURE GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; PERIPHERAL-BLOOD CELLS; WIDE ASSOCIATION; PERIODIC-SYNDROME; R92Q MUTATION; RHEUMATOID-ARTHRITIS; HAPLOTYPE MAP; INTERFERON; DISEASE; RISK AB We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency 0.02; odds ratio 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS. C1 [De Jager, Philip L.; Ottoboni, Linda; Romano, Susan; Weiner, Howard L.; Hafler, David A.] Brigham & Womens Hosp, Div Mol Immunol, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA. [De Jager, Philip L.; Ottoboni, Linda; Briskin, Rebeccah] Partners Ctr Personalized Genet Med, Boston, MA USA. [De Jager, Philip L.; de Bakker, Paul I. W.; Ottoboni, Linda; Raychaudhuri, Soumya; Tran, Dong; Aubin, Cristin; Daly, Mark J.; Hafler, David A.] Harvard Univ, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02138 USA. [De Jager, Philip L.; de Bakker, Paul I. W.; Ottoboni, Linda; Raychaudhuri, Soumya; Tran, Dong; Aubin, Cristin; Daly, Mark J.; Hafler, David A.] MIT, Cambridge, MA 02139 USA. [Jia, Xiaoming; de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA. [Wang, Joanne; Baranzini, Sergio E.; Hauser, Stephen L.; Oksenberg, Jorge R.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Wang, Joanne; Hauser, Stephen L.; Oksenberg, Jorge R.] Univ Calif San Francisco, Inst Human Genet, Sch Med, San Francisco, CA 94143 USA. [Aggarwal, Neelum T.; Evans, Denis] Rush Univ, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Aggarwal, Neelum T.; Evans, Denis] Rush Univ, Dept Neurol Sci, Chicago, IL 60612 USA. [Piccio, Laura; Cross, Anne H.] Washington Univ, Dept Neurol, St Louis, MO USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Immunol Allergy & Rheumatol, Boston, MA 02115 USA. [McCauley, Jacob L.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Miami Inst Human Genom, Miami, FL 33136 USA. [Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Gibson, Rachel A.; Matthews, Paul M.] Univ London Imperial Coll Sci Technol & Med, Dept Clin Neurosci, London SW7 2AZ, England. [Gibson, Rachel A.; Matthews, Paul M.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, GlaxoSmithKline Clin Imaging Ctr, London SW7 2AZ, England. [Naeglin, Yvonne; Kappos, Ludwig] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Uitdehaag, Bernard; Polman, Chris] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, Amsterdam, Netherlands. [McArdle, Wendy L.] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Strachan, David P.] Univ London, Div Community Hlth Sci, London, England. [Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Compston, Alastair; Sawcer, Stephen J.] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England. RP De Jager, PL (reprint author), Brigham & Womens Hosp, Div Mol Immunol, Ctr Neurol Dis, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM pdejager@rics.bwh.harvard.edu RI Haines, Jonathan/C-3374-2012; Baranzini, Sergio/A-9422-2013; Fuller, Stephen/C-1200-2009; de Bakker, Paul/B-8730-2009; Hauser, Stephen/J-2978-2016; OI Baranzini, Sergio/0000-0003-0067-194X; de Bakker, Paul/0000-0001-7735-7858; OTTOBONI, LINDA/0000-0001-5412-7785; Matthews, Paul M/0000-0002-1619-8328 FU Medical Research Council [G0000934, MC_QA137934]; NIAID NIH HHS [P01 AI039671]; NIAMS NIH HHS [K08 AR055688, K08 AR055688-01A1]; NINDS NIH HHS [K08 NS046341, K08 NS46341, R01 NS046630, R01 NS049477]; Wellcome Trust [068545/Z/02] NR 48 TC 400 Z9 402 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2009 VL 41 IS 7 BP 776 EP U26 DI 10.1038/ng.401 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 468AS UT WOS:000267786200006 PM 19525953 ER PT J AU Viswanathan, SR Powers, JT Einhorn, W Hoshida, Y Ng, TL Toffanin, S O'Sullivan, M Lu, J Phillips, LA Lockhart, VL Shah, SP Tanwar, PS Mermel, CH Beroukhim, R Azam, M Teixeira, J Meyerson, M Hughes, TP Llovet, JM Radich, J Mullighan, CG Golub, TR Sorensen, PH Daley, GQ AF Viswanathan, Srinivas R. Powers, John T. Einhorn, William Hoshida, Yujin Ng, Tony L. Toffanin, Sara O'Sullivan, Maureen Lu, Jun Phillips, Letha A. Lockhart, Victoria L. Shah, Samar P. Tanwar, Pradeep S. Mermel, Craig H. Beroukhim, Rameen Azam, Mohammad Teixeira, Jose Meyerson, Matthew Hughes, Timothy P. Llovet, Josep M. Radich, Jerald Mullighan, Charles G. Golub, Todd R. Sorensen, Poul H. Daley, George Q. TI Lin28 promotes transformation and is associated with advanced human malignancies SO NATURE GENETICS LA English DT Article ID HUMAN HEPATOCELLULAR-CARCINOMA; EPITHELIAL OVARIAN-CANCER; LUNG-CANCER; WILMS-TUMOR; MICRORNA EXPRESSION; GENE-EXPRESSION; CELL-DIFFERENTIATION; STEM-CELLS; LET-7; METASTASIS AB Multiple members of the let-7 family of miRNAs are often repressed in human cancers(1,2), thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc(3,4). However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins LIN28 and LIN28B block let-7 precursors from being processed to mature nmiRNAs(5-8), suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency B15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. LIN28 and LIN28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis. C1 [Viswanathan, Srinivas R.; Powers, John T.; Einhorn, William; Shah, Samar P.; Azam, Mohammad; Daley, George Q.] Harvard Univ, Childrens Hosp, Dept Biol Chem & Mol Pharmacol, Med Sch,Harvard Stem Cell Inst, Boston, MA 02115 USA. [Hoshida, Yujin; Golub, Todd R.; Daley, George Q.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Cambridge, MA USA. [Hoshida, Yujin; Golub, Todd R.; Daley, George Q.] Dana Farber Canc Inst, Cambridge, MA USA. [Hoshida, Yujin; Lu, Jun; Mermel, Craig H.; Beroukhim, Rameen; Meyerson, Matthew; Golub, Todd R.] MIT & Harvard, Broad Inst, Canc Program, Cambridge, MA USA. [Hoshida, Yujin; Lu, Jun; Mermel, Craig H.; Beroukhim, Rameen; Meyerson, Matthew; Golub, Todd R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hoshida, Yujin; Lu, Jun; Mermel, Craig H.; Beroukhim, Rameen; Meyerson, Matthew; Golub, Todd R.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Ng, Tony L.; Sorensen, Poul H.] Univ British Columbia, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Ng, Tony L.; Sorensen, Poul H.] BC Canc Res Ctr, Dept Mol Oncol, Vancouver, BC, Canada. [Toffanin, Sara; Llovet, Josep M.] Mt Sinai Sch Med, Div Liver Dis, Mt Sinai Liver Canc Program, New York, NY USA. [Toffanin, Sara] IRCSS Fdn, Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, Milan, Italy. [O'Sullivan, Maureen] Our Ladys Childrens Hosp, Dept Pathol, Dublin, Ireland. [O'Sullivan, Maureen] Trinity Coll Dublin, Dept Pathol, Dublin, Ireland. [Phillips, Letha A.; Mullighan, Charles G.] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Lockhart, Victoria L.; Radich, Jerald] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Tanwar, Pradeep S.; Teixeira, Jose] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Hughes, Timothy P.] Inst Med & Vet Sci, Div Haematol, Adelaide, SA 5000, Australia. [Llovet, Josep M.] Hosp Clin Barcelona, HCC Translat Res Lab, Barcelona Clin Liver Canc Grp,CIBERehd, Liver Unit,Inst Invest Biomed August Pi & Sunyer, Catalonia, Spain. [Llovet, Josep M.] Inst Catalana Recerca & Estudis Avancats, Catalonia, Spain. [Golub, Todd R.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA USA. RP Daley, GQ (reprint author), Harvard Univ, Childrens Hosp, Dept Biol Chem & Mol Pharmacol, Med Sch,Harvard Stem Cell Inst, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu RI Meyerson, Matthew/E-7123-2012; Llovet, Josep M /D-4340-2014; OI Llovet, Josep M /0000-0003-0547-2667; Teixeira, Jose/0000-0002-6438-5064; Mullighan, Charles/0000-0002-1871-1850 FU Howard Hughes Medical Institute; NHLBI NIH HHS [T32-HL 66987]; NICHD NIH HHS [R01 HD052701, R01 HD052701-02]; NIDDK NIH HHS [1 R01 DK076986-01, R01 DK076986]; NIGMS NIH HHS [T32 GM007753]; NIH HHS [DP1 OD000256, DP1 OD000256-01] NR 55 TC 415 Z9 430 U1 2 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2009 VL 41 IS 7 BP 843 EP U109 DI 10.1038/ng.392 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 468AS UT WOS:000267786200018 PM 19483683 ER PT J AU Perrigoue, JG Saenz, SA Siracusa, MC Allenspach, EJ Taylor, BC Giacomin, PR Nair, MG Du, YR Zaph, C van Rooijen, N Comeau, MR Pearce, EJ Laufer, TM Artis, D AF Perrigoue, Jacqueline G. Saenz, Steven A. Siracusa, Mark C. Allenspach, Eric J. Taylor, Betsy C. Giacomin, Paul R. Nair, Meera G. Du, Yurong Zaph, Colby van Rooijen, Nico Comeau, Michael R. Pearce, Edward J. Laufer, Terri M. Artis, David TI MHC class II-dependent basophil-CD4(+) T cell interactions promote T(H)2 cytokine-dependent immunity SO NATURE IMMUNOLOGY LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; ANTIGEN-PRESENTING CELLS; DENDRITIC CELLS; IN-VIVO; HELMINTH INFECTION; TYPE-2 IMMUNITY; CUTTING EDGE; MAST-CELLS; GASTROINTESTINAL-TRACT; EFFECTOR MECHANISMS AB Dendritic cells can prime naive CD4(+) T cells; however, here we demonstrate that dendritic cell-mediated priming was insufficient for the development of T helper type 2 cell-dependent immunity. We identify basophils as a dominant cell population that coexpressed major histocompatibility complex class II and interleukin 4 message after helminth infection. Basophilia was promoted by thymic stromal lymphopoietin, and depletion of basophils impaired immunity to helminth infection. Basophils promoted antigen-specific CD4(+) T cell proliferation and interleukin 4 production in vitro, and transfer of basophils augmented the population expansion of helminth-responsive CD4(+) T cells in vivo. Collectively, our studies suggest that major histocompatibility complex class II-dependent interactions between basophils and CD4(+) T cells promote T helper type 2 cytokine responses and immunity to helminth infection. C1 [Perrigoue, Jacqueline G.; Saenz, Steven A.; Siracusa, Mark C.; Taylor, Betsy C.; Giacomin, Paul R.; Nair, Meera G.; Du, Yurong; Pearce, Edward J.; Artis, David] Univ Penn, Dept Pathobiol, Philadelphia, PA 19104 USA. [Allenspach, Eric J.; Laufer, Terri M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Zaph, Colby] Univ British Columbia, Biomed Res Ctr, Dept Pathol & Lab Med, Vancouver, BC, Canada. [van Rooijen, Nico] Vrije Univ Amsterdam, Dept Mol Cell Biol, Amsterdam, Netherlands. [Comeau, Michael R.] Amgen Inc, Inflammat Res, Seattle, WA USA. [Laufer, Terri M.] Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Artis, D (reprint author), Univ Penn, Dept Pathobiol, Philadelphia, PA 19104 USA. EM dartis@vet.upenn.edu OI Zaph, Colby/0000-0002-9889-9848 FU NCI NIH HHS [T32 CA09140-30, T32 CA009140]; NIAID NIH HHS [AI074878, AI32573, AI53825, AI61570, R01 AI032573, R01 AI053825, R01 AI061570, R01 AI061570-05, R01 AI074878, R01 AI074878-02, R56 AI032573, T32 AI007532, T32 AI007532-08]; NIDDK NIH HHS [DK50306, P30 DK050306]; NIGMS NIH HHS [F31 GM082187] NR 59 TC 347 Z9 356 U1 3 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2009 VL 10 IS 7 BP 697 EP U45 DI 10.1038/ni.1740 PG 10 WC Immunology SC Immunology GA 459WF UT WOS:000267142600008 PM 19465906 ER PT J AU Schmitz, AM Morrison, MF Agunwamba, AO Nibert, ML Lesser, CF AF Schmitz, Alexa M. Morrison, Monica F. Agunwamba, Akochi O. Nibert, Max L. Lesser, Cammie F. TI Protein interaction platforms: visualization of interacting proteins in yeast SO NATURE METHODS LA English DT Article ID III SECRETION APPARATUS; SHIGELLA-FLEXNERI; SACCHAROMYCES-CEREVISIAE; CHAPERONE; INVASION; LOCALIZATION; SYSTEM; ASSAYS; SPA15 AB Here we describe the protein interaction platform assay, a method for identifying interacting proteins in Saccharomyces cerevisiae. This assay relies on the reovirus scaffolding protein mu NS, which forms large focal inclusions in living cells. When a query protein is fused to mu NS and potential interaction partners are fused to a fluorescent reporter, interactors can be identified by screening for yeast that display fluorescent foci. C1 [Schmitz, Alexa M.; Morrison, Monica F.; Agunwamba, Akochi O.; Lesser, Cammie F.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med Microbiol & Mol Genet, Cambridge, MA USA. [Schmitz, Alexa M.; Morrison, Monica F.; Agunwamba, Akochi O.; Lesser, Cammie F.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Nibert, Max L.; Lesser, Cammie F.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Lesser, CF (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Dept Med Microbiol & Mol Genet, Cambridge, MA USA. EM clesser@partners.org FU US National Institutes of Health [R56 AI067445, R01 AI064285]; Rockefeller Brothers Fund; Goldman Philanthropic FX We thank S. Alberti and S. Lindquist (Whitehead Institute, Massachusetts Institute of Technology) for providing the pAG destination clones; A. Gray, K. Fixen and M. Goldberg ( Massachusetts General Hospital, Harvard Medical School) for providing plasmids pNG162 and pDSW206 and antibodies to IcsA and isocitrate dehydrogenase; J. Heindl (Massachusetts General Hospital, Harvard Medical School) for providing the IpgB2 W62A construct; T. Hao, D. Hill and M. Vidal (Dana Farber Cancer Institute, Harvard Medical School) for assistance in designing primers to create the S. flexneri Gateway entry clones and for providing the Gateway-compatible Y2H vectors; and R. Levy and C. Koser (Massachusetts General Hospital, Harvard Medical School) for cloning and expressing S. typhimurium effectors in yeast. We also thank the US National Institute of Allergy and Infectious Diseases and the J. Craig Venter Institute for supplying the S. typhimurium Gateway entry clones. Partial support for this work was provided by US National Institutes of Health grants R56 AI067445 to M.L.N. and R01 AI064285 to C. F. L., and by a Charles E. Culpeper Medical Scholarship from the Rockefeller Brothers Fund and Goldman Philanthropic Partnerships to C. F. L. NR 24 TC 18 Z9 18 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD JUL PY 2009 VL 6 IS 7 BP 500 EP U43 DI 10.1038/nmeth.1337 PG 5 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 463PA UT WOS:000267442900016 PM 19483691 ER PT J AU Razansky, D Distel, M Vinegoni, C Ma, R Perrimon, N Koster, RW Ntziachristos, V AF Razansky, Daniel Distel, Martin Vinegoni, Claudio Ma, Rui Perrimon, Norbert Koester, Reinhard W. Ntziachristos, Vasilis TI Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo SO NATURE PHOTONICS LA English DT Article ID HIGH-RESOLUTION; MICROSCOPY; BRAIN AB Fluorescent proteins have become essential reporter molecules for studying life at the cellular and sub-cellular level, re-defining the ways in which we investigate biology. However, because of intense light scattering, most organisms and tissues remain inaccessible to current fluorescence microscopy techniques at depths beyond several hundred micrometres. We describe a multispectral opto-acoustic tomography technique capable of high-resolution visualization of fluorescent proteins deep within highly light-scattering living organisms. The method uses multiwavelength illumination over multiple projections combined with selective-plane opto-acoustic detection for artifact-free data collection. Accurate image reconstruction is enabled by making use of wavelength-dependent light propagation models in tissue. By performing whole-body imaging of two biologically important and optically diffuse model organisms, Drosophila melanogaster pupae and adult zebrafish, we demonstrate the facility to resolve tissue-specific expression of eGFP and mCherrry fluorescent proteins for precise morphological and functional observations in vivo. C1 [Razansky, Daniel; Ma, Rui; Ntziachristos, Vasilis] Tech Univ Munich, Inst Biol & Med Imaging, D-85764 Neuherberg, Germany. [Distel, Martin; Koester, Reinhard W.] Helmholtz Ctr Munich, Inst Dev Genet, D-85764 Neuherberg, Germany. [Vinegoni, Claudio] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Vinegoni, Claudio] Harvard Univ, Sch Med, Richard B Simches Res Ctr, Boston, MA 02114 USA. [Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Perrimon, Norbert] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Razansky, D (reprint author), Tech Univ Munich, Inst Biol & Med Imaging, Landstr 1, D-85764 Neuherberg, Germany. EM dr@tum.de; v.ntziachristos@tum.de FU Deutsche Forschungsgemeinschaft (DFG) [RA 1848/1-1]; Studienstiftung des deutschen Volkes; German Ministry for Education and Research (BMBF) [0311889] FX D. R. acknowledges financial support by the Deutsche Forschungsgemeinschaft (DFG) research grant RA 1848/1-1. M. D. is a fellow of the Studienstiftung des deutschen Volkes. R. W. K. is supported by a BioFuture Award Grant (0311889) of the German Ministry for Education and Research (BMBF). We thank R. Jagasia for providing Hela mitodsRed cells. NR 31 TC 331 Z9 334 U1 3 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1749-4885 J9 NAT PHOTONICS JI Nat. Photonics PD JUL PY 2009 VL 3 IS 7 BP 412 EP 417 DI 10.1038/NPHOTON.2009.98 PG 6 WC Optics; Physics, Applied SC Optics; Physics GA 471OL UT WOS:000268067700018 ER PT J AU Brown, JR Freedman, AS AF Brown, Jennifer R. Freedman, Arnold S. TI ASCT in follicular lymphoma SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; HIGH-DOSE THERAPY; PROGRESSION-FREE SURVIVAL; NON-HODGKINS-LYMPHOMA; 1ST REMISSION; TRIAL; CHEMOTHERAPY; MULTICENTER; TIME C1 [Brown, Jennifer R.; Freedman, Arnold S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Brown, JR (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM jbrown2@partners.org NR 10 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD JUL PY 2009 VL 6 IS 7 BP 380 EP 382 DI 10.1038/nrclinonc.2009.87 PG 4 WC Oncology SC Oncology GA 463OK UT WOS:000267441300004 PM 19561632 ER PT J AU Rupnik, M Wilcox, MH Gerding, DN AF Rupnik, Maja Wilcox, Mark H. Gerding, Dale N. TI Clostridium difficile infection: new developments in epidemiology and pathogenesis SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID HUMAN GUT MODEL; SURFACE-LAYER PROTEINS; TERM-CARE FACILITY; TOXIN-B; BINARY TOXIN; ANTIBODY-RESPONSE; PCR RIBOTYPES; ADP-RIBOSYLTRANSFERASE; HYPERVIRULENT STRAIN; PATHOGENICITY LOCUS AB Clostridium difficile is now considered to be one of the most important causes of health care-associated infections. C. difficile infections are also emerging in the community and in animals used for food, and are no longer viewed simply as unpleasant complications that follow antibiotic therapy. Since 2001, the prevalence and severity of C. difficile infection has increased significantly, which has led to increased research interest and the discovery of new virulence factors, and has expanded and focused the development of new treatment and prevention regimens. This Review summarizes the recent epidemiological changes in C. difficile infection, our current knowledge of C. difficile virulence factors and the clinical outcomes of C. difficile infection. C1 [Rupnik, Maja] Inst Publ Hlth Maribor, Ctr Microbiol, Maribor 2000, Slovenia. [Rupnik, Maja] Univ Maribor, Fac Med, Maribor 2000, Slovenia. [Wilcox, Mark H.] Leeds Gen Infirm, Leeds LS1 3EX, W Yorkshire, England. [Gerding, Dale N.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Gerding, Dale N.] Loyola Univ Chicago, Stritch Sch Med, ACOS Res & Dev, Hines, IL 60141 USA. RP Rupnik, M (reprint author), Inst Publ Hlth Maribor, Ctr Microbiol, Prvomajska 1, Maribor 2000, Slovenia. EM maja.rupnik@uni-mb.si; mark.wilcox@leedsth.nhs.uk; dale.gerding2@med.va.gov FU EU [223585]; ERA NET PathoGenoMics; ARRS [J3-0194-0377-08] FX M. R. was supported by EU grant 223585, ERA NET PathoGenoMics grant and ARRS grant J3-0194-0377-08. NR 129 TC 580 Z9 608 U1 28 U2 202 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD JUL PY 2009 VL 7 IS 7 BP 526 EP 536 DI 10.1038/nrmicro2164 PG 11 WC Microbiology SC Microbiology GA 458KF UT WOS:000267016700013 PM 19528959 ER PT J AU Chen, Z Vijayan, S Barbieri, R Wilson, MA Brown, EN AF Chen, Zhe Vijayan, Sujith Barbieri, Riccardo Wilson, Matthew A. Brown, Emery N. TI Discrete- and Continuous-Time Probabilistic Models and Algorithms for Inferring Neuronal UP and DOWN States SO NEURAL COMPUTATION LA English DT Article ID CHAIN MONTE-CARLO; HIDDEN MARKOV-MODELS; ACTIVITY IN-VIVO; MAXIMUM-LIKELIHOOD-ESTIMATION; SINGLE-CHANNEL RECORDINGS; NEURAL SPIKING ACTIVITY; TRAIN DATA-ANALYSIS; EM ALGORITHM; BAYESIAN-INFERENCE; SEIZURE COUNTS AB UP and DOWN states, the periodic fluctuations between increased and decreased spiking activity of a neuronal population, are a fundamental feature of cortical circuits. Understanding UP-DOWN state dynamics is important for understanding how these circuits represent and transmit information in the brain. To date, limited work has been done on characterizing the stochastic properties of UP-DOWN state dynamics. We present a set of Markov and semi-Markov discrete-and continuous-time probability models for estimating UP and DOWN states from multiunit neural spiking activity. We model multiunit neural spiking activity as a stochastic point process, modulated by the hidden (UP and DOWN) states and the ensemble spiking history. We estimate jointly the hidden states and the model parameters by maximum likelihood using an expectation-maximization (EM) algorithm and a Monte Carlo EM algorithm that uses reversible-jump Markov chain Monte Carlo sampling in the E-step. We apply our models and algorithms in the analysis of both simulated multiunit spiking activity and actual multiunit spiking activity recorded from primary somatosensory cortex in a behaving rat during slow-wave sleep. Our approach provides a statistical characterization of UP-DOWN state dynamics that can serve as a basis for verifying and refining mechanistic descriptions of this process. C1 [Chen, Zhe; Barbieri, Riccardo; Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab,Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Vijayan, Sujith] Harvard Univ, Program Neurosci, Cambridge, MA 02139 USA. [Wilson, Matthew A.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Wilson, Matthew A.] MIT, Picower Inst Learning & Memory, RIKEN MIT Neurosci Res Ctr, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Chen, Z (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab,Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM zhechen@mit.edu; vijayan@post.harvard.edu; barbieri@neurostat.mit.edu; mwilson@mit.edu; enb@neurostat.mit.edu OI Barbieri, Riccardo/0000-0001-9381-3833; Chen, Zhe/0000-0002-6483-6056 FU NHLBI NIH HHS [T32 HL07901, R01 HL084502-03, T32 HL007901, R01-HL084502, R01 HL084502]; NIDA NIH HHS [R01-DA015644, R01 DA015644]; NIH HHS [DP1 OD003646, DP1 OD003646-03, DP1-OD003646] NR 78 TC 14 Z9 14 U1 0 U2 4 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0899-7667 EI 1530-888X J9 NEURAL COMPUT JI Neural Comput. PD JUL PY 2009 VL 21 IS 7 BP 1797 EP 1862 DI 10.1162/neco.2009.06-08-799 PG 66 WC Computer Science, Artificial Intelligence; Neurosciences SC Computer Science; Neurosciences & Neurology GA 457UK UT WOS:000266959100001 PM 19323637 ER PT J AU Strozyk, D Launer, LJ Adlard, PA Cherny, RA Tsatsanis, A Volitakis, I Blennow, K Petrovitch, H White, LR Bush, AI AF Strozyk, Dorothea Launer, Lenore J. Adlard, Paul A. Cherny, Robert A. Tsatsanis, Andrew Volitakis, Irene Blennow, Kai Petrovitch, Helen White, Lon R. Bush, Ashley I. TI Zinc and copper modulate Alzheimer A beta levels in human cerebrospinal fluid SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyloid; Alzheimer's disease; Metalloproteinase; Cerebrospinal fluid; Zinc; Copper; Iron; Manganese; Chromium ID AMYLOID-BETA; HYDROGEN-PEROXIDE; DISEASE; PROTEIN; CLIOQUINOL; PEPTIDE; AGGREGATION; MICE; IRON; DEGRADATION AB Abnormal interaction of beta-amyloid 42 (A beta 42) with copper, zinc and iron induce peptide aggregation and oxidation in Alzheimer's disease (AD). However, in health, A beta degradation is mediated by extracellular metalloproteinases, neprilysin, insulin degrading enzyme (IDE) and matrix metalloproteinases. We investigated the relationship between levels of A beta and biological metals in CSF. We assayed CSF copper, zinc, other metals and A beta 42 in ventricular autopsy samples of Japanese American men (N=131) from the population-based Honolulu Asia Aging Study. There was a significant inverse correlation of CSF A beta 42 with copper, zinc, iron, manganese and chromium. The association was particularly strong in the subgroup with high levels of both zinc and copper. Selenium and aluminum levels were not associated to CSF A beta 42. In vitro, the degradation of synthetic A beta substrate added to CSF was markedly accelerated by low levels (2 mu M) of exogenous zinc and copper. While excessive interaction with copper and zinc may induce neocortical A beta precipitation in AD, soluble A beta degradation is normally promoted by physiological copper and zinc concentrations. (C) 2007 Elsevier Inc. All rights reserved. C1 [Strozyk, Dorothea; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Neuroepidemiol Sect, NIH, Bethesda, MD 20892 USA. [Strozyk, Dorothea] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. [Adlard, Paul A.; Cherny, Robert A.; Tsatsanis, Andrew; Volitakis, Irene; Bush, Ashley I.] Univ Melbourne, Dept Pathol, Mental Hlth Res Inst Victoria, Melbourne, Vic 3010, Australia. [Blennow, Kai] Sahlgrens Univ Hosp, Dept Clin Neurosci, Molndal, Sweden. [Petrovitch, Helen; White, Lon R.] Kuakini Med Ctr, Pacific Hlth Res Inst, Honolulu, HI USA. [Bush, Ashley I.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, Neuroepidemiol Sect, NIH, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov; abush@mhri.edu.au RI Bush, Ashley/A-1186-2007; OI Bush, Ashley/0000-0001-8259-9069; Volitakis, Irene/0000-0003-0766-817X FU NIH (National Institute on Aging) [1RO1 AG12686, 1 U01 AG19349-01, 5 R01 AG017155-04]; Intramural Research Program of the NIH; National Institute on Aging; Australian Research Council Federation Fellowship; National health and Medical Research Council of Australia; American Health Assistance Foundation; University of Melbourne; Mental Health Research Institute of Victoria, Victorian Forensic Institute of Medicine; Neurosciences Australia and the National Health & Medical Research Council FX This study was supported by NIH (National Institute on Aging); Grant Numbers 1RO1 AG12686 (to AIB), 1 U01 AG19349-01, 5 R01 AG017155-04, and in part by the Intramural Research Program of the NIH, National Institute on Aging, as well as (to AIB) the Australian Research Council Federation Fellowship, the National health and Medical Research Council of Australia, the Alzheimer Association Zenith Award and the American Health Assistance Foundation. The Victorian Brain Bank Network is supported by The University of Melbourne, The Mental Health Research Institute of Victoria, Victorian Forensic Institute of Medicine and funded by Neurosciences Australia and the National Health & Medical Research Council. NR 43 TC 68 Z9 71 U1 6 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2009 VL 30 IS 7 BP 1069 EP 1077 DI 10.1016/j.neurobiolaging.2007.10.012 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 453OI UT WOS:000266619800007 PM 18068270 ER PT J AU Huang, SN Liu, C Dai, GP Kim, YR Rosen, BR AF Huang, Shuning Liu, Christina Dai, Guangping Kim, Young Ro Rosen, Bruce R. TI Manipulation of tissue contrast using contrast agents for enhanced MR microscopy in ex vivo mouse brain SO NEUROIMAGE LA English DT Article ID MAGNETIC-RESONANCE MICROSCOPY; PROTON RELAXATION; HIGH-RESOLUTION; MANGANESE IONS; RAT MYOCARDIUM; IN-VIVO; ATLAS; SUSCEPTIBILITY; ACTIVATION; TRANSPORT AB Detailed 3D mouse brain images may promote better understanding of phenotypical differences between normal and transgenic/mutant Mouse models. Previously, a number of magnetic resonance microscopy (MRM) studies have successfully established brain atlases, revealing genotypic traits of several commonly used mouse strains. In such Studies, MR contrast agents, mainly gadolinium (Gd) based, were often used to reduce acquisition time and improve signal-to-noise ratio (SNR). In this paper, we intended to extend the utility of contrast agents for MRM applications. Using Gd-DTPA and MnCl(2), we exploited the potential use of MR Contrast agents to manipulate image contrast by drawing upon the multiple relaxation mechanisms and tissue-dependent staining properties characteristic of each contrast agent. We quantified r(1) and r(2) of GdDTPA and MnCl(2) in both aqueous solution and brain tissue and demonstrated the presence of divergent relaxation mechanisms between solution and tissue for each contrast agent. Further analyses using nuclear magnetic resonance dispersion (NMRD) of Mn(2+) in ex vivo tissue strongly suggested macromolecule binding of Mn(2+), leading to increased T(1) relaxation. Moreover, inductively coupled plasma (ICP) mass spectroscopy revealed that MnCl(2) had higher tissue affinity than Gd-DTPA. As a result, multiple regions of the brain stained by the two agents exhibited different image contrasts. Our results show that differential MRM staining can be achieved using multiple MR contrast agents, revealing detailed cytoarchitecture, and may ultimately offer a window for investigating new techniques by which to understand biophysical MR relaxation mechanisms and perhaps to Visualize tissue anomalies even at the molecular level. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kim, Young Ro] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Huang, Shuning; Rosen, Bruce R.] MIT, Cambridge, MA 02139 USA. RP Kim, YR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, E Bldg 149,13th St, Charlestown, MA 02129 USA. EM shuning@mit.edu; chliu@nmr.mgh.harvard.edu; dai@nmr.mgh.harvard.edu; spmn@nmr.mgh.harvard.edu; bruce@nmr.mgh.harvard.edu OI Liu, Christina/0000-0002-5723-177X FU NCRR [P41RR14075]; NIBIB [8R01EB002066-14]; MIND Institute; Athinoula A. Martincis Center for Biomedical Imaging FX This project is supported by NCRR (P41RR14075), NIBIB (8R01EB002066-14), the MIND Institute, and the Athinoula A. Martincis Center for Biomedical Imaging. The authors would also like to thank Dr. Peter Caravan and Dr. Ritika Uppal for their help and discussion on ICP analysis. We would also like to thank Dr. Philip Liu for his technical support on brain preparation. NR 39 TC 20 Z9 21 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 1 PY 2009 VL 46 IS 3 BP 589 EP 599 DI 10.1016/j.neuroimage.2009.02.027 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 443VK UT WOS:000265938700005 PM 19264139 ER PT J AU Ou, WM Nissila, I Radhakrishnan, H Boas, DA Hamalainen, MS Franceschini, MA AF Ou, Wanmei Nissila, Ilkka Radhakrishnan, Harsha Boas, David A. Hamalainen, Matti S. Franceschini, Maria Angela TI Study of neurovascular coupling in humans via simultaneous magnetoencephalography and diffuse optical imaging acquisition SO NEUROIMAGE LA English DT Article DE Magnetoencephalography (MEG); Diffuse optical imaging (DOI); Near infrared spectroscopy (NIRS); Neurovascular coupling; Somatosensory response; Primary sensory area (SI) ID NEAR-INFRARED SPECTROSCOPY; RAT SOMATOSENSORY CORTEX; CEREBRAL-BLOOD-FLOW; TOTAL-HEMOGLOBIN CONCENTRATION; ACTIVITY-DEPENDENT INCREASES; MEDIAN NERVE-STIMULATION; LASER-DOPPLER FLOWMETRY; EVOKED MAGNETIC-FIELDS; SURFACE-BASED ANALYSIS; RODENT BARREL CORTEX AB By combining diffuse optical imaging (DOI) and magnetoencephalography (MEG) we investigate neurovascular coupling non-invasively in human subjects using median-nerve stimulation. Previous fMRI studies have shown a habituation effect in the hemodynamic blood oxygen level-dependent (BOLD) response for stimulation periods longer than 2 s. With DOI and MEG we can test whether this effect in hemodynamic response can be accounted for by a habituation effect in the neural response. Our experimental results show that the habituation effect in the hemodynamic response is stronger than that in the earliest cortical neural response (N20). Using a linear convolution model to predict hemodynamic responses we found that including late neural components (>= 30 ms) improves the prediction of the hemoglobin response. This finding suggests that in addition to the initial evoked-response deflections related to the talamic afferent input, later cortical activity is needed to predict the hemodynamic response. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ou, Wanmei] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Nissila, Ilkka; Radhakrishnan, Harsha; Boas, David A.; Hamalainen, Matti S.; Franceschini, Maria Angela] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA USA. RP Ou, WM (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. EM wanmei@mit.edu; ilkka.nissila@hut.fi; harsha@nmr.mgh.harvard.edu; dboas@nmr.mgh.harvard.edu; msh@nmr.mgh.harvard.edu; mari@nmr.mgh.harvard.edu RI Nissila, Ilkka/G-6879-2012; Radhakrishnan, Harsha/K-5557-2012; Hamalainen, Matti/C-8507-2013 OI Nissila, Ilkka/0000-0001-6534-8436; FU US National Institutes of Health (NIH) [R01-EB001954, P41-RR14075, R01-EB006385]; NSF; PHS [DA022759-03] FX We thank Dr. Solomon Diamond and Dr. Ted Huppert for helping with probe design and Deirdre Foxe and Natsuko Mori for helping with MEG measurements. This research is supported by the US National Institutes of Health (NIH) grants R01-EB001954, P41-RR14075 and R01-EB006385. Wanmei Ou is partially supported by the NSF graduate fellowship and the PHS training grant DA022759-03. NR 70 TC 30 Z9 31 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 1 PY 2009 VL 46 IS 3 BP 624 EP 632 DI 10.1016/j.neuroimage.2009.03.008 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 443VK UT WOS:000265938700009 PM 19286463 ER PT J AU Neema, M Goldberg-Zimring, D Guss, ZD Healy, BC Guttmann, CRG Houtchens, MK Weiner, HL Horsfield, MA Hackney, DB Alsop, DC Bakshi, R AF Neema, Mohit Goldberg-Zimring, Daniel Guss, Zachary D. Healy, Brian C. Guttmann, Charles R. G. Houtchens, Maria K. Weiner, Howard L. Horsfield, Mark A. Hackney, David B. Alsop, David C. Bakshi, Rohit TI 3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis SO NEUROIMAGE LA English DT Article ID CLINICALLY ISOLATED SYNDROMES; T-2 RELAXATION; GRAY-MATTER; BRAIN ATROPHY; SPINAL-CORD; HIGH-FIELD; 3.0 TESLA; IN-VIVO; TIME; LESIONS AB MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin-spin relaxometry detected damage in NAWM of MS patients (n = 13) vs. age-matched normal controls [(NL) (n = 11)]. Baseline characteristics of the MS group were: age (mean +/- SD) 42.5 +/- 5.4 (range 33-51 years), disease duration 9.0 +/- 6.4 (range 1-22 years), Expanded Disability Status Scale score 2.5 +/- 1.7 (range 1-6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (=1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL, in the whole brain (p = 0.00047). frontal NAWM (p = 0.00015), parietal NAWM (p = 0.0069) and callosal genu (p = 0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p = 0.019). However, the normalized WM Volume fractions were similar in both MS and NL (p > 0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss. (C) 2009 Elsevier Inc. All rights reserved. C1 [Neema, Mohit; Goldberg-Zimring, Daniel; Guss, Zachary D.; Healy, Brian C.; Guttmann, Charles R. G.; Houtchens, Maria K.; Weiner, Howard L.; Bakshi, Rohit] Harvard Univ, Sch Med, Dept Neurol,Partners MS Ctr, Brigham & Womens Hosp,Lab Neuroimaging Res, Boston, MA 02115 USA. [Goldberg-Zimring, Daniel; Guttmann, Charles R. G.; Bakshi, Rohit] Harvard Univ, Sch Med, Dept Radiol,Partners MS Ctr, Brigham & Womens Hosp,Lab Neuroimaging Res, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Horsfield, Mark A.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Hackney, David B.; Alsop, David C.] Harvard Univ, Sch Med, Dept Radiol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Neema, M (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Lab Neuroimaging Res, 1 Brookline Pl,Suite 602, Brookline, MA 02445 USA. EM mneema@bwh.harvard.edu RI Horsfield, Mark/C-6569-2013; Alsop, David/J-5764-2013; Hackney, David/A-5337-2010 OI Horsfield, Mark/0000-0002-0815-6697; Alsop, David/0000-0002-8206-1995; FU National Institutes of Health [K23 NS42379-01, 1101 NS055083-01]; National Multiple Sclerosis Society [RG3705A1, RG3798A2, RG4032A1/1] FX This work was Supported by research grants from the National Institutes of Health (NIH-NINDS K23 NS42379-01 and 1101 NS055083-01) and National Multiple Sclerosis Society (RG3705A1; RG3798A2; RG4032A1/1). We thank Ms. Sophie Tamm for her assistance with manuscript preparations. NR 56 TC 44 Z9 44 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 1 PY 2009 VL 46 IS 3 BP 633 EP 641 DI 10.1016/j.neuroimage.2009.03.001 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 443VK UT WOS:000265938700010 PM 19281850 ER PT J AU Latorre, JGS Greer, DM AF Latorre, Julius Gene S. Greer, David M. TI Management of Acute Intracranial Hypertension A Review SO NEUROLOGIST LA English DT Review DE intracranial pressure; intracranial hypertension; acute brain injury; neurocritical care ID TRAUMATIC BRAIN-INJURY; SEVERE HEAD-INJURY; CEREBRAL-BLOOD-FLOW; INTENSIVE INSULIN THERAPY; ARTERY TERRITORY INFARCTION; INTRA-CRANICAL PRESSURE; ACUTE ISCHEMIC STROKE; SPONTANEOUS INTRACEREBRAL HEMORRHAGE; FRAMELESS STEREOTACTIC ASPIRATION; PROLONGED PROPOFOL INFUSION AB Background: Patients with acute brain injury from various etiologies commonly develop increased intracranial pressure. Acute intracranial hypertension resulting from elevation of intracranial pressure is a medical emergency requiring prompt diagnosis and management. Appropriate and timely management strategies result in better patient outcome in an otherwise severely debilitating or fatal disease process. Review Summary: The clinical manifestation and principles of management of acute intracranial hypertension are discussed and reviewed. Acute treatment protocols are presented in an algorithm-based format aimed at utilizing the current available management strategies and suggested therapeutic goals. Individualization of specific therapeutic modalities is emphasized to optimize the clinical outcome. Conclusions: Clinicians treating patients with acute brain injury should be familiar with the principles of management of increased intracranial pressure. Since acute intracranial hypertension is a potentially reversible condition, high index of suspicion, and low threshold for diagnostic and therapeutic strategies will improve patient care. C1 [Latorre, Julius Gene S.] SUNY Upstate Med Univ, Dept Neurol, Syracuse, NY 13210 USA. [Greer, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Latorre, JGS (reprint author), SUNY Upstate Med Univ, Dept Neurol, 7134UH,750 E Adams St, Syracuse, NY 13210 USA. EM latorrej@upstate.edu NR 275 TC 12 Z9 15 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1074-7931 J9 NEUROLOGIST JI Neurologist PD JUL PY 2009 VL 15 IS 4 BP 193 EP 207 DI 10.1097/NRL.0b013e31819f956a PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA 469PC UT WOS:000267911000004 PM 19590379 ER PT J AU Stella, SL Hu, WD Brecha, NC AF Stella, Salvatore L., Jr. Hu, Wanda D. Brecha, Nicholas C. TI Adenosine suppresses exocytosis from cone terminals of the salamander retina SO NEUROREPORT LA English DT Article DE activity-dependent dye; ATP; Ca(2+) channel; L-glutamate; purines; Synaptored-C2 ID CALCIUM-CHANNELS; RECEPTORS; PHOTORECEPTORS; RODS; CA2+; SYNAPSES; SLICES; FM1-43; INFLUX; RAT AB In the retina, adenosine is released in the dark and has been shown to inhibit Ca(2+) influx through voltage-gated Ca(2+) channels in cones. Therefore, we tested whether adenosine can inhibit exocytosis from isolated cone photoreceptors. Simultaneous measurements of membrane exocytosis and Ca(2+) were made from cones using the activity-dependent dye, Synaptored-C2, and the Ca(2+) indicator dye, Fluo-4. Adenosine suppressed exocytosis in cones, indicating that transmitter release is also reduced from cone terminals, and further supports an inhibitory mechanism for modulating transmitter release onto second-order neurons. Furthermore, this raises the possibility that adenosine might be neuroprotective for photoreceptors and second-order neurons by suppressing Ca(2+) levels in cones and reducing exocytosis of L-glutamate, respectively. NeuroReport 20:923-929 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Stella, Salvatore L., Jr.; Hu, Wanda D.; Brecha, Nicholas C.] Univ Calif Los Angeles, Dept Neurobiol, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, Jules Stein Eye Inst, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Stella, SL (reprint author), Univ Calif Los Angeles, Dept Neurobiol, David Geffen Sch Med, 10833 Conte Blvd,Box 951763,CHS 73-323, Los Angeles, CA 90095 USA. EM sstella@mednet.ucla.edu OI Stella Jr., Salvatore/0000-0003-1971-2537 FU NIH [04067, 41301]; VA Senior Career Scientist; Fight-For-Sight Student Fellowship; Jeanette Duval Scholarship; UCLA Undergraduate Research Scholars Program FX The authors thank Alejandro Vila and Uyenchi Huynh for providing technical support, and Arlene Hirano for critically reading earlier versions of this manuscript and providing insightful comments. This research was supported by NIH grants EY 04067, and DK 41301 and a VA Senior Career Scientist to N.C.B., Fight-For-Sight, Grant-in-Aid to S.L.S., and Fight-For-Sight Student Fellowship, Jeanette Duval Scholarship, and UCLA Undergraduate Research Scholars Program to W.D.H. NR 23 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 1 PY 2009 VL 20 IS 10 BP 923 EP 929 DI 10.1097/WNR.0b013e32832ca4b0 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 466AW UT WOS:000267633600006 PM 19491713 ER PT J AU Reed, CL Hagler, DJ Marinkovic, K Dale, A Halgren, E AF Reed, Catherine L. Hagler, Donald J., Jr. Marinkovic, Ksenija Dale, Anders Halgren, Eric TI Sequences of cortical activation for tactile pattern discrimination using magnetoencephalography SO NEUROREPORT LA English DT Article DE magnetoencephalography; neuroimaging; object recognition; pattern recognition; somatosensory; spatiotemporal maps; tactile; touch ID OBJECT RECOGNITION; SURFACE RECONSTRUCTION; FMRI; MEG; LOCALIZATION; SYSTEM; FIELDS; CORTEX; TOUCH; SHAPE AB To observe sequential stages in tactile pattern discrimination and their modification with and without attention, we used whole-head anatomically constrained magnetoencephalography to spatiotemporally map brain responses. Eight, normal, right-handed participants discriminated between two patterns presented on the palm. Latencies of neural activity were determined from stimulus contact with the palm. Early cortical activation moved from sensorimotor cortex (SM1) to secondary somatosensory cortex (SII), Broca's area (BA), and superior parietal cortex by 65 ms. It continued bilaterally to temporal and frontal poles by 290 ms. Subtraction of nonattended from attended conditions removed primarily the early contralateral sensory components. There was some indication of a preferred order of sensory processing that may express and optimize hemispheric computational specializations. Results indicate similar functional organizations for tactile and visual pattern recognition. NeuroReport 20:941-945 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Reed, Catherine L.] Claremont Mckenna Coll, Dept Psychol, Claremont, CA 91711 USA. [Reed, Catherine L.] Univ Denver, Dept Psychol, Denver, CO 80208 USA. [Hagler, Donald J., Jr.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Dale, Anders; Halgren, Eric] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders; Halgren, Eric] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Marinkovic, Ksenija; Halgren, Eric] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Marinkovic, Ksenija] Massachusetts Gen Hosp, Martinos Ctr, Boston, MA 02114 USA. RP Reed, CL (reprint author), Claremont Mckenna Coll, Dept Psychol, 850 Columbia Ave, Claremont, CA 91711 USA. EM cathy.reed@cmc.edu RI Dale, Anders/A-5180-2010 NR 25 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 1 PY 2009 VL 20 IS 10 BP 941 EP 945 DI 10.1097/WNR.0b013e32832c5f65 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 466AW UT WOS:000267633600009 PM 19525880 ER PT J AU Hu, R Eskandar, E Williams, Z AF Hu, Rollin Eskandar, Emad Williams, Ziv TI Role of deep brain stimulation in modulating memory formation and recall SO NEUROSURGICAL FOCUS LA English DT Article DE deep brain stimulation; learning; memory ID 3 MOTOR AREAS; BASAL GANGLIA; NEURONAL-ACTIVITY; STRIATUM; CORTEX; MONKEY; MOVEMENT; ENHANCEMENT; HIPPOCAMPAL; EXPECTATION AB Deep brain stimulation (DBS) has become an increasingly popular tool for treating a variety of medically refractory neurological and psychiatric disorders such as Parkinson disease, essential tremor, depression, and obsessive-compulsive disorder. Several targets have been identified for ablation or stimulation based on their anatomical location and presumed function. Areas such as the subthalamic nucleus, globus pallidus, and thalamus, for example, are believed to play a key role in motor control and execution, and they are commonly used in the treatment of motor disorders. Limbic structures such as the cingulate cortex and ventral striatum, believed to be important in motivation, emotion, and higher cognition, have also been targeted for treatment of a number of psychiatric disorders. In all of these settings, DBS is largely aimed at addressing the deleterious aspects of these diseases. In Parkinson disease, for example, DBS has been used to reduce rigidity and tremor, whereas in obsessive-compulsive disorder it has been used to limit compulsive behavior. More recently, however, attention has also turned to the potential use of DBS for enhancing or improving otherwise nonpathological aspects of cognitive function. This review explores the potential role of DBS in augmenting memory formation and recall, and the authors discuss recent studies and future trends in this emerging field. (DOI:10.3171/2009.4.FOCUS0975) C1 [Hu, Rollin; Eskandar, Emad; Williams, Ziv] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Williams, Z (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,WAC 745K, Boston, MA 02114 USA. EM zwilliams@partners.org FU NEI NIH HHS [R01 EY017658-03, R01 EY017658, R01 EY017658-01A1, R01 EY017658-02]; NIDA NIH HHS [R01 DA026297-02, R01 DA026297-01, R01 DA026297] NR 41 TC 9 Z9 9 U1 0 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD JUL PY 2009 VL 27 IS 1 AR E3 DI 10.3171/2009.4.FOCUS0975 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 478JI UT WOS:000268583300003 PM 19569891 ER PT J AU Pezaris, JS Eskandar, EN AF Pezaris, John S. Eskandar, Emad N. TI Getting signals into the brain: visual prosthetics through thalamic microstimulation SO NEUROSURGICAL FOCUS LA English DT Article DE visual prosthesis; deep brain stimulation; visual function ID LATERAL GENICULATE-NUCLEUS; HUMAN OCCIPITAL CORTEX; ELECTRICAL-STIMULATION; OPTIC-NERVE; PARKINSONS-DISEASE; INTRACORTICAL MICROSTIMULATION; MAGNETIC STIMULATION; RETINITIS-PIGMENTOSA; RETINAL PROSTHESIS; ARTIFICIAL VISION AB Common causes of blindness are diseases that affect the ocular structures, such as glaucoma, retinitis pigmentosa, and macular degeneration, rendering the eyes no longer sensitive to light. The visual pathway, however, as a predominantly central structure, is largely spared in these cases. It is thus widely thought that a device-based prosthetic approach to restoration of visual function will be effective and will enjoy similar success as cochlear implants have for restoration of auditory function. In this article the authors review the potential locations for stimulation electrode placement for visual prostheses, assessing the anatomical and functional advantages and disadvantages of each. Of particular interest to the neurosurgical community is placement of deep brain stimulating electrodes in thalamic structures that has shown substantial promise in an animal model. The theory of operation of visual prostheses is discussed, along with a review of the current state of knowledge. Finally, the visual prosthesis is proposed as a model for a general high-fidelity machine-brain interface. (DOI:10.3171/2009.4.FOCUS0986) C1 [Pezaris, John S.; Eskandar, Emad N.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Pezaris, JS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,THR 425, Boston, MA 02114 USA. EM pezaris.john@mgh.harvard.edu FU NEI NIH HHS [R01 EY017658-01A1, R01 EY017658, R01 EY017658-02, R01 EY017658-03, R01 EY019679]; NIDA NIH HHS [R01 DA026297, R01 DA026297-01, R01 DA026297-02] NR 92 TC 27 Z9 30 U1 3 U2 12 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD JUL PY 2009 VL 27 IS 1 AR E6 DI 10.3171/2009.4.FOCUS0986 PG 11 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 478JI UT WOS:000268583300006 PM 19569894 ER PT J AU Oh, MC Lim, DA AF Oh, Michael C. Lim, Daniel A. TI Novel Treatment Strategies for Malignant Gliomas Using Neural Stem Cells SO NEUROTHERAPEUTICS LA English DT Review DE Neural stem cells; brain tumor stem cells; glioma; gene therapy ID APOPTOSIS-INDUCING LIGAND; TUMOR-INITIATING CELLS; GENE-THERAPY; PROGENITOR CELLS; PRECURSOR CELLS; BRAIN-TUMORS; GLIOBLASTOMA-MULTIFORME; SUBVENTRICULAR ZONE; ADULT BRAIN; IN-VIVO AB Recent studies in stem cell biology have refined our understanding of the origin and progression of cancer. Identification and characterization of endogenous neural stem cells (NSCs), especially those in the adult human brain, have inspired new ideas for selectively targeting and destroying malignant gliomas. Gliomas consist of a heterogeneous population of cells, and some of these cells have characteristics of cancer stem cells. These brain tumor stem cells (BTSCs) share certain characteristics with normal NSCs. It is still unclear, however, whether malignant gliomas in human patients originate from these aberrant BTSCs. Nonetheless, the cellular and molecular similarities between BTSCs and normal NSCs suggest a common research landscape underlying both normal and cancer stem cell biology, wherein findings of one field are relevant to the other. Furthermore, the natural tropism of NSCs to gliomas has generated the idea that modified NSCs can deliver modified genes to selectively destroy malignant brain tumor cells, and even BTSCs, while leaving healthy surrounding neurons intact. These studies and others on the basic biology of both BTSCs and NSCs will be crucial to expanding our treatment strategies for malignant gliomas. C1 [Oh, Michael C.; Lim, Daniel A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Lim, Daniel A.] San Francisco VA Med Ctr, Surg Serv, Neurosurg Sect, Dept Vet Affairs, San Francisco, CA 94121 USA. RP Oh, MC (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave, San Francisco, CA 94143 USA. EM ohmc@neurosurg.ucsf.edu NR 66 TC 10 Z9 10 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-7213 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2009 VL 6 IS 3 BP 458 EP 464 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 465KE UT WOS:000267581800005 PM 19560736 ER PT J AU Chi, AS Norden, AD Wen, PY AF Chi, Andrew S. Norden, Andrew D. Wen, Patrick Y. TI Antiangiogenic Strategies for Treatment of Malignant Gliomas SO NEUROTHERAPEUTICS LA English DT Review DE Malignant glioma; glioblastoma; angiogenesis; vascular endothelial growth factor; edema; biomarker ID ENDOTHELIAL-GROWTH-FACTOR; PHASE-II TRIAL; HIGH-GRADE GLIOMAS; NEWLY-DIAGNOSED GLIOBLASTOMA; BEVACIZUMAB PLUS IRINOTECAN; LOW-DOSE CHEMOTHERAPY; ANTI-ANGIOGENIC THERAPY; RENAL-CELL CARCINOMA; RECURRENT GLIOBLASTOMA; TUMOR ANGIOGENESIS AB Numerous antiangiogenic agents with diverse mechanisms of action are currently under investigation for the treatment of patients with glioblastoma (GBM), a diagnosis that continues to carry a poor prognosis despite maximal conventional therapy. Early clinical trials suggest that antiangiogenic drugs, which target the blood vessels of these highly angiogenic tumors, may have clinical benefit in GBM patients. Antiangiogenic agents have potent antiedema and steroid-sparing effects in patients, and emerging data suggest that these drugs may modestly improve progression-free survival. Although these early results are encouraging, several issues arise regarding the use and efficacy of these agents. Interpretation of the radiographic changes that occur after treatment with antiangiogenic agents presents a major challenge. Still lacking are reliable radiographic and biologic markers that can predict which patients will benefit from treatment and that accurately indicate response and progression during therapy. In addition, most patients treated with antiangiogenic drugs eventually progress, and the mechanisms by which tumors escape from therapy are only beginning to be understood. Larger prospective trials that incorporate correlative biomarker studies will be required to address these challenges. Here, we summarize the clinical experience with antiangiogenic therapy in patients with malignant gliomas (MG), review the major issues concerning the use and development of these agents, and discuss strategies that may build upon the initial gains observed with antiangiogenic agents. C1 [Norden, Andrew D.; Wen, Patrick Y.] Dana Farber Brigham & Womans Canc Ctr, Ctr Neurooncol, Dept Med Oncol, Boston, MA 02115 USA. [Norden, Andrew D.; Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02115 USA. [Chi, Andrew S.; Norden, Andrew D.; Wen, Patrick Y.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chi, Andrew S.; Norden, Andrew D.; Wen, Patrick Y.] Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Chi, Andrew S.] Massachusetts Gen Hosp, Ctr Canc,Dept Neurol, Stephen E & Catherine Pappas Ctr Neurooncol, Div Hematol & Oncol, Boston, MA 02115 USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womans Canc Ctr, Ctr Neurooncol, Dept Med Oncol, SW430 D,44 Binney St, Boston, MA 02115 USA. EM patrick_wen@dfci.harvard.edu FU Melinda Wanatick Brain Tumor Research Fund FX We gratefully acknowledge the support of the Melinda Wanatick Brain Tumor Research Fund. NR 127 TC 23 Z9 23 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2009 VL 6 IS 3 BP 513 EP 526 PG 14 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 465KE UT WOS:000267581800010 PM 19560741 ER PT J AU Janulewicz, P Walsh, J Nixon, T Olson, S Holmes, L Adams, J AF Janulewicz, Patricia Walsh, Jessica Nixon, Tanya Olson, Sam Holmes, Lewis Adams, Jane TI Attention and working memory in children exposed prenatally to anticonvulsant monotherapy SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the Neurobehavioral-Teratology-Society/49th Annual Meeting of the Teratology-Society/22nd Annual Meeting of the Organization-of-Teratology-Information-Specialists CY JUN 28-JUL 01, 2009 CL Rio Grande, PR SP Neurobehav Teratol Soc, Teratol Soc, Org Teratol Informat Specialists C1 [Janulewicz, Patricia; Walsh, Jessica; Nixon, Tanya; Olson, Sam; Adams, Jane] Univ Massachusetts, Boston, MA 02125 USA. [Holmes, Lewis] MassGen Hosp Children, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-SEP PY 2009 VL 31 IS 4 MA NBTS51 BP 249 EP 250 DI 10.1016/j.ntt.2009.04.055 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 461GY UT WOS:000267253900058 ER PT J AU Naamati, G Askenazi, M Linial, M AF Naamati, Guy Askenazi, Manor Linial, Michal TI ClanTox: a classifier of short animal toxins SO NUCLEIC ACIDS RESEARCH LA English DT Article ID 3-FINGER TOXINS; EVOLUTION; DATABASE; PREDICTION; SEQUENCES; PEPTIDES; PROTEINS; SERVER AB Toxins are detected in sporadic species along the evolutionary tree of the animal kingdom. Venomous animals include scorpions, snakes, bees, wasps, frogs and numerous animals living in the sea such as the stonefish, snail, jellyfish, hydra and more. Interestingly, proteins that share a common scaffold with animal toxins also exist in non-venomous species. However, due to their short length and primary sequence diversity, these, toxin-like proteins remain undetected by classical search engines and genome annotation tools. We construct a toxin classification machine and web server called ClanTox (Classifier of Animal Toxins) that is based on the extraction of sequence-driven features from the primary protein sequence followed by the application of a classification system trained on known animal toxins. For a given input list of sequences, from venomous or non-venomous settings, the ClanTox system predicts whether each sequence is toxin-like. ClanTox provides a ranked list of positively predicted candidates according to statistical confidence. For each protein, additional information is presented including the presence of a signal peptide, the number of cysteine residues and the associated functional annotations. ClanTox is a discovery-prediction tool for a relatively overlooked niche of toxin-like cell modulators, many of which are therapeutic agent candidates. The ClanTox web server is freely accessible at http://www.clantox.cs.huji.ac.il. C1 [Askenazi, Manor; Linial, Michal] Hebrew Univ Jerusalem, Sudarsky Ctr Computat Biol, Inst Life Sci, Dept Biol Chem, IL-91905 Jerusalem, Israel. [Askenazi, Manor] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. RP Linial, M (reprint author), Hebrew Univ Jerusalem, Sudarsky Ctr Computat Biol, Inst Life Sci, Dept Biol Chem, IL-91905 Jerusalem, Israel. EM michall@cc.huji.ac.il OI Naamati, Guy/0000-0002-0523-4071 FU Israel Science Foundation (ISF); US-Israel Binational Science Foundation (BSF); Sudarsky Center for Computational Biology (SCCB) FX Israel Science Foundation (ISF) and the US-Israel Binational Science Foundation (BSF); Sudarsky Center for Computational Biology (SCCB) (to G. N.). NR 23 TC 19 Z9 19 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2009 VL 37 BP W363 EP W368 DI 10.1093/nar/gkp299 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469IG UT WOS:000267889100064 PM 19429697 ER PT J AU Oeffinger, KC Ford, JS Moskowitz, CS Diller, LR Hudson, MM Chou, JF Smith, SM Mertens, AC Henderson, TO Friedman, DL Leisenring, WM Robison, LL AF Oeffinger, Kevin C. Ford, Jennifer S. Moskowitz, Chaya S. Diller, Lisa R. Hudson, Melissa M. Chou, Joanne F. Smith, Stephanie M. Mertens, Ann C. Henderson, Tara O. Friedman, Debra L. Leisenring, Wendy M. Robison, Leslie L. TI Breast Cancer Surveillance Practices Among Women Previously Treated With Chest Radiation for a Childhood Cancer EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. St Jude Childrens Hosp, Memphis, TN 38105 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Chicago, Chicago, IL 60637 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Oeffinger, KC (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 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 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUL PY 2009 VL 64 IS 7 BP 466 EP 467 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 463AQ UT WOS:000267401100020 ER PT J AU Winkfield, KM Harris, JR AF Winkfield, Karen M. Harris, Jay R. TI Effective Local Therapy and Long-Term Survival in Breast Cancer SO ONCOLOGY-NEW YORK LA English DT Article AB The causal link between local control and long-term survival in breast cancer has become clearer over the past few years. Although the prevalence of breast cancer is high, there has been a steady decline in breast cancer mortality since the early 1990s. Improvements in breast cancer-specific mortality are the result of greater emphasis on cancer screening and improved treatment modalities, principally the development of effective adjuvant systemic therapy. Adjuvant radiation therapy (RT) substantially reduces local recurrence rates, and this reduction is even greater when combined with systemic therapy. Randomized controlled trials and meta-analyses have shown that reducing local recurrence improves overall long-term survival following both mastectomy and breast-conserving therapy. Clinical and translational research has begun to shed light on new prognostic and predictive markers that can assist in the assessment of an individual patient's risk of local recurrence without RT and the likelihood of a survival benefit with RT. The ability to appropriately tailor therapy to reduce local recurrence rates is vital toward continuing the decline in breast cancer mortality. C1 [Harris, Jay R.] Harvard Univ, Dana Farber Canc Inst, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Harris, Jay R.] Harvard Univ, Dept Radiat Oncol, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Winkfield, Karen M.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02115 USA. RP Harris, JR (reprint author), Harvard Univ, Dana Farber Canc Inst, Brigham & Womens Hosp, Sch Med, 44 Binney St,Dana 1622, Boston, MA 02115 USA. EM JHarris@LROC.Harvard.edu NR 31 TC 3 Z9 3 U1 0 U2 1 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUL PY 2009 VL 23 IS 8 BP 669 EP 675 PG 7 WC Oncology SC Oncology GA V18PR UT WOS:000208017200001 PM 19711579 ER PT J AU Jakobiec, FA Mehta, M Sutula, F AF Jakobiec, Frederick A. Mehta, Manisha Sutula, Francis TI Keratinous Cyst of the Palpebral Conjunctiva SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article AB A whitish-opalescent, mildly elevated superior tarsal conjunctival lesion measuring 3.0 mm in diameter caused a refractory corneal abrasion in a 54-year-old man. Complete local excision without entering the tarsus produced relief of symptoms. There has been no recurrence during 9 months of follow-up. Histopathologically, a unique keratinous cyst was delimited mostly by basaloid cells resembling the matrical cells in pilomatrixoma. There were no keratohyalin granules in the lining cells, which focally transformed in ghost cells. These histopathologic features are characteristic of trichilemmal keratinization, a heretofore undescribed metaplasia of the conjunctival epithelium. C1 [Jakobiec, Frederick A.; Mehta, Manisha] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Mehta, Manisha; Sutula, Francis] Massachusetts Eye & Ear Infirm, Oculoplast Serv, Dept Ophthalmol, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St,Room 321, Boston, MA 02114 USA. NR 9 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD JUL-AUG PY 2009 VL 25 IS 4 BP 337 EP 339 DI 10.1097/IOP.0b013e3181aada9a PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 474MQ UT WOS:000268288600028 PM 19617807 ER PT J AU Salti, HI Nasrallah, M Haddad, S Khairallah, W Salti, IS AF Salti, Haytham I. Nasrallah, Mona Haddad, Sandra Khairallah, Walid Salti, I. S. TI Enhancing Nonmydriatic Color Photographs of the Retina With Monochromatic Views and a Stereo Pair to Detect Diabetic Retinopathy SO OPHTHALMIC SURGERY LASERS & IMAGING LA English DT Article ID OPHTHALMOSCOPY; CAMERA; SPECIFICITY; SENSITIVITY; IMAGES AB BACKGROUND AND OBJECTIVE: Nonmydriatic digital color imaging is rapidly gaining an important role in screening for diabetic retinopathy. However, it has yet to equal a dilated fundus examination or seven Early Treatment Diabetic Retinopathy Study field 35-mm photography. The authors therefore attempted to enhance efficacy and validity by adding two low-cost steps to the nonmydriatic digital image evaluation. PATIENTS AND METHODS: The fundi of 145 consecutive patients with diabetes mellitus were evaluated for diabetic retinopathy using two different nonmydriatic reading techniques: creating a red-free view (using digital filters) and looking at a stereo pair of each field taken. These methods were each compared to a mydriatic fundus examination. RESULTS: although the first technique yielded views with sensitivities and specificities similar to what exists in the literature using this same technique, enhancing these photographs (second technique) yielded a statistically significant increase in sensitivity and specificity (P < .005). CONCLUSION: The authors recommend using both low-cost steps when screening for diabetic retinopathy through nonmydriatic digital color imaging. C1 [Salti, Haytham I.; Haddad, Sandra] Amer Univ Beirut, Med Ctr, Dept Ophthalmol, Beirut 11072020, Lebanon. [Nasrallah, Mona; Salti, I. S.] Amer Univ Beirut, Med Ctr, Div Endocrinol & Metab, Beirut 11072020, Lebanon. [Khairallah, Walid] Joslin Diabet Ctr, Manama, Bahrain. RP Salti, HI (reprint author), Amer Univ Beirut, Med Ctr, Dept Ophthalmol, POB 110236, Beirut 11072020, Lebanon. NR 19 TC 1 Z9 2 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1542-8877 J9 OPHTHAL SURG LAS IM JI Ophthalmic Surg. Lasers Imaging PD JUL-AUG PY 2009 VL 40 IS 4 BP 373 EP 378 DI 10.3928/15428877-2006030-04 PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 472JV UT WOS:000268127800004 PM 19634741 ER PT J AU Savar, A Vavvas, D AF Savar, Aaron Vavvas, Demetrios TI Optical Coherence Tomography Appearance of a Retinal Artery Macroaneurysm SO OPHTHALMIC SURGERY LASERS & IMAGING LA English DT Article AB Macroaneuysms are saccular dilatations of the retinal arterioles commonly seen in systemic hypertension. The authors present the first report of the high-resoultion optical coherence tomography appearance of all unruptured retinal artery macroaneurysm. [Ophthalmic Surg Lasers Imaging 2009;40:403-404.] C1 [Savar, Aaron; Vavvas, Demetrios] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Savar, A (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. OI Vavvas, Demetrios/0000-0002-8622-6478 NR 7 TC 3 Z9 3 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1542-8877 J9 OPHTHAL SURG LAS IM JI Ophthalmic Surg. Lasers Imaging PD JUL-AUG PY 2009 VL 40 IS 4 BP 403 EP 404 DI 10.3928/15428877-20096030-09 PG 2 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 472JV UT WOS:000268127800009 PM 19634746 ER PT J AU Kumar, ATN Chung, E Raymond, SB van de Water, JAJM Shah, K Fukumura, D Jain, RK Bacskai, BJ Boas, DA AF Kumar, Anand T. N. Chung, Euiheon Raymond, Scott B. van de Water, Jeroen A. J. M. Shah, Khalid Fukumura, Dai Jain, Rakesh K. Bacskai, Brian J. Boas, David A. TI Feasibility of in vivo imaging of fluorescent proteins using lifetime contrast SO OPTICS LETTERS LA English DT Article ID TOMOGRAPHY; MICROSCOPY; DOMAIN; CELLS AB We show that fluorescence lifetime is a powerful contrast mechanism that can enhance the whole-body imaging of fluorescent proteins (FPs), in the presence of background tissue autofluorescence (AF). The nonexponential AF decay is characterized from time-domain (TD) measurements on multiple nude mice and separated from the FP fluorescence using a linear fit to a priori basis functions. We illustrate this approach using an orthotopic mouse tumor model of breast adenocarcinoma. We also report that four commonly used FPs show distinct lifetimes, indicating their suitability for in vivo lifetime multiplexing. These results suggest the potential for exploiting fluorescence lifetime for imaging Fps for a variety of whole-body small-animal imaging applications. (C) 2009 Optical Society of America C1 [Kumar, Anand T. N.; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Chung, Euiheon; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02129 USA. [Raymond, Scott B.] Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA. [van de Water, Jeroen A. J. M.; Shah, Khalid] Massachusetts Gen Hosp, Dept Radiol & Neurol, Mol Neurotherapy & Imaging Lab, Charlestown, MA 02129 USA. [Bacskai, Brian J.] Massachusetts Gen Hosp, Dept Neurol, Alzheimers Dis Res Unit, Charlestown, MA 02129 USA. RP Kumar, ATN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM ankumar@nmr.mgh.harvard.edu RI van de Water, Jeroen/F-1302-2011; OI van de Water, Jeroen/0000-0001-6974-2270; Raymond, Scott/0000-0001-7008-8974 FU National Institutes of Health (NIH) [AG026240, CA80124, CA85140, CA96915, CA115767, CA126642]; Federal Share/NCI Proton Beam Program FX This study was supported by the National Institutes of Health (NIH) grants AG026240, CA80124, CA85140, CA96915, CA115767, and CA126642 and Federal Share/NCI Proton Beam Program Income grant(s). NR 11 TC 16 Z9 16 U1 0 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD JUL 1 PY 2009 VL 34 IS 13 BP 2066 EP 2068 PG 3 WC Optics SC Optics GA 475QV UT WOS:000268376200052 PM 19572001 ER PT J AU Haddad, R Braschayko, P Sonis, S Posner, M Wirth, L Tishler, R AF Haddad, R. Braschayko, P. Sonis, S. Posner, M. Wirth, L. Tishler, R. TI Randomized phase II study of concomitant chemoradiation using weekly carboplatin/paclitaxel/concomitant boost radiation with or without daily subcutaneous amifostine in patients with newly diagnosed locally advanced head and neck cancer SO ORAL ONCOLOGY LA English DT Meeting Abstract CT 2nd World Congress of the International-Academy-of-Oral-Oncology CY JUL 08-11, 2009 CL Toronto, CANADA SP Int Acad Oral Oncol C1 [Haddad, R.; Braschayko, P.; Sonis, S.; Posner, M.; Wirth, L.; Tishler, R.] Dana Farber Canc Inst, Boston, MA USA. [Haddad, R.; Sonis, S.; Posner, M.; Tishler, R.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2009 BP 65 EP 65 DI 10.1016/j.oos.2009.06.113 PG 1 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 509KJ UT WOS:000271015100069 ER PT J AU Xu, L Polur, I Lim, C Servais, JM Dobeck, J Li, Y Olsen, BR AF Xu, L. Polur, I. Lim, C. Servais, J. M. Dobeck, J. Li, Y. Olsen, B. R. TI Early-onset osteoarthritis of mouse temporomandibular joint induced by partial discectomy SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Temporomandibular joint; Articular cartilage; Discectomy; Osteoarthritis ID DISCOIDIN DOMAIN RECEPTOR-2; MATRIX-METALLOPROTEINASE; ARTICULAR-CARTILAGE; DEFICIENT MICE; IN-VITRO; EXPRESSION; COLLAGEN; DEGRADATION; CLONING; DDR2 AB Objective: The objective of this study is to characterize mouse temporomandibular joint (TMJ) following partial discectomy, since there is no documentation of whether or not partial discectomy can induce early-onset osteoarthritis (OA) in mouse TMJ. Methods: Partial discs of TMJ in mice were removed by microsurgery. Histology was performed to characterize articular cartilages from the TMJ of mice. The morphology of the articular cartilages was evaluated using a modified Mankin scoring system. Immunohistostaining was carried out to examine the expression of discoidin domain receptor 2 (Ddr2), a type II collagen receptor, matrix metalloproteinase-13 (Mmp-13), and Mmp-derived type II collagen fragments in the articular cartilage of condyles from the mouse TMJ. Results: Articular cartilage degeneration was seen in the mouse TMJ post-discectomy, including increased proteoglycan staining in the extracellular matrix at 4 weeks, the appearance of chondrocyte clusters at 8 weeks, reduced proteoglycan staining and fibrillation at 12 weeks and the loss of articular cartilage at 16 weeks. Increased immunostaining for Ddr2, Mmp-13, and Mmp-derived type 11 collagen fragments was detected. Conclusion: Results indicate that partial discectomy induces early-onset OA in mouse TMJ and that increased expression of Mmp-13, likely due to the elevated expression of Ddr2, may be one of the factors responsible for the early-onset OA in mouse TMJ. (C) 2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Xu, L.] Forsyth Inst, Boston, MA 02115 USA. [Xu, L.; Polur, I.; Lim, C.; Servais, J. M.; Dobeck, J.; Li, Y.; Olsen, B. R.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Olsen, B. R.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Xu, L (reprint author), Forsyth Inst, 140 Fenway, Boston, MA 02115 USA. EM lin_xu@hms.harvard.edu FU Jaw Joints & Allied Musculo-Skeletal Disorders Foundation [JJAMD]; NIH [R01-AR-051989, R01-AR-36819] FX This work was supported by Renee and Milton Glass TMJD Fellowship from Jaw Joints & Allied Musculo-Skeletal Disorders Foundation [JJAMD] (to Xu) and by NIH grants R01-AR-051989 (to Xu and Li) and R01-AR-36819 (to Olsen). NR 29 TC 20 Z9 20 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUL PY 2009 VL 17 IS 7 BP 917 EP 922 DI 10.1016/j.joca.2009.01.002 PG 6 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 474DN UT WOS:000268262800013 PM 19230720 ER PT J AU Roditi, RE Eppsteiner, RW Sauter, TB Lee, DJ AF Roditi, Rachel E. Eppsteiner, Robert W. Sauter, Todd B. Lee, Daniel J. TI Cervical vestibular evoked myogenic potentials (cVEMPs) in patients with superior canal dehiscence syndrome (SCDS) SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article; Proceedings Paper CT 112th Annual Meeting of the American-Academy-of-Otolaryngology-Head-and-Neck-Surgery CY SEP 21-24, 2008 CL Chicago, IL SP Amer Acad Otolaryngol Head & Neck Surg ID SOUND; VERTIGO AB OBJECTIVE: To determine the usefulness of both amplitude and threshold data from tone-burst cervical vestibular evoked myogenic potential (cVEMP) testing for the evaluation of superior canal dehiscence syndrome (SCDS). STUDY DESIGN: Case series with chart review. SUBJECTS AND METHODS: Sixty-seven patients underwent cVEMP testing. We correlated mean tone burst cVEMP amplitude and threshold data with temporal bone CT findings. Patients were excluded for Meniere's disease, middle ear disease. or otologic surgery. RESULTS: Superior canal dehiscence patients had higher mean cVEMP amplitudes (SCDS 173.8 mu V vs non-SCDS 69.7 mu V, P = 0.031) and lower mean thresholds (SCDS 72.8 dB nHL vs non-SCDS 80.9 dB nHL) at 500 Hz. CONCLUSION: Patients with SCDS have larger amplitudes and lower thresholds on cVEMP testing at 500 Hz. This study supports the utility of tone burst cVEMPs for the evaluation of SCDS and is one of few large single-center studies to establish normative data. (C) 2009 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved. C1 [Lee, Daniel J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Sauter, Todd B.] UMass Mem Med Ctr, Dept Audiol, Worcester, MA USA. [Roditi, Rachel E.; Eppsteiner, Robert W.; Sauter, Todd B.] Univ Massachusetts, Sch Med, Dept Otolaryngol, Worcester, MA USA. RP Lee, DJ (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM daniel_lee@meei.harvard.edu NR 18 TC 11 Z9 11 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUL PY 2009 VL 141 IS 1 BP 24 EP 28 DI 10.1016/j.otohns.2009.03.012 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 463CB UT WOS:000267404900008 PM 19559953 ER PT J AU Leung, MK Platt, MP Metson, R AF Leung, Man-Kit Platt, Michael P. Metson, Ralph TI Revision endoscopic orbital decompression in the management of Graves' orbitopathy SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID OPTIC-NERVE DECOMPRESSION; OPHTHALMOPATHY; REACTIVATION AB OBJECTIVE: Endoscopic orbital decompression has proved to be an effective treatment for Graves' orbitopathy. In select patients, however, persistent or recurrent orbital symptoms necessitate additional therapy. The objective of this study is to determine the safety and effectiveness of revision endoscopic orbital decompression in patients with refractory Graves' orbitopathy. STUDY DESIGN: Case-control series. SETTING: Academic medical center. METHODS: The study population consisted of 10 patients with Graves' orbitopathy who underwent 13 revision endoscopic orbital decompressions (three bilateral cases) between 1991 and 2008. Outcome measures, including reduction in proptosis, improvement in visual acuity, and complication rates, were compared with a control cohort of 10 consecutive patients (16 orbits) who underwent primary endoscopic decompression during the same time period. RESULTS: Indications for revision decompression included exposure keratopathy (n = 8, 62%), optic neuropathy (n = 3, 23%), and gaze restriction (n = 2, 15%). There were no intraoperative complications. Mean reduction in proptosis was 1.4 mm less for patients who underwent revision decompression compared with primary cases (mean decompression 3.6 +/- 1.0 mm vs 5.0 +/- 2.1 mm, respectively), although this difference was not statistically significant (P = 0.13). Visual acuity improved in 62 percent of revision cases, compared with 20 percent of primary cases (P = 0.09). Rates for postoperative complications, which included sinusitis and frontal mucocele formation, were also similar between revision and primary decompression groups (38% vs 13% respectively, P = 0.17). CONCLUSIONS: This report is the first to describe the endoscopic technique for revision orbital decompression. It appears to be a safe and effective procedure for the treatment of refractory orbitopathy in patients with Graves' disease. (C) 2009 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved. C1 [Leung, Man-Kit; Metson, Ralph] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Platt, Michael P.] Boston Univ, Dept Otolaryngol Head & Neck Surg, Boston, MA 02215 USA. [Leung, Man-Kit; Metson, Ralph] Boston Univ, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02215 USA. RP Leung, MK (reprint author), 0 Emerson Pl, Boston, MA 02114 USA. EM Man-Kit_Leung@meei.harvard.edu NR 11 TC 4 Z9 4 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUL PY 2009 VL 141 IS 1 BP 46 EP 51 DI 10.1016/j.otohns.2009.04.007 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 463CB UT WOS:000267404900012 PM 19559957 ER PT J AU Lindsay, RW Hadlock, TA Cheney, ML AF Lindsay, Robin W. Hadlock, Tessa A. Cheney, Mack L. TI Bilateral simultaneous free gracilis muscle transfer: A realistic option in management of bilateral facial paralysis SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article AB OBJECTIVES: Bilateral facial paralysis patients have oral incompetence, poor articulation, and dental caries. This problem is frequently addressed by performing staged gracilis transplants without specific oral sphincter reconstruction. The purpose of this study is to describe the technique of bilateral simultaneous free gracilis muscle transfer with oral sphincter reconstruction, for one-stage facial reanimation in patients with bilateral facial paralysis. STUDY DESIGN: Case series. METHODS/RESULTS: One-stage bilateral gracilis transfer was performed in three patients with bilateral facial paralysis. Muscle transplants produced a meaningful smile in all transferred muscles. All patients reported improved speech and decreased drooling. CONCLUSIONS: Bilateral gracilis transplants with reconstruction of the oral commissure is a realistic option in management of the bilaterally paralyzed face. In this small series, it appears to improve oral competence, restore smiling, and contribute favorably to lower lip support. This technique has been made more feasible because the operative time for free tissue transfer has continuously declined with the use of two-team surgery, improved microsurgical techniques, and the advent of venous coupling devices. (C) 2009 American Academy of Otolaryngology-l-lead and Neck Surgery Foundation. All rights reserved. C1 [Lindsay, Robin W.] Massachusetts Eye & Ear Infirm, Div Facial Plast & Reconstruct Surg, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lindsay, RW (reprint author), Massachusetts Eye & Ear Infirm, Div Facial Plast & Reconstruct Surg, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM robin_lindsay@meei.harvard.edu NR 5 TC 9 Z9 9 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUL PY 2009 VL 141 IS 1 BP 139 EP 141 DI 10.1016/j.otohns.2009.03.005 PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 463CB UT WOS:000267404900029 PM 19559974 ER PT J AU Hansen, LK Brown, M Johnson, D Palme, DF Love, C Darouiche, R AF Hansen, Linda K. Brown, Mary Johnson, David Palme, Donald F., II Love, Charles Darouiche, Rabih TI In Vivo Model of Human Pathogen Infection and Demonstration of Efficacy by an Antimicrobial Pouch for Pacing Devices SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE device infection; pacemaker ID CENTRAL VENOUS CATHETERS; PACEMAKER IMPLANTATION; PERMANENT PACEMAKER; COLONIZATION; PREVENTION; GUIDELINES; MANAGEMENT; TRIAL AB Objective: The purpose of this study was to determine the efficacy of the AIGIS(RX)(TM) antibacterial envelope (TyRx Pharma, Inc., Monmouth Junction, NJ, USA) designed to reduce device-related infections by incorporating minocycline and rifampin in a controlled release polymer. Methods: An infection was established in a rabbit model by creating bilateral subcutaneous implant pockets, into which a pacing device with or without AIGIS(RX)(TM) was placed. The incisions were closed, and a defined dose of bacteria was infused into each implant pocket. After 7 days, devices were explanted and sampled for viable bacteria by swabbing and sonication. Results: Initial studies evaluated the ability of the AIGIS(RX) pouch to reduce Staphylococcus epidermidis (S. epi) infection in this model using clinical and quantitative microbial endpoints. Results demonstrate S. epi infection in all control samples, while no pathogens were recovered from samples with the AIGIS(RX)(TM) pouch. Systemic antibiotic levels were undetectable. Additional studies tested the efficacy of the AIGIS(RX)(TM) pouch with additional bacterial strains, Staphylococcus capitis, Escherichia coli, and Acinetobacter Baumannii. In each case, the device and implant pocket with the AIGIS(RX)(TM) pouch was free of any signs of infection. An assessment of biofilm produced by Acinetobacter demonstrated the elimination of biofilm formation on the implanted device. Conclusion: These results demonstrate that in this animal model, the AIGIS(RX)(TM) device reduces the risk for infection of viable pathogens within implant pockets. (PACE 2009; 32:898-907). C1 [Hansen, Linda K.; Brown, Mary; Johnson, David; Palme, Donald F., II] WuXi AppTec Inc, St Paul, MN 55120 USA. [Love, Charles] Ohio State Univ, Med Ctr, Dept Internal Med, Div Cardiovasc Med, Columbus, OH 43210 USA. [Darouiche, Rabih] Michael E Debakey Vet Affairs Med Ctr, Houston, TX USA. RP Hansen, LK (reprint author), WuXi AppTec Inc, St Paul, MN 55120 USA. EM linda.hansen@wuxiapptec.com FU TyRx Pharma, Inc. FX The testing presented in this manuscript was sponsored by TyRx Pharma, Inc., manufacturer of the AIGISRX(TM) product. NR 18 TC 19 Z9 19 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD JUL PY 2009 VL 32 IS 7 BP 898 EP 907 PG 10 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 462CD UT WOS:000267322500011 PM 19572866 ER PT J AU Kabra, R Gopinathannair, R Sandesara, C Messinger, C Olshansky, B AF Kabra, Rajesh Gopinathannair, Rakesh Sandesara, Chirag Messinger, Catherine Olshansky, Brian TI The Dual Role of Implantable Loop Recorder in Patients with Potentially Arrhythmic Symptoms: A Retrospective Single-Center Study SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE implantable loop recorders; syncope; palpitations ID UNEXPLAINED SYNCOPE; MONITORING STRATEGY AB Methods: This large single-center retrospective study sought to assess the role of ILR in the evaluation of potentially arrhythmic symptoms, both in terms of diagnosis of an arrhythmia as well as to rule out an arrhythmic cause. Clinical data, indications for ILR, interrogation reports, and further management strategies were collected in all 86 patients who received ILR from June 1999 to April 2008 at the University of Iowa Hospitals and Clinics. The indications for ILR were unexplained syncope (76%), palpitations (14%), and presyncope or dizziness (10%). Results: During a mean follow-up period of 10 +/- 7 months, 53 patients (62%) had recurrent symptoms after ILR placement with the mean time to recurrence of 12 +/- 17 weeks. Of these, an arrhythmic diagnosis was established in 12 patients (14%). Forty-one patients (48%) did not have any arrhythmia during their symptoms. These patients were discharged from the electrophysiology clinic. Thirty-three patients (38%) did not have any symptoms following ILR placement. Out of these, device was explanted in 10 patients, while the rest are still being followed. Conclusions: In patients with potentially arrhythmic symptoms, ILR plays an important role not only in diagnosing an arrhythmia, but also to rule out an arrhythmic cause. (PACE 2009; 32:908-912). C1 [Kabra, Rajesh] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Gopinathannair, Rakesh; Sandesara, Chirag; Messinger, Catherine; Olshansky, Brian] Univ Iowa Hosp & Clin, Dept Internal Med, Iowa City, IA 52242 USA. RP Kabra, R (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA. EM rkabra@partners.org NR 14 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD JUL PY 2009 VL 32 IS 7 BP 908 EP 912 PG 5 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 462CD UT WOS:000267322500012 PM 19572867 ER PT J AU Gallagher, RM AF Gallagher, Rollin M. TI AAPM and Health Care Reform: Your Voice Is Needed SO PAIN MEDICINE LA English DT Editorial Material C1 [Gallagher, Rollin M.] Univ Penn, Amer Acad Pain Med, Philadelphia, PA 19104 USA. [Gallagher, Rollin M.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Gallagher, RM (reprint author), Univ Penn, Amer Acad Pain Med, Philadelphia, PA 19104 USA. NR 0 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 1526-2375 J9 PAIN MED JI Pain Med. PD JUL-AUG PY 2009 VL 10 IS 5 BP 781 EP 783 DI 10.1111/j.1526-4637.2009.00674.x PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 476ZI UT WOS:000268485000003 PM 19682271 ER PT J AU Meghani, SH Wiedemer, NL Becker, WC Gracely, EJ Gallagher, RM AF Meghani, Salimah H. Wiedemer, Nancy L. Becker, William C. Gracely, Ed J. Gallagher, Rollin M. TI Predictors of Resolution of Aberrant Drug Behavior in Chronic Pain Patients Treated in a Structured Opioid Risk Management Program SO PAIN MEDICINE LA English DT Article DE Opioids; Chronic Pain; Aberrant Drug Behavior; Substance Abuse; Primary Care; Opioid Renewal Clinic ID PRIMARY-CARE PHYSICIANS; CHRONIC NONCANCER PAIN; SOCIAL SUPPORT; ABUSE; THERAPY; MISUSE; ADJUSTMENT; DEPENDENCE; ADDICTION; NETWORK AB Objective. To identify demographic and clinical predictors of the resolution of aberrant drug-related behaviors (ADRBs) in a group of patients referred to the Opioid Renewal Clinic (ORC) by their primary care providers (PCPs). ORC is a program supporting PCPs' use of opioids for chronic pain in patients perceived as at risk for opioid abuse or those with demonstrated ADRBs. Methods. A retrospective chart review was conducted for 195 consecutive subjects referred to the ORC from January 17, 2002 to August 27, 2004, for ADRBs. Binary logistic regression was employed to identify independent predictors of aberrant behavior outcome at 1 year. Results. Of the 195 referred, 45.6% (N = 89) resolved their ADRB at 1 year. Other outcomes, classified as nonresolution of ADRB, self-discharged or discharged by the ORC for inability to adhere to the opioid treatment agreement (N = 86, 44.1%) and acceptance of referral for addiction treatment (N = 20, 10.2%). A history of cocaine abuse increased the odds of failing the program by five times (odds ratio [OR] = 4.97, P = 0.001). Each additional pain diagnosis reduced the odds of failure by 16% (OR = 0.837, P = 0.008). When compared with singles, married individuals were 62% less likely to fail the ORC program (OR = 0.38, P = 0.028). Conclusions. Nearly half of the patients resolved their aberrant behavior within the ORC. Patients with cocaine abuse were at higher risk for failure, suggesting a need for further research into safe and effective ways to manage pain in this complex subset of patients. Aberrant behaviors tended to resolve in patients with multiple pain locations, possibly because of their desire for relief. C1 [Wiedemer, Nancy L.; Becker, William C.; Gallagher, Rollin M.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Meghani, Salimah H.] Univ Penn, Sch Nursing, NewCourtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Gracely, Ed J.] Drexel Univ, Coll Med, Philadelphia, PA USA. [Gallagher, Rollin M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Wiedemer, NL (reprint author), Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM Nancy.Wiedemer@va.gov OI Becker, William/0000-0002-0788-1467 NR 25 TC 9 Z9 9 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD JUL-AUG PY 2009 VL 10 IS 5 BP 858 EP 865 DI 10.1111/j.1526-4637.2009.00643.x PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 476ZI UT WOS:000268485000015 PM 19523029 ER PT J AU Manchikanti, L Boswell, MV Singh, V Benyamin, RM Fellows, B Abdi, S Buenaventura, RM Conn, A Datta, S Derby, R Falco, FJE Erhart, S Diwan, S Hayek, SM Helm, S Parr, AT Schultz, DM Smith, HS Wolfer, LR Hirsch, JA AF Manchikanti, Laxmaiah Boswell, Mark V. Singh, Vijay Benyamin, Ramsin M. Fellows, Bert Abdi, Salahadin Buenaventura, Ricardo M. Conn, Ann Datta, Sukdeb Derby, Richard Falco, Frank J. E. Erhart, Stephanie Diwan, Sudhir Hayek, Salim M. Helm, Standiford, II Parr, Allan T. Schultz, David M. Smith, Howard S. Wolfer, Lee R. Hirsch, Joshua A. TI Comprehensive Evidence-Based Guidelines for Interventional Techniques in the Management of Chronic Spinal Pain SO PAIN PHYSICIAN LA English DT Review DE Interventional techniques; chronic spinal pain; diagnostic blocks; therapeutic interventions; facet joint interventions; epidural injections; epidural adhesiolysis; discography; radiofrequency; disc decompression; spinal cord stimulation; intrathecal implantable systems ID LOW-BACK-PAIN; EPIDURAL STEROID INJECTION; INTRADISCAL ELECTROTHERMAL THERAPY; LUMBAR FACET JOINT; 2000-2010 TASK-FORCE; HIGH-INTENSITY ZONE; OF-THE-LITERATURE; 5-YEAR FOLLOW-UP; LASER DISC DECOMPRESSION; DORSAL-ROOT GANGLION AB Background: Comprehensive, evidence-based guidelines for interventional techniques in the management of chronic spinal pain are described here to provide recommendations for clinicians. Objective: To develop evidence-based clinical practice guidelines for interventional techniques in the diagnosis and treatment of chronic spinal pain. Design: Systematic assessment of the literature. Methods: Strength of evidence was assessed by the U.S. Preventive Services Task Force (USPSTF) criteria utilizing 5 levels of evidence ranging from Level I to III with 3 subcategories in Level II. Outcomes: Short-term pain relief was defined as relief lasting at least 6 months and long-term relief was defined as longer than 6 months, except for intradiscal therapies, mechanical disc decompression, spinal cord stimulation and intrathecal infusion systems, wherein up to one year relief was considered as short-term. Results: The indicated evidence for accuracy of diagnostic facet joint nerve blocks is Level I or 111 in the diagnosis of lumbar, thoracic, and cervical facet joint pain. The evidence for lumbar and cervical provocation discography and sacroiliac joint injections is Level II-2, whereas it is Level II-3 for thoracic provocation discography The indicated evidence for therapeutic interventions is Level I for caudal epidural steroid injections in managing disc herniation or radiculitis, and discogenic pain without disc herniation or radiculitis. The evidence is Level I or II-1 for percutaneous adhesiolysis in management of pain secondary to post-lumbar surgery syndrome. The evidence is Level II-1 or II-2 for therapeutic cervical, thoracic, and lumbar facet joint nerve blocks; for caudal epidural injections in managing pain of post-lumbar surgery syndrome, and lumbar spinal stenosis, for cervical interlaminar epidural injections in managing cervical pain (Level II-1); for lumbar transforaminal epidural injections; and spinal cord stimulation for post-lumbar surgery syndrome. The indicated evidence for intradiscal electrothermal therapy (IDET), mechanical disc decompression with automated percutaneous lumbar discectomy (APLD), and percutaneous lumbar laser discectomy (PLDD) is Level II-2. Limitations: The limitations of these guidelines include a continued paucity of the literature, lack of updates, and conflicts in preparation of systematic reviews and guidelines by various organizations. Conclusion: The indicated evidence for diagnostic and therapeutic interventions is variable from Level I to III. These guidelines include the evaluation of evidence for diagnostic and therapeutic procedures in managing chronic spinal pain and recommendations for managing spinal pain, However, these guidelines do not constitute inflexible treatment recommendations. Further, these guidelines also do not represent "standard of care." C1 [Manchikanti, Laxmaiah; Fellows, Bert] Pain Management Ctr Paducah, Paducah, KY USA. [Boswell, Mark V.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Abdi, Salahadin] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Buenaventura, Ricardo M.] Pain Relief Dayton, Centerville, OH USA. [Conn, Ann; Parr, Allan T.] Premier Pain Ctr, Covington, LA USA. [Datta, Sukdeb] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Derby, Richard; Wolfer, Lee R.] Spinal Diagnost & Treatment Ctr, Daly City, CA USA. [Falco, Frank J. E.; Erhart, Stephanie] Mid Atlantic Spine & Pain Specialists, Newark, DE USA. [Diwan, Sudhir] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Hayek, Salim M.] Weill Cornell Med Coll, New York Presbyterian Hosp, New York, NY USA. [Helm, Standiford, II] Pacific Coast Pain Management Ctr, Laguna Hills, CA USA. [Schultz, David M.] Med Adv Pain Specialists, Minneapolis, MN USA. [Smith, Howard S.] Albany Med Coll, Albany, NY 12208 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Hayek, Salim M.] Outcomes Res Consortium, Cleveland, OH USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com OI Roth, Stephanie/0000-0001-5415-1718 NR 1072 TC 224 Z9 230 U1 6 U2 39 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2009 VL 12 IS 4 BP 699 EP 802 PG 104 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 485RG UT WOS:000269140800001 PM 19644537 ER PT J AU Manchikanti, L Singh, V Datta, S Cohen, SP Hirsch, JA AF Manchikanti, Laxmaiah Singh, Vijay Datta, Sukdeb Cohen, Steven P. Hirsch, Joshua A. TI Comprehensive Review of Epidemiology, Scope, and Impact of Spinal Pain SO PAIN PHYSICIAN LA English DT Article DE Chronic pain; chronic spinal pain; chronic low back pain; chronic neck pain; chronic thoracic pain; prevalence; health care utilization; loss of productivity; interventional techniques; surgery; comorbid factors; socioeconomic effects; health care impact ID LOW-BACK-PAIN; 2000-2010 TASK-FORCE; CHRONIC WIDESPREAD PAIN; ZYGAPOPHYSIAL JOINT PAIN; QUALITY-OF-LIFE; LUMBAR INTERVERTEBRAL-DISK; LOCAL-ANESTHETIC BLOCKS; CHRONIC NECK PAIN; 5-YEAR FOLLOW-UP; PREDOMINANTLY NEUROPATHIC ORIGIN AB Persistent pain interfering with daily activities is common. Chronic pain has been defined in many ways. Chronic pain syndrome is a separate entity from chronic pain. Chronic pain is defined as, "pain that persists 6 months after an injury and beyond the usual course of an acute disease or a reasonable time for a comparable injury to heal, that is associated with chronic pathologic processes that cause continuous or intermittent pain for months or years, that may continue in the presence or absence of demonstrable pathologies; may not be amenable to routine pain control methods; and healing may never occur." In contrast, chronic pain syndrome has been defined as a complex condition with physical, psychological, emotional, and social components. The prevalence of chronic pain in the adult population ranges from 2% to 40%, with a median point prevalence of 15%. Among chronic pain disorders, pain arising from various structures of the spine constitutes the majority of the problems. The lifetime prevalence of spinal pain has been reported as 54% to 80%. Studies of the prevalence of low back pain and neck pain and its impact in general have shown 23% of patients reporting Grade II to IV low back pain (high pain intensity with disability) versus 15% with neck pain. Further, age related prevalence of persistent pain appears to be much more common in the elderly associated with functional limitations and difficulty in performing daily life activities. Chronic persistent low back and neck pain is seen in 25% to 60% of patients, one-year or longer after the initial episode. Spinal pain is associated with significant economic, societal, and health impact. Estimates and patterns of productivity losses and direct health care expenditures among individuals with back and neck pain in the United States continue to escalate. Recent studies have shown significant increases in the prevalence of various pain problems including low back pain. Frequent use of opioids in managing chronic non-cancer pain has been a major issue for health care in the United States placing a significant strain on the economy with the majority of patients receiving opioids for chronic pain necessitating an increased production of opioids, and escalating costs of opioid use, even with normal intake. The additional costs of misuse, abuse, and addiction are enormous. Comorbidities including psychological and physical conditions and numerous other risk factors are common in spinal pain and add significant complexities to the interventionalist's clinical task. This section of the American Society of Interventional Pain Physicians (ASIPP)/Evidence-Based Medicine (EBM) guidelines evaluates the epidemiology, scope, and impact of spinal pain and its relevance to health care interventions. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, NY USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Cohen, Steven P.] Johns Hopkins Sch Med, Baltimore, MD USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), Pain Management Ctr Paducah, Paducah, NY USA. NR 557 TC 163 Z9 172 U1 11 U2 32 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2009 VL 12 IS 4 BP E35 EP E70 PG 36 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA V20HC UT WOS:000208130100002 PM 19668291 ER PT J AU Manchikanti, L Singh, V Pampati, V Boswell, MV Benyamin, RM Hirsch, JA AF Manchikanti, Laxmaiah Singh, Vijay Pampati, Vidyasagar Boswell, Mark V. Benyamin, Ramsin M. Hirsch, Joshua A. TI Description of Documentation in the Management of Chronic Spinal Pain SO PAIN PHYSICIAN LA English DT Article DE Documentation; billing; coding; compliance; fraud and abuse; interventional techniques; evaluation and management services; office visit; consultation; new patient; established patient AB Documentation assists health care professionals in providing appropriate services to patients by documenting indications and medical necessity, and reflects the competency and character of the physician. Documentation is considered a cornerstone of the quality of patient care. This is nowhere more true than in interventional pain management. Thus, documentation in physicians' offices, hospital settings, ambulatory surgery centers, rehabilitation centers, and other settings must be accurate, complete, and reflect all of the services provided during each encounter. The Centers for Medicare and Medicaid Services (CMS) defines medical necessity in these terms: "no payment may be made under Part A or Part B for any expense incurred for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a participant." The American Medical Association (AMA) defines medical necessity as, "health care services or procedures that a prudent physician would provide to a patient for the purpose of preventing, diagnosing, or treating an illness, injury, disease, or its symptoms in a manner that is in accordance with generally accepted standards of medical practice, clinically appropriate in terms of type, frequency, extent, site, and duration, and not primarily for the convenience of the patient, physician, or other health care provider." Documentation requirements include an appropriate medical record utilizing recognized and acceptable standards of documentation and an established process. However, the evolution of electronic medical records (EMRs) or electronic health records (EHRs) nullifies many of the issues faced in handwritten documentation. Multiple types of documentation include evaluation and management services and documentations in ambulatory surgery centers, hospital outpatient departments, and in office settings, specifically while performing interventional procedures. Evaluation and management services incorporate 5 levels of service for consultations and visits, with multiple key elements of service including history, physical examination, and medical decision making. Documentation of interventional procedures in general requires a history and physical, indication and medical necessity, intra-operative procedural description, post-operative monitoring and ambulation, discharge, and disposition. With minor variations, these requirements are similar for an in-office setting, hospital out patient department, and ambulatory surgery centers. C1 [Manchikanti, Laxmaiah; Pampati, Vidyasagar] Pain Management Ctr Paducah, Paducah, KY USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Boswell, Mark V.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 73 TC 17 Z9 17 U1 1 U2 4 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2009 VL 12 IS 4 BP E199 EP E224 PG 26 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA V20HC UT WOS:000208130100005 PM 19668282 ER PT J AU Manchikanti, L Boswell, MV Singh, V Derby, R Fellows, B Falco, FJE Datta, S Smith, HS Hirsch, JA AF Manchikanti, Laxmaiah Boswell, Mark V. Singh, Vijay Derby, Richard Fellows, Bert Falco, Frank J. E. Datta, Sukdeb Smith, Howard S. Hirsch, Joshua A. TI Comprehensive Review of Neurophysiologic Basis and Diagnostic Interventions in Managing Chronic Spinal Pain SO PAIN PHYSICIAN LA English DT Review DE Diagnostic interventional techniques; chronic spinal pain; facet joint interventions; epidural procedures; provocation discography; sacroiliac joint blocks; post lumbar surgery syndrome; spinal stenosis; provocation discography AB Background: Understanding the neurophysiological basis of chronic spinal pain and diagnostic interventional techniques is crucial in the proper diagnosis and management of chronic spinal pain.Central to the understanding of the structural basis of chronic spinal pain is the provision of physical diagnosis and validation of patient symptomatology. It has been shown that history, physical examination, imaging, and nerve conduction studies in non-radicular or discogenic pain are unable to diagnose the precise cause in 85% of the patients. In contrast, controlled diagnostic blocks have been shown to determine the cause of pain in as many as 85% of the patients. Objective: To provide evidence-based clinical practice guidelines for diagnostic interventional techniques. Design: Best evidence synthesis. Methods: Strength of evidence was assessed by the U.S. Preventive Services Task Force (USPSTF) criteria utilizing 5 levels of evidence ranging from Level I to III with 3 subcategories in Level II. Diagnostic Criteria: Diagnostic criteria established by systematic reviews were utilized with controlled diagnostic blocks. Diagnostic criteria included at least 80% pain relief with controlled local anesthetic blocks with the ability to perform multiple maneuvers which were painful prior to the diagnostic blocks for facet joint and sacroiliac joint blocks, whereas for provocation discography, the criteria included concordant pain upon stimulation of the target disc with 2 adjacent discs producing no pain at all. Results: The indicated level of evidence for diagnostic lumbar, cervical, and thoracic facet joint nerve blocks is Level I or II-1. The indicated evidence is Level II-2 for lumbar and cervical discography, whereas it is Level II-3 for thoracic provocation discography. The evidence for diagnostic sacroiliac joint nerve blocks is Level II-2. Level of evidence for selective nerve root blocks for diagnostic purposes is Level II-3. Limitations: Limitations of this guideline preparation include a continued paucity of literature and conflicts in preparation of systematic reviews and guidelines. Conclusion: These guidelines include the evaluation of evidence for diagnostic interventional procedures in managing chronic spinal pain and recommendations. However, these guidelines do not constitute inflexible treatment recommendations. These guidelines also do not represent a "standard of care." C1 [Manchikanti, Laxmaiah; Fellows, Bert] Pain Management Ctr Paducah, Paducah, KY USA. [Boswell, Mark V.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Derby, Richard] Spinal Diagnost & Treatment Ctr, Daly City, CA USA. [Falco, Frank J. E.] Spinal Diagnost & Treatment Ctr, Daly City, CA USA. [Datta, Sukdeb] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Smith, Howard S.] Albany Med Coll, Albany, NY 12208 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com FU Sucampo Pharmaceuticals FX Dr. Hirsch is a consultant for Cardinal Healthcare and Medtronic, he has previously served as a consultant for Arthrocare, he serves on the Steering Committee for KAVIAR trial (volunteer position), and on the Data and Safety Monitoring Board (DSMB): CEEP trial (volunteer position).Dr. Datta receives research support from Sucampo Pharmaceuticals and an honorarium from Smith and Nephew. Dr. Derby has stock options of less than $10,000 with Laurimed and Kyphon. NR 783 TC 75 Z9 78 U1 1 U2 4 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2009 VL 12 IS 4 BP E71 EP E121 PG 51 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA V20HC UT WOS:000208130100003 PM 19668292 ER PT J AU Manchikanti, L Singh, V Helm, S Schultz, DM Datta, S Hirsch, J AF Manchikanti, Laxmaiah Singh, Vijay Helm, Standiford, II Schultz, David M. Datta, Sukdeb Hirsch, Joshua TI An Introduction to an Evidence-Based Approach to Interventional Techniques in the Management of Chronic Spinal Pain SO PAIN PHYSICIAN LA English DT Article DE Evidence-based medicine; clinical practice guidelines; critical appraisal; guideline development; interventional pain management; interventional techniques; evidence synthesis; clinical relevance; grading recommendations; systematic reviews ID LOW-BACK-PAIN; CLINICAL-PRACTICE GUIDELINES; EVIDENCE-BASED MEDICINE; RANDOMIZED CONTROLLED-TRIALS; CHRONIC NONCANCER PAIN; FACET JOINT INTERVENTIONS; LUMBAR SURGERY SYNDROME; SYSTEMATIC REVIEWS; HEALTH-CARE; CORD STIMULATION AB Practice guidelines are systematically developed statements to assist practitioners and patients in making decisions about appropriate health care for specific clinical circumstances. Clinical practice guidelines present statements of best practice based on a thorough evaluation of the evidence from published studies on the outcomes of treatment. In November 1989, Congress mandated the creation of the Agency for Healthcare Policy and Research (AHCPR). AHCPR was given broad responsibility for supporting research, data development, and related activities. Associated with this mandate, the National Academy of Sciences published a document indicating that guidelines are expected to enhance the quality, appropriateness, and effectiveness of health care services. Guidelines as a whole have been characterized by multiple conflicts in terminology and technique. These conflicts are notable for the confusion they create and for what they reflect about differences in values, experiences, and interest among different parties. Despite this confusion, public and private development of guidelines is growing exponentially. There are only limited means to coordinate these guidelines in order to resolve inconsistencies, fill in gaps, track applications and results, and assess the soundness of individual guidelines. Significant diversity exists in clinical practice guidelines. The inconsistency amongst guidelines arises from variations in values, tolerance for risks, preferences, expertise, and conflicts of interest. In 2000, the American Society of Interventional Pain Physicians (ASIPP) first created treatment guidelines to help practitioners. There have been 4 subsequent updates. These guidelines address the issues of systematic: evaluation and ongoing care of chronic or persistent pain, and provide information about the scientific basis of recommended procedures. These guidelines are expected to increase patient compliance, dispel misconceptions among providers and patients, manage patient expectations reasonably, and form the basis of a therapeutic partnership between the patient, the provider, and payors. The ASIPP guidelines are based on evidence-based medicine (EBM). EBM is in turn based on 4 basic contingencies: the recognition of the patient's problem and the construction of a structured clinical question; the ability to efficiently and effectively search the medical literature to retrieve the best available evidence to answer the clinical question; clinical appraisal of the evidence; and integration of the evidence with all aspects of the individual patient's decision-making to determine the best clinical care of the patient. Evidence synthesis for guidelines includes the review of all relevant systematic reviews and individual articles, grading them for relevance, methodologic quality, consistency, and recommendations. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Helm, Standiford, II] Pacific Coast Pain Management Ctr, Laguna Hills, CA USA. [Schultz, David M.] Med Adv Pain Specialists, Minneapolis, MN USA. [Datta, Sukdeb] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Hirsch, Joshua] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com FU Medtronic FX There was no external funding in the preparation of this manuscript. No statement on this article should be construed as an official position of ASIPP. Dr. Hirsch is a consultant for Cardinal Healthcare and Medtronic, he has previously served as a consultant for Arthrocare, he serves on the Steering Committee for KAVIAR trial (volunteer position), and on the Data and Safety Monitoring Board (DSMB): CEEP trial (volunteer position). Dr. Schultz receives funding from Medtronic. NR 265 TC 34 Z9 34 U1 2 U2 3 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2009 VL 12 IS 4 BP E1 EP E33 PG 33 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA V20HC UT WOS:000208130100001 PM 19668280 ER PT J AU Larochelle, MR Rodriguez, KL Arnold, RM Barnato, AE AF Larochelle, M. R. Rodriguez, K. L. Arnold, R. M. Barnato, A. E. TI Hospital staff attributions of the causes of physician variation in end-of-life treatment intensity SO PALLIATIVE MEDICINE LA English DT Article DE decision making; practice variation; qualitative research; terminal care ID CARE-UNIT; ADVANCE DIRECTIVES; PREFERENCES; DECISIONS; COMMUNICATION; PROGNOSES; SUPPORT; PATIENT; DEATH; TRIAL AB Discrepancies between patient wishes and end-of-life treatment decisions have been documented, and the determinants of end-of-life treatment decisions are not well understood. Our objective was to understand hospital staff perceptions of the role of acute care hospital medical doctors in end-of-life treatment intensity. In 11 purposively sampled Pennsylvania hospitals, we completed 108 audiotaped semistructured interviews with key informants involved in decision making or discharge planning. Using grounded theory, we qualitatively analysed transcripts using constant comparison to identify factors affecting end-of-life treatment decisions. A predominant theme identified was that end-of-life treatment intensity depends on the doctor. Communication with patients and families and collaboration with other care team members also were reported to vary, contributing to treatment variation. Informants attributed physician variation to individual beliefs and attitudes regarding the end-of-life (religion and culture, determination of when a patient is dying, quality-of-life determination and fear of failing) and to socialization by and interaction with the healthcare system (training, role perception, experience and response to incentives). When end-of-life treatment depends on the doctor, patient and family preferences may be neglected. Targeted interventions may reduce variability and align end-of-life treatment with patient wishes. Palliative Medicine (2009); 23: 460-470 C1 [Barnato, A. E.] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA 15213 USA. [Larochelle, M. R.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Rodriguez, K. L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Arnold, R. M.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Sect Palliat Care & Med Eth, Pittsburgh, PA 15213 USA. RP Barnato, AE (reprint author), Univ Pittsburgh, Ctr Res Hlth Care, 200 Meyran St,Suite 200, Pittsburgh, PA 15213 USA. EM aeb2@pitt.edu FU National Institute on Aging [K08 AG021921, P01 AG19783] FX Financial support for this research was from National Institute on Aging grants K08 AG021921 and P01 AG19783. Amber Barnato would like to thank research mentors Derek Angus and Judith Lave for their intellectual and personal contributions. NR 30 TC 30 Z9 30 U1 2 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-2163 J9 PALLIATIVE MED JI Palliat. Med. PD JUL PY 2009 VL 23 IS 5 BP 460 EP 470 DI 10.1177/0269216309103664 PG 11 WC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medicine, General & Internal SC Health Care Sciences & Services; Public, Environmental & Occupational Health; General & Internal Medicine GA 457ON UT WOS:000266941500011 PM 19324922 ER PT J AU Jenner, P Mori, A Hauser, R Morelli, M Fredholm, BB Chen, JF AF Jenner, P. Mori, A. Hauser, R. Morelli, M. Fredholm, B. B. Chen, J. F. TI Adenosine, adenosine A(2A) antagonists, and Parkinson's disease SO PARKINSONISM & RELATED DISORDERS LA English DT Review DE Parkinson's disease; Adenosine; Adenosine antagonists ID RECEPTOR MESSENGER-RNA; INDUCED MOTOR COMPLICATIONS; DEEP BRAIN-STIMULATION; MPTP-TREATED MONKEYS; L-DOPA; GLOBUS-PALLIDUS; 6-HYDROXYDOPAMINE-LESIONED RATS; MEDIATED MODULATION; POSSIBLE RELEVANCE; A-2A RECEPTORS AB Adenosine derived from the degradation of ATP/AMP functions as a signalling molecule in the nervous system through the occupation of A1, A2, and A3 adenosine receptors. Adenosine A(2A) receptors have a selective localization to the basal ganglia and specifically to the indirect output pathway, and as a consequence offer a unique opportunity to modulate the output from the striatum that is believed critical to the occurrence of motor components of PD. Indeed, the ability of A(2A) antagonists to modulate basal ganglia neurotransmission has been shown to be associated with improved motor function in experimental models of PD. This suggests that A(2A) antagonists would be effective as a symptomatic treatment in humans without provoking marked dyskinesia. Indeed, the A(2A) antagonist istradefylline reduces OFF time in moderate- to late-stage patients with PD already receiving dopaminergic therapy, with an increase in non-troublesome dyskinesia. Adenosine and adenosine receptors also exert actions relevant to pathogenesis in PD, raising the possibility of their use as neuroprotective agents. Both epidemiologic evidence and the current preclinical data strongly support a role for A(2A) antagonists in protecting dopaminergic neurons and influencing the onset and progression of PD. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved. C1 [Jenner, P.] Kings Coll London, Neurodegenerat Dis Res Ctr, Sch Hlth & Biomed Sci, London SE1 1UL, England. [Mori, A.] Kyowa Hakko Kogyo Co Ltd, Div Pharmaceut Res & Dev, Tokyo, Japan. [Hauser, R.] Univ S Florida, Dept Neurol, Tampa, FL 33620 USA. [Hauser, R.] Univ S Florida, Dept Pharmacol & Expt Therapeut, Tampa, FL 33620 USA. [Hauser, R.] Natl Parkinson Fdn Ctr Excellence, Tampa, FL USA. [Morelli, M.] Univ Cagliari, Dept Toxicol, Cagliari, Italy. [Fredholm, B. B.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Chen, J. F.] Massachusetts Gen Hosp, Mol Neurobiol Lab, Dept Neurol, Charlestown, MA USA. RP Jenner, P (reprint author), Kings Coll London, Neurodegenerat Dis Res Ctr, Sch Hlth & Biomed Sci, London SE1 1UL, England. EM peter.jenner@kcl.ac.uk OI morelli, micaela/0000-0003-0394-5782 NR 99 TC 114 Z9 116 U1 2 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2009 VL 15 IS 6 BP 406 EP 413 DI 10.1016/j.parkreldis.2008.12.006 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 473MH UT WOS:000268210500002 PM 19446490 ER PT J AU Ross, OA Spanaki, C Griffith, A Lin, CH Kachergus, J Haugarvoll, K Latsoudis, H Plaitakis, A Ferreira, JJ Sampaio, C Bonifati, V Wu, RM Zabetian, CP Farrer, MJ AF Ross, Owen A. Spanaki, Cleanthe Griffith, Alida Lin, Chin-Hsien Kachergus, Jennifer Haugarvoll, Kristoffer Latsoudis, Helen Plaitakis, Andreas Ferreira, Joaquim J. Sampaio, Cristina Bonifati, Vincenzo Wu, Ruey-Meei Zabetian, Cyrus P. Farrer, Matthew J. TI Haplotype analysis of Lrrk2 R1441H carriers with parkinsonism SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Leucine-rich repeat kinase 2; R1441H ID DISEASE; MUTATIONS; RISK; GENE AB The Roc domain of the Lrrk2 protein harbors two pathogenic mutations which cause autosomal dominant parkinsonism (R1441C and R1441G). A third putatively pathogenic variant (R1441H) has been identified in four probands of diverse ethnicity with parkinsonism. Herein we show that the R1441H substitutions lie on different haplotypes within our patients, confirming this codon as a mutational hotspot. The absence of this variant in control subjects and the presence of two other pathogenic variants at this amino acid position collectively support the contention that 81441 H is a pathogenic substitution. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Ross, Owen A.] Mayo Clin, Morris K Udall Parkinsons Dis Res Ctr Excellence, Dept Neurosci, Jacksonville, FL 32224 USA. [Spanaki, Cleanthe; Latsoudis, Helen; Plaitakis, Andreas] Univ Crete, Dept Neurol, Sch Med, Iraklion, Crete, Greece. [Griffith, Alida] Evergreen Hosp, Med Ctr, Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA. [Lin, Chin-Hsien; Wu, Ruey-Meei] Natl Taiwan Univ, Natl Taiwan Univ Hosp, Coll Med, Dept Neurol, Taipei 10764, Taiwan. [Ferreira, Joaquim J.; Sampaio, Cristina] Lisbon Sch Med, Inst Mol Med, Neurol Clin, Res Unit, Lisbon, Portugal. [Bonifati, Vincenzo] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Zabetian, Cyrus P.] VA Puget Sound Hlth Care Syst, Geriatr Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA USA. [Zabetian, Cyrus P.] VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. RP Ross, OA (reprint author), Mayo Clin, Morris K Udall Parkinsons Dis Res Ctr Excellence, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM ross.owen@mayo.edu RI Ross, Owen/D-7573-2013; Haugarvoll, Kristoffer/L-1486-2015; OI Haugarvoll, Kristoffer/0000-0001-9381-1109; Wu, Ruey-Meei/0000-0002-4947-5467; Lin, Chin-Hsien/0000-0001-8566-7573; Zabetian, Cyrus/0000-0002-7739-4306; Ferreira, Joaquim J/0000-0003-3950-5113 FU Morris K. Udall Parkinson's Disease Research Center of Excellence [NS40256]; Department of Veterans Affairs; Taiwan National Science Council [96-2628-B-002-103-MY2]; Internationaal Parkinson Fonds, The Netherlands; Parkinson Disease Foundation FX We would like to thank all those who have contributed to our research. This work is supported by a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS40256), the Department of Veterans Affairs (Merit Review Award), the Taiwan National Science Council (96-2628-B-002-103-MY2), by a grant from the "Internationaal Parkinson Fonds" (The Netherlands) to VB, and by a research grant from the "Parkinson Disease Foundation" to CS. NR 10 TC 20 Z9 21 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2009 VL 15 IS 6 BP 466 EP 467 DI 10.1016/j.parkreldis.2008.09.001 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 473MH UT WOS:000268210500014 PM 18952485 ER PT J AU Kennifer, SL Alexander, SC Pollak, KI Jeffreys, AS Olsen, MK Rodriguez, KL Arnold, RM Tulsky, JA AF Kennifer, Sarah L. Alexander, Stewart C. Pollak, Kathryn I. Jeffreys, Amy S. Olsen, Maren K. Rodriguez, Keri L. Arnold, Robert M. Tulsky, James A. TI Negative emotions in cancer care: Do oncologists' responses depend on severity and type of emotion? SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Doctor-patient relations; Communication; Cancer; Emotion ID COMMUNICATION; DOCTOR; NEWS AB Objective: To examine how type and severity of patients' negative emotions influence oncologists' responses and subsequent conversations. Methods: We analyzed 264 audio-recorded conversations between advanced cancer patients and their oncologists. Conversations were coded for patients' expressions of negative emotion, which were categorized by type of emotion and severity. Oncologists' responses were coded as using either empathic language or blocking and distancing approaches. Results: Patients presented fear more often than anger or sadness; severity of disclosures was most often moderate. Oncologists responded to 35% of these negative emotional disclosures with empathic language. They were most empathic when patients presented intense emotions. Responding empathically to patients' emotional disclosures lengthened discussions by an average of only 21 s. Conclusion: Greater response rates to severe emotions suggest oncologists may recognize negative emotions better when patients express them more intensely. Oncologists were least responsive to patient fear and responded with greatest empathy to sadness. Practice implications: Oncologists may benefit from additional training to recognize negative emotions, even when displayed without intensity. Teaching cancer patients to better articulate their emotional concerns may also enhance patient-oncologist communication. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Kennifer, Sarah L.; Alexander, Stewart C.; Tulsky, James A.] Duke Univ, Med Ctr, Ctr Palliat Care, Durham, NC 27705 USA. [Alexander, Stewart C.; Jeffreys, Amy S.; Olsen, Maren K.; Tulsky, James A.] Durham VA Med Ctr, Hlth Serv Res & Dev, Durham, NC USA. [Pollak, Kathryn I.; Tulsky, James A.] Duke Univ, Med Ctr, Duke Canc Prevent Detect & Control Res Program, Durham, NC 27705 USA. [Rodriguez, Keri L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Rodriguez, Keri L.; Arnold, Robert M.] Univ Pittsburgh, Sch Med, Dept Gen Internal Med, Pittsburgh, PA 15260 USA. RP Kennifer, SL (reprint author), Duke Univ, Med Ctr, Ctr Palliat Care, Hock Plaza,Suite 1105,Box 2720,2424 Erwin Rd, Durham, NC 27705 USA. EM sarah.kennifer@duke.edu FU National Cancer Institute [R01-CA100387] FX This work has been funded by a grant from the National Cancer Institute (R01-CA100387). NR 24 TC 29 Z9 32 U1 2 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JUL PY 2009 VL 76 IS 1 BP 51 EP 56 DI 10.1016/j.pec.2008.10.003 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 467HO UT WOS:000267729500010 PM 19041211 ER PT J AU Cote, CJ Hartnick, CJ AF Cote, Charles J. Hartnick, Christopher J. TI Pediatric transtracheal and cricothyrotomy airway devices for emergency use: which are appropriate for infants and children? SO PEDIATRIC ANESTHESIA LA English DT Review DE cricothyrotomy; tracheostomy; transtracheal; emergency; airway; airway obstruction; pediatric ID PERCUTANEOUS DILATATIONAL TRACHEOSTOMY; TRANS-TRACHEAL VENTILATION; LARYNGEAL MASK AIRWAY; FIBEROPTIC INTUBATION; NEEDLE TRACHEOSTOMY; SURGICAL CRICOTHYROIDOTOMY; LARYNGOTRACHEAL TRAUMA; RANDOMIZED CROSSOVER; DIFFICULT-AIRWAY; JET VENTILATION AB P>Cricothyrotomy or insertion of a transtracheal device is a life-saving maneuver that may be performed on an emergent or semi-elective basis as a means of bypassing an obstructed upper airway. A surgeon is trained to perform this life-saving procedure whereas most anesthesiologists are not facile with the scalpel. It is for this reason that many percutaneous devices have been developed for use by surgeons and nonsurgeons alike. Unfortunately, the majority of such devices are designed for use in adults and/or teenagers but are not appropriate for neonates and infants. The unique anatomy of the infant larynx, the small size of the cricothyroid membrane, and the technical difficulty of locating the correct anatomical structures make the use of most of these devices impractical if not outright dangerous in neonates and infants. This paper will review many (but not all) of the available devices, associated literature, pitfalls and dangers. It is emphasized that each clinician should become familiar with the advantages and disadvantages of these devices and obtain training with simulators or animal models. A strategy for management of the 'cannot ventilate, cannot oxygenate, cannot intubate' situation should be developed with age and size appropriate equipment. C1 [Cote, Charles J.] Harvard Univ, Massachusetts Gen Hosp,Sch Med, Div Pediat Anesthesia,Dept Anesthesia & Crit Care, MassGen Hosp Children, Boston, MA 02115 USA. [Hartnick, Christopher J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. RP Cote, CJ (reprint author), Harvard Univ, Massachusetts Gen Hosp,Sch Med, Div Pediat Anesthesia,Dept Anesthesia & Crit Care, MassGen Hosp Children, 55 Fruit St, Boston, MA 02115 USA. EM cjcole@partners.org NR 73 TC 26 Z9 26 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1155-5645 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD JUL PY 2009 VL 19 SU 1 BP 66 EP 76 DI 10.1111/j.1460-9592.2009.02996.x PG 11 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA 463JI UT WOS:000267427800009 PM 19572846 ER PT J AU Fidkowski, CW Fuzaylov, G Sheridan, RL Cote, CJ AF Fidkowski, Christina W. Fuzaylov, Gennadiy Sheridan, Robert L. Cote, Charles J. TI Inhalation burn injury in children SO PEDIATRIC ANESTHESIA LA English DT Review DE inhalation injury; burn injury; pediatric ID ACUTE LUNG INJURY; INHALED NITRIC-OXIDE; SMOKE-INHALATION; CARBON-MONOXIDE; PULSE OXIMETRY; EMERGENCY-DEPARTMENT; SODIUM NITROPRUSSIDE; PEDIATRIC-PATIENTS; CYANIDE TOXICITY; MORTALITY AB P>With advances in burn care, many children are surviving severe burn injuries. Inhalation injury remains a predictor of morbidity and mortality in burn injury. Inhalation of smoke and toxic gases leads to pulmonary complications, including airway obstruction from bronchial casts, pulmonary edema, decreased pulmonary compliance, and ventilation-perfusion mismatch, as well as systemic toxicity from carbon monoxide poisoning and cyanide toxicity. The diagnosis of inhalation injury is suggested by the history and physical exam and can be confirmed by bronchoscopy. Management consists of supportive measures, pulmonary toilet, treatment of pulmonary infection and ventilatory support as needed. This review details the pathophysiology, diagnosis, and management options for inhalation injury. C1 [Fuzaylov, Gennadiy; Cote, Charles J.] Harvard Univ, Massachusetts Gen Hosp,Mass Gen Hosp Children, Pediat Anesthesia Serv,Sch Med, Dept Anesthesia & Crit Care,Div Pediat Anesthesia, Boston, MA 02155 USA. [Sheridan, Robert L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02155 USA. RP Fuzaylov, G (reprint author), Harvard Univ, Massachusetts Gen Hosp,Mass Gen Hosp Children, Pediat Anesthesia Serv,Sch Med, Dept Anesthesia & Crit Care,Div Pediat Anesthesia, 55 Fruit St,Clin 309, Boston, MA 02155 USA. EM gfuzaylov@partners.org NR 67 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1155-5645 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD JUL PY 2009 VL 19 SU 1 BP 147 EP 154 DI 10.1111/j.1460-9592.2008.02884.x PG 8 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA 463JI UT WOS:000267427800016 PM 19143954 ER PT J AU Janeway, KA Albritton, KH Van Den Abbeele, AD D'Amato, GZ Pedrazzoli, P Siena, S Picus, J Butrynski, JE Schlemmer, M Heinrich, MC Demetri, GD AF Janeway, Katherine A. Albritton, Karen H. Van Den Abbeele, Annick D. D'Amato, Gina Z. Pedrazzoli, Paolo Siena, Salvatore Picus, Joel Butrynski, James E. Schlemmer, Marcus Heinrich, Michael C. Demetri, George D. TI Sunitinib Treatment in Pediatric Patients With Advanced GIST Following Failure of Imatinib SO PEDIATRIC BLOOD & CANCER LA English DT Article DE clinical trials; drug resistance; new agents; pediatric oncology; soft tissue sarcoma ID GASTROINTESTINAL STROMAL TUMORS; TYROSINE KINASE INHIBITOR; OF-THE-LITERATURE; POSITRON-EMISSION-TOMOGRAPHY; GROWTH-FACTOR; IN-VIVO; MESYLATE; SU11248; KIT; MUTATIONS AB Background. Sunitinib inhibits KIT and other members of the split-kirase-domain family of receptor tyrosine kinases. Sunitinib prolong; survival in adult patients with imatinib-resistant gastrointestinal stroinal tumor (GIST). We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib. Procedure. Sunitinib therapy was provided through a treatment-use protocol. Patients were 10-17 years old at enrollment. All patients had GIST resistant to imatinib therapy. Sunitinib was administered daily for 4 weeks in 6-week treatment cycles. KIT and platelet-derived growth factor receptor alpha (PDGFRA) genotyping of tumor tissue were performed. Results. One patient achieved a partial response, five patients had stable disease and one patient had progressive disease on sunitinib. The duration of disease stabilization was between 7 and 21 + months, with a mean of 15 months. Time to tumor progression was longer on sunitinib than on prior imatinib treatment for five of six patients. Two patients experienced grade 3 adverse events. All other adverse events were grade 1-2. None of the five patients tested had mutations in KIT or PDGFRA. Conclusion. Sunitinib treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib-resistant GIST. Pediatr Blood Cancer 2009;52:767-771. (C) 2009 Wiley-Liss, Inc. C1 [Demetri, George D.] Dana Farber Canc Inst, Ludwig Ctr Dana Farber, Harvard Canc Ctr, Boston, MA 02115 USA. [Janeway, Katherine A.; Albritton, Karen H.] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Van Den Abbeele, Annick D.] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [D'Amato, Gina Z.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Pedrazzoli, Paolo; Siena, Salvatore] Osped Niguarda Ca Granda, Div Oncol Med Falck, Milan, Italy. [Picus, Joel] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. [Butrynski, James E.; Demetri, George D.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Butrynski, James E.; Demetri, George D.] Harvard Univ, Sch Med, Boston, MA USA. [Butrynski, James E.] Univ Washington, Seattle, WA 98195 USA. [Butrynski, James E.] Seattle Canc Care Alliance, Seattle, WA USA. [Schlemmer, Marcus] Univ Munich, Klinikum Grosshadern, Med Ctr, Dept Internal Med 3, D-8000 Munich, Germany. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Ludwig Ctr Dana Farber, Harvard Canc Ctr, D1212,44 Binney St, Boston, MA 02115 USA. EM gdemetri@partners.org OI SIENA, SALVATORE/0000-0002-2681-2846 FU Pfizer Inc FX We greatly appreciate the assistance of the following additional contributors: Christopher Corless, Travis Quigley, Samuel Agresta, Chris Garrett, and Dana Matthews. The manuscript was written by Katherine Janeway with substantive input frorn all authors. Logistical and editorial assistance were provided by ACUMED (Tytherington, UK), with funding from Pfizer Inc. NR 29 TC 65 Z9 70 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL 1 PY 2009 VL 52 IS 7 BP 767 EP 771 DI 10.1002/pbc.21909 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 435LT UT WOS:000265346100006 PM 19326424 ER PT J AU Grace, RF Mednick, RE Neufeld, EJ AF Grace, Rachael F. Mednick, Rachel E. Neufeld, Ellis J. TI Compliance With Immunizations in Splenectomized Individuals With Hereditary Spherocytosis SO PEDIATRIC BLOOD & CANCER LA English DT Article DE hereditary spherocytosis; immunizations; splenectomy ID OVERWHELMING POSTSPLENECTOMY INFECTION; SEPSIS; RISK; CHILDHOOD; ADULTS AB Overwhelming infection by encapsulated bacteria is a significant risk of splenectomy. Strict adherence to immunizations against encapsulated organisms is recommended. We performed a cross-sectional study to determine immunization Status after splenectomy in the hereditary spherocytosis (HS) Population. As HS is most often autosomal dominant, we used a strategy of ascertaining older affected individuals by expanding pedigrees from patients in Our pediatric hematology center. Only 26% of asplenic patients reported receiving all recommended post-splenectomy vaccines. This study demonstrates that pediatric hematology clinics have a unique opportunity to provide or recommend catch-Up and booster vaccinations to splenectomized adult relatives of their patients. Pediatr Blood Cancer 2009;52:865-867. (C) 2009 Wiley-Liss, Inc. C1 [Grace, Rachael F.; Mednick, Rachel E.; Neufeld, Ellis J.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Grace, Rachael F.; Neufeld, Ellis J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Grace, Rachael F.; Neufeld, Ellis J.] Harvard Univ, Sch Med, Boston, MA USA. RP Neufeld, EJ (reprint author), Childrens Hosp, Div Hematol Oncol, 300 Longwood Ave,Karp 8, Boston, MA 02115 USA. EM ellis.neufeld@tch.harvard.edu RI Neufeld, Ellis/F-9331-2011; OI Grace, Fergal/0000-0002-3144-5999 NR 20 TC 6 Z9 7 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL 1 PY 2009 VL 52 IS 7 BP 865 EP 867 DI 10.1002/pbc.21961 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 435LT UT WOS:000265346100024 PM 19214975 ER PT J AU Langman, CB Alon, U Ingelfinger, J Englund, M Saland, J Somers, MJG Stapleton, FB Sibu, NO Cochat, P Wong, W Eke, FU Satlin, L Salusky, I AF Langman, Craig B. Alon, Uri Ingelfinger, Julie Englund, Marta Saland, Jeffrey M. Somers, Michael J. G. Stapleton, F. Bruder Orta Sibu, Nelson Cochat, Pierre Wong, William Eke, Felicia U. Satlin, Lisa Salusky, Isidro TI A position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants SO PEDIATRIC NEPHROLOGY LA English DT Editorial Material DE Acute kidney failure; Infant nutrition; Nephrolithiasis; Poisoning ID CARCINOGENICITY; DOGS AB Melamine, a man-made non-nutritive substance containing nitrogen, can falsely elevate measures of protein content in foodstuffs. Several manufacturers of powdered infant formula in China apparently added melamine to raise the measured protein content and thereby exposed thousands of infants and young children to very high levels of melamine. Such exposure resulted in cases of acute kidney failure and nephrolithiasis. This Editorial from members of the world-wide Pediatric Nephrology community provides a common-sense approach to the care of infants who may have been exposed to powdered infant formula in 2007-2008. C1 [Langman, Craig B.] Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, Chicago, IL 60614 USA. [Alon, Uri] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Ingelfinger, Julie] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Englund, Marta] Karolinska Inst, Sachs Childrens Hosp, Stockholm, Sweden. [Saland, Jeffrey M.; Satlin, Lisa] Mt Sinai Med Ctr, Dept Pediat, New York, NY 10029 USA. [Somers, Michael J. G.] Harvard Univ, Sch Med, Boston, MA USA. [Stapleton, F. Bruder] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Orta Sibu, Nelson] Univ Carabobo, Hosp Ninos Insalud, Valencia, Venezuela. [Cochat, Pierre] Hop Edouard Herriot, INSERM, U820, Ctr Reference Malad Renales Hereditaires, Lyon, France. [Wong, William] Starship Childrens Hosp, Dept Nephrol, Auckland, New Zealand. [Eke, Felicia U.] Univ Port Harcourt, Port Harcourt, Nigeria. [Salusky, Isidro] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Stapleton, F. Bruder] Seattle Childrens Hosp, Seattle, WA USA. [Somers, Michael J. G.] Childrens Hosp Boston, Boston, MA USA. [Englund, Marta] Soder Sjukhuset, Dept Clin Sci & Educ, S-10064 Stockholm, Sweden. [Cochat, Pierre] Univ Lyon 1, F-69365 Lyon, France. RP Langman, CB (reprint author), Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, 2300 Childrens Plaza 37, Chicago, IL 60614 USA. EM c-langman@northwestern.edu NR 10 TC 25 Z9 26 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2009 VL 24 IS 7 BP 1263 EP 1266 DI 10.1007/s00467-009-1129-6 PG 4 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 451XN UT WOS:000266504300001 PM 19198884 ER PT J AU Wesseling-Perry, K Harkins, GC Wang, HJ Sahney, S Gales, B Elashoff, RM Juppner, H Salusky, IB AF Wesseling-Perry, Katherine Harkins, G. Chris Wang, He-Jing Sahney, Shobha Gales, Barbara Elashoff, Robert M. Juppner, Harald Salusky, Isidro B. TI Response of different PTH assays to therapy with sevelamer or CaCO3 and active vitamin D sterols SO PEDIATRIC NEPHROLOGY LA English DT Article DE Calcium carbonate; Parathyroid hormone; Secondary hyperparathyroidism; Sevelamer; Vitamin D ID INTACT PARATHYROID-HORMONE; SECONDARY HYPERPARATHYROIDISM; HEMODIALYSIS-PATIENTS; PEDIATRIC-PATIENTS; RENAL-FAILURE; BONE-DISEASE; CALCIFICATION; FRAGMENTS; CALCIUM; CORONARY AB Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 +/- 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO3) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 +/- 0.1 to 9.7 +/- 0.1 mg/dl during CaCO3 therapy (p < 0.01 from baseline) but remained unchanged during sevelamer therapy. In the CaCO3 and sevelamer groups, baseline serum PTH levels (1st PTH-IMA; Nichols Institute Diagnostics, San Clemente, CA) were 964 +/- 75 and 932 +/- 89 pg/ml, and levels declined to 491 +/- 55 and 543 +/- 59 pg/ml, respectively (nonsignificant between groups). Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO3. The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs, despite differences in serum calcium levels. C1 [Wesseling-Perry, Katherine] Univ Calif Los Angeles, Div Pediat Nephrol, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Harkins, G. Chris] Immutop Int, San Clemente, CA USA. [Wang, He-Jing; Elashoff, Robert M.] Univ Calif Los Angeles, Dept Biomath, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Sahney, Shobha] Loma Linda Med Ctr, Dept Pediat, Loma Linda, CA USA. [Juppner, Harald] Harvard Univ, Sch Med, Mass Gen Hosp, Dept Pediat, Boston, MA USA. [Wesseling-Perry, Katherine; Gales, Barbara; Salusky, Isidro B.] Univ Calif Los Angeles, Dept Pediat, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Wesseling-Perry, K (reprint author), Univ Calif Los Angeles, Div Pediat Nephrol, David Geffen Sch Med, A2-383 MDCC,10833 LeConte Ave, Los Angeles, CA 90095 USA. EM kwesseling@mednet.ucla.edu FU USPHS [DK-35423, DK-67563, RR-00865]; Casey Lee Ball Foundation; National Kidney Foundation FX This work was supported in part by USPHS grants DK-35423, DK-67563 and RR-00865 and funds from the Casey Lee Ball Foundation. Dr. Katherine Wesseling-Perry was a recipient of a fellowship award from the National Kidney Foundation. PTH-IMA (Immutopics) values were kindly provided by Immutopics International. NR 27 TC 12 Z9 12 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2009 VL 24 IS 7 BP 1355 EP 1361 DI 10.1007/s00467-009-1143-8 PG 7 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 451XN UT WOS:000266504300012 PM 19301038 ER PT J AU Biederman, J Monuteaux, MC Spencer, T Wilens, TE Faraone, SV AF Biederman, Joseph Monuteaux, Michael C. Spencer, Thomas Wilens, Timothy E. Faraone, Stephen V. TI Do Stimulants Protect Against Psychiatric Disorders in Youth With ADHD? A 10-Year Follow-up Study SO PEDIATRICS LA English DT Article DE ADHD; psychopharmacology; stimulants; comorbidity ID ATTENTION-DEFICIT HYPERACTIVITY; DEFICIT/HYPERACTIVITY DISORDER; BIPOLAR DISORDER; PHARMACOLOGICAL-TREATMENT; CONDUCT DISORDER; SUBSTANCE USE; METHYLPHENIDATE; CHILDREN; DEPRESSION; ADOLESCENTS AB OBJECTIVE: Little is known about the effect of stimulant treatment in youth with attention-deficit/hyperactivity disorder (ADHD) on the subsequent development of comorbid psychiatric disorders. We tested the association between stimulant treatment and the subsequent development of psychiatric comorbidity in a longitudinal sample of patients with ADHD. METHODS: We conducted a case-control, 10-year prospective follow-up study into young-adult years of youth with ADHD. At baseline, we assessed consecutively referred white male children with (n = 140) and without (n = 120) ADHD, aged 6 to 18 years. At the 10-year follow-up, 112 (80%) and 105 (88%) of the children in the ADHD and control groups, respectively, were reassessed (mean age: 22 years). We examined the association between stimulant treatment in childhood and adolescence and subsequent comorbid disorders and grade retention by using proportional hazards survival models. RESULTS: Of the 112 participants with ADHD, 82 (73%) were previously treated with stimulants. Participants with ADHD who were treated with stimulants were significantly less likely to subsequently develop depressive and anxiety disorders and disruptive behavior and less likely to repeat a grade compared with participants with ADHD who were not treated. CONCLUSIONS: We found evidence that stimulant treatment decreases the risk for subsequent comorbid psychiatric disorders and academic failure in youth with ADHD. Pediatrics 2009;124:71-78 C1 [Biederman, Joseph] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Pediat Psychopharmacol Unit ACC 725, Boston, MA 02114 USA. [Biederman, Joseph; Monuteaux, Michael C.; Spencer, Thomas; Wilens, Timothy E.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Adult ADHD, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Genet Res Program, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Pediat Psychopharmacol Unit ACC 725, Fruit St, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU US Department of Health and Human Services; National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development [5RO1 HD36317]; National Institute on Drug Abuse [K24 DA016264] FX This work was supported in part by the following grants awarded by the US Department of Health and Human Services, National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development grant 5RO1 HD36317 (to Dr Biederman) and National Institute on Drug Abuse grant K24 DA016264 (to Dr Wilens). NR 41 TC 86 Z9 87 U1 3 U2 20 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2009 VL 124 IS 1 BP 71 EP 78 DI 10.1542/peds.2008-3347 PG 8 WC Pediatrics SC Pediatrics GA 463QY UT WOS:000267448100010 PM 19564285 ER PT J AU Sittig, DF Teich, JM Osheroff, JA Singh, H AF Sittig, Dean F. Teich, Jonathan M. Osheroff, Jerome A. Singh, Hardeep TI Improving Clinical Quality Indicators Through Electronic Health Records: It Takes More Than Just a Reminder SO PEDIATRICS LA English DT Editorial Material ID PHYSICIAN ORDER ENTRY; DECISION-SUPPORT; SYSTEM; CARE; OUTCOMES C1 [Sittig, Dean F.] Univ Texas Houston, Sch Hlth Informat Sci, Houston, TX USA. [Sittig, Dean F.] UT Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. [Teich, Jonathan M.] Elsevier Hlth Sci, Philadelphia, PA USA. [Teich, Jonathan M.] Harvard Univ, Dept Med, Boston, MA 02115 USA. [Osheroff, Jerome A.] Thomson Reuters, Ann Arbor, MI USA. [Osheroff, Jerome A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Hlth Policy & Qual Program, Houston Vet Affairs Hlth Serv Res & Dev Ctr Excel, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Ctr Inquiry Improve Outpatient Safety Effect Elec, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Sittig, DF (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Hlth Informat Sci, 6410 Fannin St, Houston, TX 77030 USA. EM dean.f.sittig@uth.tmc.edu FU NCI NIH HHS [K23 CA125585, K23 CA125585-04] NR 16 TC 19 Z9 19 U1 2 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2009 VL 124 IS 1 BP 375 EP 377 DI 10.1542/peds.2009-0339 PG 3 WC Pediatrics SC Pediatrics GA 463QY UT WOS:000267448100046 PM 19564321 ER PT J AU Joshi, VA Duffy, E Funke, BH Farwell, LM Mancini-Dinardo, D Kucherlapati, R AF Joshi, Victoria A. Duffy, Elizabeth Funke, Birgit H. Farwell, Lisa M. Mancini-Dinardo, Debora Kucherlapati, Raju TI Platform evaluation for rapid genotyping of CYP2C9 and VKORC1 alleles SO PERSONALIZED MEDICINE LA English DT Article DE CYP2C9; genotyping; VKORC1; warfarin ID WARFARIN; PROBES; ASSAY; DNA AB Aims: Warfarin is a commonly prescribed drug with a narrow therapeutic index. Adverse drug reactions owing to over- or under-dosing are common. It is now established that genetic differences between individuals play a major role in warfarin metabolism. In particular, common variants in CYP2C9 ((star)2 and (star)3) and VKORC1 (-1639G>A) have been associated with a reduced drug-dosage requirement. Materials & methods: We have evaluated the performance of five platforms that can be used to genotype individuals for these variants. These include Third Wave Technologies Invader (R), Applied Biosystems TaqMan (R), AutoGenomics INFINITI (TM) 2C9-VKORC1 assay, Osmetech eSensor (R) XT-8 warfarin sensitivity test and the Idaho Technologies LightScanner (R). Results & conclusions: Excluding failures, all of these technologies had 100% concordance rates with either Sanger sequencing or another validated technology. All of these platforms had high sensitivity and specificity and are therefore appropriate for clinical molecular diagnostics. Therefore, platform choice is likely to be driven by clinical laboratories interested in performing this service taking other factors into account, including turnaround time, capacity, cost and ease of use. C1 [Joshi, Victoria A.; Duffy, Elizabeth; Funke, Birgit H.; Farwell, Lisa M.; Kucherlapati, Raju] Partners HealthCare, Ctr Personalized Genet Med, Cambridge, MA 02139 USA. [Joshi, Victoria A.; Funke, Birgit H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Joshi, VA (reprint author), Partners HealthCare, Ctr Personalized Genet Med, 65 Landsdowne St, Cambridge, MA 02139 USA. EM vjoshi@partners.org NR 16 TC 1 Z9 1 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD JUL PY 2009 VL 6 IS 4 BP 449 EP 457 DI 10.2217/PME.09.8 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 481BC UT WOS:000268780500017 ER PT J AU Barrett, LF AF Barrett, Lisa Feldman TI The Future of Psychology: Connecting Mind to Brain SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article ID NEUROIMAGING TELL; COGNITION; EMOTION; CORTEX; COMMUNICATION; ASSOCIATION; INFORMATION; PREDICTIONS; EXPERIENCE; NEOCORTEX AB Psychological states such as thoughts and feelings are real. Brain states are real. The problem is that the two are not real in the same way, creating the mind-brain correspondence problem. In this article, I present a possible solution to this problem that involves two suggestions. First, complex psychological states such as emotion and cognition can be thought of as constructed events that can be causally reduced to a set of more basic, psychologically primitive ingredients that are more clearly respected by the brain. Second, complex psychological categories like emotion and cognition are the phenomena that require explanation in psychology, and, therefore, they cannot be abandoned by science. Describing the content and structure of these categories is a necessary and valuable scientific activity. C1 [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Dept Psychol, Boston Coll, Chestnut Hill, MA 02467 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Barrett, LF (reprint author), Massachusetts Gen Hosp, Dept Psychol, Boston Coll, Chestnut Hill, MA 02467 USA. EM barretli@bc.edu FU NIA NIH HHS [R01 AG030311]; NIH HHS [DP1 OD003312, DP1 OD003312-01]; NIMH NIH HHS [K02 MH001981] NR 74 TC 97 Z9 98 U1 5 U2 19 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD JUL PY 2009 VL 4 IS 4 BP 326 EP 339 PG 14 WC Psychology, Multidisciplinary SC Psychology GA 467QB UT WOS:000267755400002 PM 19844601 ER PT J AU Zeman, RJ Zhao, JB Zhang, YF Zhao, WD Wen, XL Wu, Y Pan, JP Bauman, WA Cardozo, C AF Zeman, Richard J. Zhao, Jingbo Zhang, Yuangfei Zhao, Weidong Wen, Xialing Wu, Yong Pan, Jiangping Bauman, William A. Cardozo, Christopher TI Differential skeletal muscle gene expression after upper or lower motor neuron transection SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Ubiquitin ligases; Atrogin-1; Paralysis; Muscle atrophy ID SPINAL-CORD-INJURY; GROWTH-FACTOR-I; FOXO TRANSCRIPTION FACTORS; NF-KAPPA-B; DENERVATION ATROPHY; UBIQUITIN LIGASES; RAT; TESTOSTERONE; PROTEIN; SLOW AB Causes of disuse atrophy include loss of upper motor neurons, which occurs in spinal cord injury (SCI) or lower motor neurons (denervation). Whereas denervation quickly results in muscle fibrillations, SCI causes delayed onset of muscle spasticity. To compare the influence of denervation or SCI on muscle atrophy and atrophy-related gene expression, male rats had transection of either the spinal cord or sciatic nerve and were sacrificed 3, 7, or 14 days later. Rates of atrophy increased gradually over the first week after denervation and then were constant. In contrast, atrophy after SCI peaked at 1 week, then declined sharply. The greater atrophy after SCI compared to denervation was preceded by high levels of ubiquitin ligase genes, MAFbx and MuRF1, which then also markedly declined. After denervation, however, expression of these genes remained elevated at lower levels throughout the 2-week time course. Interestingly, expression of the muscle growth factor, IGF-1 was increased at 3 days after denervation when fibrillation also peaks compared to SCI. Expression of IGF-1R, GADD45, myogenin, and Runx1 were also initially increased after denervation or SCI, with later declines in expression levels which correlated less well with rates of atrophy. Thus, there were significant time-dependent differences in muscle atrophy and MAFbx, MuRF1, and IGF-1 expression following SCI or denervation which may result from distinct temporal patterns of spontaneous muscle contractile activity due to injury to upper versus lower motor neurons. C1 [Zhao, Jingbo; Zhang, Yuangfei; Zhao, Weidong; Wu, Yong; Pan, Jiangping; Bauman, William A.; Cardozo, Christopher] James J Peters VA Med Ctr, Ctr Excellence Med Consequences SCI, Dept Vet Affairs, Bronx, NY 10468 USA. [Zhao, Jingbo; Bauman, William A.; Cardozo, Christopher] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Bauman, William A.; Cardozo, Christopher] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY 10029 USA. [Zeman, Richard J.; Wen, Xialing] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Zeman, RJ (reprint author), New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. EM Zeman@nymc.edu FU Veterans Health Administration, Rehabilitation Research and Development Service [B4162C, B3347K]; United Spinal Association FX This work was supported by Veterans Health Administration, Rehabilitation Research and Development Service (B4162C to WAB, B3347K to CC), and United Spinal Association (to WAB). NR 66 TC 28 Z9 30 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD JUL PY 2009 VL 458 IS 3 BP 525 EP 535 DI 10.1007/s00424-009-0643-5 PG 11 WC Physiology SC Physiology GA 455TP UT WOS:000266789000008 PM 19214561 ER PT J AU Vincent, DF Yan, KP Treilleux, I Gay, F Arfi, V Kaniewsky, B Marie, JC Lepinasse, F Martel, S Goddard-Leon, S Iovanna, JL Dubus, P Garcia, S Puisieux, A Rimokh, R Bardeesy, N Scoazec, JY Losson, R Bartholin, L AF Vincent, David F. Yan, Kai-Ping Treilleux, Isabelle Gay, Fabien Arfi, Vanessa Kaniewsky, Bastien Marie, Julien C. Lepinasse, Florian Martel, Sylvie Goddard-Leon, Sophie Iovanna, Juan L. Dubus, Pierre Garcia, Stephane Puisieux, Alain Rimokh, Ruth Bardeesy, Nabeel Scoazec, Jean-Yves Losson, Regine Bartholin, Laurent TI Inactivation of TIF1 gamma Cooperates with Kras(G12D) to Induce Cystic Tumors of the Pancreas SO PLOS GENETICS LA English DT Article ID TGF-BETA; DUCTAL ADENOCARCINOMA; K-RAS; INTRAEPITHELIAL NEOPLASIA; CANCER; MICE; MOUSE; TRANSCRIPTION; GROWTH; SMAD4 AB Inactivation of the Transforming Growth Factor Beta (TGF beta) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1 gamma) has recently been proposed to be involved in TGF beta signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1 gamma in pancreatic carcinogenesis. Using conditional Tif1 gamma knockout mice (Tif1 gamma(lox/lox)), we selectively abrogated Tif1 gamma expression in the pancreas of Pdx1-Cre;Tif1 gamma(lox/lox) mice. We also generated Pdx1-Cre;LSL-Kras(G12D);Tif1 gamma(lox/lox) mice to address the effect of Tif1 gamma loss-of-function in precancerous lesions induced by oncogenic Kras(G12D). Finally, we analyzed TIF1 gamma expression in human pancreatic tumors. In our mouse model, we showed that Tif1 gamma was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre;LSL-Kras(G12D);Smad4(lox/lox) mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1 gamma don't have strictly redundant functions. Finally, we report that TIF1 gamma expression is markedly down-regulated in human pancreatic tumors by quantitative RT-PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1 gamma is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1 gamma in the multifaceted functions of TGF beta in carcinogenesis and development. C1 [Vincent, David F.; Arfi, Vanessa; Kaniewsky, Bastien; Martel, Sylvie; Puisieux, Alain; Rimokh, Ruth; Bartholin, Laurent] INSERM, U590, IFR62, F-69008 Lyon, France. [Vincent, David F.; Arfi, Vanessa; Kaniewsky, Bastien; Lepinasse, Florian; Puisieux, Alain; Rimokh, Ruth; Scoazec, Jean-Yves; Bartholin, Laurent] Univ Lyon, Lyon, France. [Vincent, David F.; Arfi, Vanessa; Kaniewsky, Bastien; Martel, Sylvie; Bartholin, Laurent] INSERM, Avenir Grp, F-69008 Lyon, France. [Yan, Kai-Ping; Losson, Regine] IGBMC, Illkirch Graffenstaden, France. [Vincent, David F.; Treilleux, Isabelle; Arfi, Vanessa; Kaniewsky, Bastien; Martel, Sylvie; Goddard-Leon, Sophie; Puisieux, Alain; Bartholin, Laurent] Ctr Leon Berard, F-69373 Lyon, France. [Gay, Fabien; Lepinasse, Florian; Scoazec, Jean-Yves] INSERM, U865, Fac Laennec, F-69008 Lyon, France. [Marie, Julien C.] INSERM, U758, F-69008 Lyon, France. [Lepinasse, Florian; Scoazec, Jean-Yves] Hop Edouard Herriot, Hosp Civils Lyon, Lyon, France. [Iovanna, Juan L.; Garcia, Stephane] INSERM, U624, F-13258 Marseille, France. [Dubus, Pierre] Univ Bordeaux, EA 2406, Bordeaux, France. [Bardeesy, Nabeel] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Vincent, DF (reprint author), INSERM, U590, IFR62, F-69008 Lyon, France. EM bartholi@lyon.fnclcc.fr RI Rimokh, Ruth/G-7506-2014; Marie, Julien/I-5084-2016; OI Vincent, David/0000-0001-6482-8040 FU ARC [3891]; INSERM; INCA; Ligue Contre le Cancer FX This work was supported by grants from, ARC 3891 (LB), INSERM "Avenir'' program (LB), INCA "libre'' (RR/LB, JYS, and JCM), INCA "plateforme'' (LB and JCM), and Ligue Contre le Cancer (LB). DFV is a MENRT doctoral fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 59 Z9 63 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2009 VL 5 IS 7 AR e1000575 DI 10.1371/journal.pgen.1000575 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 486SZ UT WOS:000269219500016 PM 19629168 ER PT J AU Ranjbar, S Boshoff, HI Mulder, A Siddiqi, N Rubin, EJ Goldfeld, AE AF Ranjbar, Shahin Boshoff, Helena I. Mulder, Amara Siddiqi, Noman Rubin, Eric J. Goldfeld, Anne E. TI HIV-1 Replication Is Differentially Regulated by Distinct Clinical Strains of Mycobacterium tuberculosis SO PLOS ONE LA English DT Article AB Background: Tuberculosis ( TB) is the largest cause of death in human immunodeficiency virus type 1 (HIV-1) infection, having claimed an estimated one third to one half of the 30 million AIDS deaths that have occurred worldwide. Different strains of Mycobacterium tuberculosis (MTb), the causative agent of TB, are known to modify the host immune response in a strain-specific manner. However, a MTb strain-specific impact upon the regulation of HIV-1 replication has not previously been established. Methology/Principal Findings: We isolated normal human peripheral blood mononuclear cells (PBMC) and co-infected them with HIV-1 and with either the well characterized CDC1551 or HN878 MTb clinical isolate. We show that HIV-1 co-infection with the CDC1551 MTb strain results in higher levels of virus replication relative to co-infection with the HN878 MTb strain ex vivo. Furthermore, we show that the distinct pattern of CDC1551 or HN878 induced HIV-1 replication is associated with significantly increased levels of TNF and IL-6, and of the transcription and nuclear translocation of the p65 subunit of the transcription factor NF-kappa B, by CDC1551 relative to HN878. Conclusions/Significance: These results provide a precedent for TB strain-specific effects upon HIV-1 replication and thus for TB strain-specific pathogenesis in the outcome of HIV-1/TB co-infection. MTb strain-specific factors and mechanisms involved in the regulation of HIV-1 during co-infection will be of importance in understanding the basic pathogenesis of HIV-1/TB co-infection. RP Ranjbar, S (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM ranjbar@idi.harvard.edu; goldfeld@idi.harvard.edu OI Rubin, Eric/0000-0001-5120-962X FU Intramural NIH HHS; NHLBI NIH HHS [HL 059838]; NIAID NIH HHS [P30 AI 060354, AI 065285, P30 AI060354, R01 AI065285, R56 AI065285] NR 66 TC 21 Z9 22 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 JUL 1 PY 2009 VL 4 IS 7 AR e6116 DI 10.1371/journal.pone.0006116 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465HA UT WOS:000267572200015 PM 19568431 ER PT J AU Hare, S Di Nunzio, F Labeja, A Wang, JM Engelman, A Cherepanov, P AF Hare, Stephen Di Nunzio, Francesca Labeja, Alfred Wang, Jimin Engelman, Alan Cherepanov, Peter TI Structural Basis for Functional Tetramerization of Lentiviral Integrase SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRAL-DNA BINDING; CARBOXYL-TERMINAL DOMAINS; TARGET SITE SELECTION; AMINO-ACID-RESIDUES; HIV-1 INTEGRASE; IN-VITRO; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; COACTIVATOR P75 AB Experimental evidence suggests that a tetramer of integrase ( IN) is the protagonist of the concerted strand transfer reaction, whereby both ends of retroviral DNA are inserted into a host cell chromosome. Herein we present two crystal structures containing the N-terminal and the catalytic core domains of maedi-visna virus IN in complex with the IN binding domain of the common lentiviral integration co-factor LEDGF. The structures reveal that the dimer-of-dimers architecture of the IN tetramer is stabilized by swapping N-terminal domains between the inner pair of monomers poised to execute catalytic function. Comparison of four independent IN tetramers in our crystal structures elucidate the basis for the closure of the highly flexible dimer-dimer interface, allowing us to model how a pair of active sites become situated for concerted integration. Using a range of complementary approaches, we demonstrate that the dimer-dimer interface is essential for HIV-1 IN tetramerization, concerted integration in vitro, and virus infectivity. Our structures moreover highlight adaptable changes at the interfaces of individual IN dimers that allow divergent lentiviruses to utilize a highly-conserved, common integration co-factor. C1 [Hare, Stephen; Labeja, Alfred; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Med, London, England. [Di Nunzio, Francesca; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Wang, Jimin] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA. RP Hare, S (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Med, St Marys Campus, London, England. EM alan_engelman@dfci.harvard.edu; p.cherepanov@imperial.ac.uk RI Di Nunzio, Francesca/A-6153-2014; Cherepanov, Peter/F-6859-2010; OI Di Nunzio, Francesca/0000-0003-2879-3164; Cherepanov, Peter/0000-0002-0634-538X; Hare, Stephen/0000-0003-2951-1595 FU NIH [AI070042]; UK Medical Research Council [G0600009] FX This work was funded by NIH Grant AI070042 ( A. E.) and UK Medical Research Council grant G0600009 ( P. C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 62 Z9 63 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2009 VL 5 IS 7 AR e1000515 DI 10.1371/journal.ppat.1000515 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 486UJ UT WOS:000269224500018 PM 19609359 ER PT J AU Lin, AE O'Brien, B Demmer, LA Almeda, KK Blanco, CL Glasow, PF Berul, CI Hamilton, R Innes, AM Lauzon, JL Sol-Church, K Gripp, KW AF Lin, Angela E. O'Brien, Barbara Demmer, Laurie A. Almeda, Kristina K. Blanco, Cynthia L. Glasow, Patrick F. Berul, Charles I. Hamilton, Robert Innes, A. Micheil Lauzon, Julie L. Sol-Church, Katia Gripp, Karen W. TI Prenatal features of Costello syndrome: ultrasonographic findings and atrial tachycardia SO PRENATAL DIAGNOSIS LA English DT Article DE chaotic atrial rhythm; chaotic atrial tachycardia; Costello syndrome; fetal arrhythmia; HRAS gene; polyhydramnios; prenatal ultrasound; supraventricular tachycardia ID FACIO-CUTANEOUS SYNDROME; GROWTH RETARDATION SYNDROME; TUMOR SCREENING PROTOCOL; HRAS MUTATION ANALYSIS; NATURAL-HISTORY; SKELETAL SYNDROME; EMBRYONAL RHABDOMYOSARCOMA; DIFFERENTIAL-DIAGNOSIS; PHENOTYPE CORRELATION; HORMONE DEFICIENCY AB Objective Delineate prenatal features of Costello syndrome (caused by HRAS mutations), which consists of mental retardation. facial. cardiovascular, skin. and musculoskeletal anomalies. and tumor predisposition. Methods Literature and new cases classified as Group I (pre-HRAS), Group II (HRAS confirmed). and Group III (HRAS confirmed ill natural history study. Plus three contributed cases). Results Polyhydramnios Occurred in most (mean 79%) pregnancies of cases in Groups 1 (98) 11 (107), and III (17); advanced paternal age and prematurity were noted in approximately half. Less frequent were nuchal thickening. ascites, shortened long, bones. abnormal hand posture. ventriculomegaly, macrosomia, and macrocephaly. Fetal arrhythmia Occurred in nine cases (six supraventricular or unspecified tachycardia, one Unspecified arrhythmia. and two premature atrial contractions. PACs); excluding three new cases and two with PACs, the estimated prenatal frequency is 4/222 (2%). Conclusion Costello syndrome can be suspected prenatally when polyhydramnios is accompanied by nuchal thickening, hydrops, shortened long bones, abnormal hand Posture. ventriculomegaly, large size, and macrocephaly, and especially fetal atrial tachycardia. Consideration should be given for timely prenatal diagnostic Studies for continuative HRAS gene mutations and for maternal treatment of serious fetal arrhythmia. Copyright (C) 22009 John Wiley & Sons. Ltd. C1 [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Dept Pediat, Boston, MA USA. [O'Brien, Barbara; Demmer, Laurie A.] Tufts Med Ctr, Div Genet, Boston, MA USA. [O'Brien, Barbara] Brown Univ, Women & Infants Hosp, Dept Obstet & Gynecol, Providence, RI USA. [Almeda, Kristina K.; Blanco, Cynthia L.] Univ Texas Hlth Sci Ctr San Antonio, Div Neonatol, San Antonio, TX 78229 USA. [Glasow, Patrick F.] Univ Texas Hlth Sci Ctr San Antonio, Div Pediat Cardiol, San Antonio, TX 78229 USA. [Berul, Charles I.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Hamilton, Robert] Hosp Sick Children, Dept Cardiol, Toronto, ON M5G 1X8, Canada. [Innes, A. Micheil; Lauzon, Julie L.] Alberta Childrens Prov Gen Hosp, Dept Med Genet, Calgary, AB, Canada. [Sol-Church, Katia] Nemours Childrens Clin, Wilmington, DE USA. [Gripp, Karen W.] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE USA. RP Lin, AE (reprint author), MassGen Hosp Children, Genet Unit, Dept Pediat, 185 Cambridge St,Simches 2222, Boston, MA USA. EM lin.angela@mgh.harvard.edu RI innes, allan micheil/A-9955-2017; OI Innes, Micheil/0000-0001-9881-5467 FU NCRR NIH HHS [P20 RR020173, P20-RR020173] NR 89 TC 26 Z9 26 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD JUL PY 2009 VL 29 IS 7 BP 682 EP 690 DI 10.1002/pd.2276 PG 9 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 472UF UT WOS:000268157000007 PM 19382114 ER PT J AU Anstead, GM Zhang, Q Melby, PC AF Anstead, G. M. Zhang, Q. Melby, P. C. TI Malnutrition promotes prostaglandin over leukotriene production and dysregulates eicosanoid-cytokine crosstalk in activated resident macrophages SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE Prostaglandin; Leukotriene; Malnutrition; Cytokine; Macrophage; Nitric oxide; Tumor necrosis factor-alpha; Interleukin-10; Granulocyte macrophage colony stimulating factor ID COLONY-STIMULATING FACTOR; PROTEIN-CALORIE MALNUTRITION; ARACHIDONIC-ACID METABOLITES; RAT ALVEOLAR MACROPHAGES; NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; KAPPA-B ACTIVATION; CELL-LINE J774; ACUTE-INFLAMMATION; CYCLIC-AMP AB We previously described a murine model of malnutrition that mimicked features of moderate human malnutrition, and led to increased dissemination of Leishmania donovani. In this study, we investigated the effect of malnutrition on macrophage production of cytokines, prostaglandins (PCs), and leukotrienes (LTs). Using either LPS or calcium ionophore A23187 as a stimulus, macrophages from the malnourished mice produced a 3-fold higher PG/LT ((PGE(2)+6-keto-PGF(1 alpha))/(LTB(4)+cysteinyl leukotrienes)) ratio than macrophages from well-nourished mice. LPS-stimulated macrophages from the malnourished mice produced decreased levels of TNF-alpha, GM-CSF, and IL-10, but similar levels of IL-6 and NO compared to well-nourished mice. A complex crosstalk between the eicosanoids and cytokines in the LPS-stimulated macrophages from the malnourished mice was evident by the following: ( I) high levels of PC secretion despite low levels of TNF-alpha; (2) Supplemental IL-10 modulated the excessive PC production; (3) GM-CSF rectified the PG/LT ratio, but did not correct the abnormal cytokine profile: and (4) inhibitors of cyclooxygenase decreased the PG/LT ratio, but did not affect TNF-alpha. Thus, in this model of malnutrition, there is a relative increase in anti-inflammatory PCs compared to pro-inflammatory LTs, which may contribute to immunodeficiency. Published by Elsevier Ltd. C1 [Anstead, G. M.; Zhang, Q.; Melby, P. C.] Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, Dept Med, San Antonio, TX 78229 USA. [Anstead, G. M.; Melby, P. C.] Audie L Murphy Mem Vet Adm Med Ctr, Res Serv, San Antonio, TX 78284 USA. RP Anstead, GM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM anstead@uthscsa.edu FU US Department of Veterans Affairs (GMA, PCM); San Antonio Area Foundation; University of Texas Health Science Center at San Antonio FX The work was supported by funding from the US Department of Veterans Affairs (GMA, PCM), the San Antonio Area Foundation, and the University of Texas Health Science Center at San Antonio (institutional Research Grant to GMA). NR 74 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD JUL PY 2009 VL 81 IS 1 BP 41 EP 51 DI 10.1016/j.plefa.2009.04.011 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 475TM UT WOS:000268384000007 PM 19541468 ER PT J AU Wang, R Kern, JT Goodfriend, TL Ball, DL Luesch, H AF Wang, Rui Kern, Jonathan T. Goodfriend, Theodore L. Ball, Dennis L. Luesch, Hendrik TI Activation of the antioxidant response element by specific oxidized metabolites of linoleic acid SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE Polyunsaturated fatty acids; Fatty acid oxidation; Fatty acid epoxides; EKODE; Antioxidants; Antioxidant response element ID HUMAN NEUROBLASTOMA-CELLS; OXIDATIVE STRESS; NAD(P)H-QUINONE OXIDOREDUCTASE; CYCLOPENTENONE PROSTAGLANDINS; INDUCED APOPTOSIS; HEME OXYGENASE-1; PALMITIC ACID; INDUCTION; ENZYMES; PROTECTION AB Linoleic acid is required for normal mammalian health and development, but is also prone to oxidation, yielding metabolites with biological effects. We screened linoleic acid, other fatty acids, and some of their derivatives and found that an epoxy-keto derivative of linoleic acid (but neither linoleic acid itself nor others of its oxidation products) strongly activates the antioxidant response element (ARE) in IMR-32 neuroblastoma cells and cerebro-cortical neurons. The active compound, 12,13-epoxy-9-keto-10(trans)-octadecenoic acid (EKODE), induces the expression of ARE-regulated cytoprotective genes such as NQO1 at the transcript and protein levels. EKODE requires transcription factor NRF2 and PI3-kinase for ARE activity. The results suggest that specific oxidation products of linoleic acid may initiate responses that lessen damage caused by oxidative stress. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Wang, Rui; Luesch, Hendrik] Univ Florida, Dept Med Chem, Gainesville, FL 32610 USA. [Kern, Jonathan T.] Univ Wisconsin, Sch Pharm, Dept Pharmaceut Sci, Madison, WI 53706 USA. [Goodfriend, Theodore L.; Ball, Dennis L.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Goodfriend, Theodore L.; Ball, Dennis L.] Univ Wisconsin, Dept Pharmacol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Goodfriend, Theodore L.; Ball, Dennis L.] Univ Wisconsin, William S Middleton Mem Vet Hosp, Madison, WI USA. RP Luesch, H (reprint author), Univ Florida, Dept Med Chem, 1600 SW Archer Rd, Gainesville, FL 32610 USA. EM luesch@cop.ufl.edu FU NCI NIH HHS [R21 CA133681, R21 CA133681-01A1, R21CA133681]; NHLBI NIH HHS [HL076238, R01 HL076238]; NIEHS NIH HHS [F32 ES013463, T32 ES007015, T32ES07015]; PHS HHS [F32 ESO13463] NR 36 TC 14 Z9 14 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD JUL PY 2009 VL 81 IS 1 BP 53 EP 59 DI 10.1016/j.plefa.2009.04.008 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 475TM UT WOS:000268384000008 PM 19481916 ER PT J AU Ferreira, GB van Etten, E Lage, K Hansen, DA Moreau, Y Workman, CT Waer, M Verstuyf, A Waelkens, E Overbergh, L Mathieu, C AF Ferreira, Gabriela Bomfim van Etten, Evelyne Lage, Kasper Hansen, Daniel Aaen Moreau, Yves Workman, Christopher T. Waer, Mark Verstuyf, Annemieke Waelkens, Etienne Overbergh, Lut Mathieu, Chantal TI Proteome analysis demonstrates profound alterations in human dendritic cell nature by TX527, an analogue of vitamin D SO PROTEOMICS LA English DT Article DE 2-D DIGE; Dendritic cell; Immunotolerance; Network; Vitamin D analogue ID MOLECULAR INTERACTION DATABASE; AUTOREACTIVE T-CELLS; 1,25-DIHYDROXYVITAMIN D-3; BIOLOGICAL-ACTIVITY; GENE-EXPRESSION; PPAR-GAMMA; IN-VITRO; ACTIN; DIFFERENTIATION; MATURATION AB Structural analogues of vitamin D have been put forward as therapeutic agents able to exploit the immunomodulatory effects of vitamin D, without its undesired calcemic side effects. We have demonstrated that TX527 affects dendritic cell (DC) maturation in vitro, resulting in the generation of a tolerogenic cell. In the present study, we aimed to explore the global protein changes induced by the analogue in immature DC (iDC) and mature human DC and to correlate them with alterations in DC morphology and function. Human CD14(+) monocytes were differentiated toward iDC or mature DCs, in the presence or absence of TX527 (10(-8) M) (n = 4). Protein samples were separated into two different pH ranges (pH4-7 and 6-9), analyzed by 2-D DIGE and differentially expressed spots (p<0.01) were identified by MALDI-TOF/TOF (76.3 and 70.7% in iDC and mature DCs, respectively). Differential protein expression revealed three protein groups predominantly affected by TX527 treatment, namely proteins involved in cytoskeleton structure, in protein biosynthesis/proteolysis and in metabolism. Moreover, protein interactome-network analysis demonstrated dose interaction between these different groups (p<0.001) and morphological and functional analyses confirmed the integrated effect of TX527 on human DCs, resulting in a cell with altered morphology, cell surface marker expression, endocytic and migratory capacity. C1 [Ferreira, Gabriela Bomfim; van Etten, Evelyne; Verstuyf, Annemieke; Overbergh, Lut; Mathieu, Chantal] Catholic Univ Louvain, Lab Expt Med & Endocrinol LEGENDO, Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Lage, Kasper; Hansen, Daniel Aaen; Workman, Christopher T.] Tech Univ Denmark, Ctr Biol Sequence Anal, Lyngby, Denmark. [Lage, Kasper] Massachusetts Gen Hosp, Pediat Surg Res Labs, MassGen Hosp Children, Boston, MA 02114 USA. [Lage, Kasper] Harvard Univ, Sch Med, Boston, MA USA. [Moreau, Yves] Catholic Univ Louvain, ESAT SDC, Dept Elect Engn, Heverlee, Belgium. [Waer, Mark] Catholic Univ Louvain, Expt Transplantat Sect, Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Waelkens, Etienne] Catholic Univ Louvain, Lab Prot Phosphorylat & Prote, Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. RP Overbergh, L (reprint author), Catholic Univ Louvain, Lab Expt Med & Endocrinol LEGENDO, Univ Hosp Gasthuisberg, Herestr 49,Bus 902, B-3000 Louvain, Belgium. EM lut.overbergh@med.kuleuven.be RI Bomfim Ferreira, Gabriela/L-8343-2014; Workman, Christopher/K-1066-2015 OI Workman, Christopher/0000-0002-2210-3743 FU Catholic University of Leuven [GOA 2004/10, 2009/10]; Flemish Research Foundation (FWO) [G.0552.06, G.0649.08]; Belgium Program on Interuniversity Poles of Attraction initiated by the Belgian State (IUAP) [P5/17, P6/40]; Centre of Excellence SymBioSys [EF/05/007]; Juvenile Diabetes Research Foundation [JDRF3-2006-33]; Forsknigsradet for Sundhed og Sygdom; Villum Kann Rasmussen Foundation; Simon Spies Foundation; National Institute of Child Health and Development (NICHD); National Institute of Health (NIH); [E06D100904BR] FX The technical experience of Karin Schildermans, Jos Depovere and Dirk Valckx is greatly appreciated. This work was supported by the Catholic University of Leuven (GOA 2004/10 and 2009/10), the Flemish Research Foundation (FWO G.0552.06 G.0649.08), the Belgium Program on Interuniversity Poles of Attraction initiated by the Belgian State (IUAP P5/17 and P6/40) and the Centre of Excellence SymBioSys (Research Council K.U.Leuven EF/05/007). G. B. F. is supported by a doctoral fellowship (Alban, no. E06D100904BR), E. V. E. by a post-doctoral fellowship (juvenile Diabetes Research Foundation, JDRF3-2006-33), K.L. by a grant from Forsknigsradet for Sundhed og Sygdom and C. M. by a clinical research fellowship (FWO). We further wish to thank the Villum Kann Rasmussen Foundation, the Simon Spies Foundation, the National Institute of Child Health and Development (NICHD) and the National Institute of Health (NIH) for financial support. NR 55 TC 26 Z9 27 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD JUL PY 2009 VL 9 IS 14 BP 3752 EP 3764 DI 10.1002/pmic.200800848 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 483MN UT WOS:000268971000011 PM 19639594 ER PT J AU Mohamed, S Neale, M Rosenheck, RA AF Mohamed, Somaia Neale, Michael Rosenheck, Robert A. TI VA Intensive Mental Health Case Management in Urban and Rural Areas: Veteran Characteristics and Service Delivery SO PSYCHIATRIC SERVICES LA English DT Article ID ASSERTIVE COMMUNITY TREATMENT; SUBSTANCE-ABUSE; SEVERITY; PROGRAM; FIDELITY; SCALE; MODEL AB Objective: The availability of mental health services in rural areas-particularly intensive services such as assertive community treatment (ACT)-has been of increasing concern and was the focus of this study. In recent decades the U. S. Department of Veterans Affairs (VA) has developed a national network of ACT-like programs called mental health intensive case management (MHICM), which have served veterans from diverse locations across the country, including urban and rural areas. Methods: This study used rural-urban commuting area codes and national VA administrative data to compare characteristics of veterans and patterns of MHICM service delivery among veterans with mental illness living in large urban, large rural, small rural, and isolated rural communities. Results: Among veterans enrolled in MHICM from FY 2000 to FY 2005 (N=5,221), 84% (N=4,373) resided in urban areas, 8% (N=421) in large cities, 6% (N=291) in small rural towns, and 3% (N=136) in isolated rural areas. MHICM participants who lived in rural areas had clinical problems broadly similar to those in urban areas, although more rural veterans were unemployed, disabled, received VA disability compensation, and had a payee or fiduciary. MHICM clients in smaller or isolated rural areas received slightly less frequent and less intensive contacts and less recovery-oriented services than those in large urban locations. Conclusions: These data highlight the need for intensive case management services in rural areas and note some challenges in providing them at the intensity and frequency observed in urban areas where travel distances and times are shorter. (Psychiatric Services 60:914-921, 2009) C1 [Mohamed, Somaia; Neale, Michael; Rosenheck, Robert A.] US Dept Vet Affairs, Vet Integrated Serv Network 1, Mental Illness Res Educ & Clin Ctr, West Haven, CT 06516 USA. [Mohamed, Somaia; Neale, Michael; Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Mohamed, S (reprint author), US Dept Vet Affairs, Vet Integrated Serv Network 1, Mental Illness Res Educ & Clin Ctr, 950 Campbell Ave, West Haven, CT 06516 USA. EM somaia.mohamed@yale.edu NR 19 TC 17 Z9 17 U1 0 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUL PY 2009 VL 60 IS 7 BP 914 EP 921 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 463TU UT WOS:000267455800008 PM 19564221 ER PT J AU Murphy, JM Leighton, AH AF Murphy, J. M. Leighton, A. H. TI Anxiety: its role in the history of psychiatric epidemiology SO PSYCHOLOGICAL MEDICINE LA English DT Review DE Autonomic hyperactivity; depression; DSM-V ID COMMON MENTAL-DISORDERS; NATIONAL-COMORBIDITY-SURVEY; DSM-III-R; GENERALIZED ANXIETY; DIAGNOSTIC INTERVIEW; 40-YEAR PERSPECTIVE; MAJOR DEPRESSION; STIRLING-COUNTY; PANIC DISORDER; UNITED-STATES AB Background. The role played by anxiety in the history of psychiatric epidemiology has not been well recognized. Such lack of understanding retarded the incremental growth of psychiatric research in general populations. It seems useful to look back oil this history while deliberations are being carried out about how anxiety will be presented in DSM-V. Method. Drawing on the literature and our own research, we examined work that was carried out during and after the Second World War by a Research Branch of the United States War Department, by the Stirling County Study, and by the Midtown Manhattan Study. The differential influences of Meyerian psychobiology and Freudian psychoanalysis are noted. Results. The instruments developed in the early epidemiologic endeavors used questions about nervousness, palpitations, sweating, trembling, shortness of breath, upset stomach, etc. These symptoms are important features of what the clinical literature called 'manifest', 'free-floating' or 'chronic anxiety'. A useful descriptive name is I autonomic anxiety'. Conclusions. Although not focusing oil specific circumstances as in Panic and Phobic disorders, a non-specific form of autonomic anxiety is a common, disabling and usually chronic disorder that received empirical verification in studies of several community populations. It is suggested that two types of general anxiety may need to be recognized, one dominated by excessive worry and feelings of stress, as in the current DSM-IV definition of Generalized Anxiety Disorder (GAD), and another emphasizing frequent unexplainable autonomic fearfulness, as in the early epidemiologic studies. C1 [Murphy, J. M.; Leighton, A. H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Murphy, JM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, 5 Longfellow Pl,Room 215, Boston, MA 02114 USA. EM murphy.jane@mgh.harvard.edu FU NIMH [R01 MH39576-23, 80M0142800101D] FX This report draws on experience in the Stirling County Study, which is currently supported by NIMH Grant R01 MH39576-23 (J.M.M.) and on NIMH Contract 80M0142800101D 'Psychiatric Screening Development for Primary Care' (J.M.M.). NR 76 TC 3 Z9 3 U1 0 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2009 VL 39 IS 7 BP 1055 EP 1064 DI 10.1017/S0033291708004625 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 461TZ UT WOS:000267296100002 PM 18940025 ER PT J AU Nicolaidis, C McFarland, B Curry, M Gerrity, M AF Nicolaidis, Christina McFarland, Bentson Curry, MaryAnn Gerrity, Martha TI Differences in Physical and Mental Health Symptoms and Mental Health Utilization Associated With Intimate-Partner Violence Versus Childhood Abuse SO PSYCHOSOMATICS LA English DT Article ID SELF-REPORTED ABUSE; PRIMARY-CARE; CLINICAL CHARACTERISTICS; DOMESTIC VIOLENCE; SOMATIC SYMPTOMS; BATTERED WOMEN; CHECKLIST HSCL; SEXUAL-ABUSE; CONSEQUENCES; EXPERIENCES AB Background: There is ample evidence that both intimate-partner violence (IPV) and childhood abuse adversely affect the physical and mental health of adult women over the long term. Objective: The authors assessed the associations between abuse, symptoms, and mental health utilization. Method: The authors performed a cross-sectional survey of 380 adult female, internal-medicine patients. Results: Although both IPV and childhood abuse were associated with depressive and physical symptoms, IPV was independently associated with physical symptoms, and childhood abuse was independently associated with depression. Women with a history of childhood abuse had higher odds, whereas women with IPV had lower odds, of receiving care from mental health providers. Conclusion: IPV and childhood abuse may have different effects on women's symptoms and mental health utilization. (Psychosomatics 2009; 50: 340-346) C1 [Nicolaidis, Christina] Oregon Hlth & Sci Univ, Div Gen Internal Med, Dept Med, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Sch Nursing, Portland, OR 97239 USA. Portland VA Med Ctr, Portland, OR USA. RP Nicolaidis, C (reprint author), Oregon Hlth & Sci Univ, Div Gen Internal Med, Dept Med, 3181 SW Sam Jackson Pk Rd,L475, Portland, OR 97239 USA. EM nicolaid@ohsu.edu FU Robert Wood Johnson Foundation Depression; National Institute of Mental Health [K23 MH073008-03] FX This study was funded by a grant from the Robert Wood Johnson Foundation Depression in Primary Care Program. Dr. Nicolaidis' time is supported by a grant from the National Institute of Mental Health (K23 MH073008-03). NR 31 TC 9 Z9 9 U1 2 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 2009 VL 50 IS 4 BP 340 EP 346 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 484NJ UT WOS:000269052200006 PM 19687174 ER PT J AU Bankier, B Barajas, J Martinez-Rumayor, A Januzzi, JL AF Bankier, Bettina Barajas, Justine Martinez-Rumayor, Abelardo Januzzi, James L. TI Association Between Anxiety and C-Reactive Protein Levels in Stable Coronary Heart Disease Patients SO PSYCHOSOMATICS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CARDIOVASCULAR EVENTS; STATIN THERAPY; CARDIAC EVENTS; PHOBIC ANXIETY; RISK-FACTORS; DEPRESSION; MEN; SYMPTOMS; PERSISTENCE AB Background: Anxiety is highly prevalent among patients with stable coronary heart disease (CHD). However, the biologic effects that may connect these two seemingly unrelated disorders is not well understood. Objective: This study aimed for a comprehensive evaluation of anxiety in stable CHD patients, in addition to cardiac biomarkers such as C-reactive protein (CRP), troponin T, and amino-terminal pro-B-type brain natriuretic peptide. Method: The study included 43 CHD patients with anxiety disorder and 42 CHD patients without psychiatric disorder given the Structured Clinical Interview for DSM-IV. Results: Regression analyses showed an association between anxiety (anxiety disorder, not otherwise specified) and CRP levels, despite model adjustment for various related demographic and clinical variables. Anxiety was associated with CRP levels. Conclusion: There are significant associations between anxiety and CHD risk, with a potential biologic link between anxiety and elevations in a biomarker with powerful prognostic risk, namely CRP. It is not clear whether this association is directly causal or relates to other medical processes among patients with heightened anxiety. The findings suggest that the current focus on depressive disorders with respect to biomarkers and CHD outcomes should be broadened to include anxiety disorders, as well. (Psychosomatics 2009; 50: 347-353) C1 [Bankier, Bettina] Med Univ Vienna, Dept Psychiat & Psychotherapy, A-1090 Vienna, Austria. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Bankier, B (reprint author), Med Univ Vienna, Dept Psychiat & Psychotherapy, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM bettina.bankier@meduniwien.ac.at FU NARSAD Young Investigator Award; Mental Health Research Association, Great Neck, NY [760-2339-5, 218960] FX This work was fully supported by a NARSAD Young Investigator Award 2005, Mental Health Research Association, Great Neck, NY (NARSAD Fund No. 760-2339-5, Grant 218960 to B. B). NR 26 TC 16 Z9 18 U1 0 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 2009 VL 50 IS 4 BP 347 EP 353 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 484NJ UT WOS:000269052200007 PM 19687175 ER PT J AU Welch, CA Czerwinski, D Ghimire, B Bertsimas, D AF Welch, Charles A. Czerwinski, David Ghimire, Bijay Bertsimas, Dimitris TI Depression and Costs of Health Care SO PSYCHOSOMATICS LA English DT Article ID MAINTENANCE ORGANIZATION; ADMINISTRATIVE DATABASES; DIABETES COMPLICATIONS; COMORBID DEPRESSION; OUTCOMES RESEARCH; MAJOR DEPRESSION; MEDICAL ILLNESS; MOOD DISORDERS; RISK-FACTORS; CLAIMS DATA AB Background: In spite of its global importance, the interaction between depression and chronic comorbid diseases remains incompletely understood with regard to prevalence, severity of disease, and potential causative factors mediating this interaction. Objective: The authors sought to compare overall medical costs in nondepressed and depressed individuals. Method: Insurance claims for 618,780 patients were examined for total annual non-mental health cost of care in 11 chronic diseases. In each disease cohort, median annual non-mental health cost was calculated for individuals with and without depression. Results: Patients with depression had higher median per-patient annual non-mental health costs than patients without depression in all 11 diseases studied. There was a higher-than-random comorbidity between depression and all 11 chronic comorbid diseases. Conclusion: Even when controlling for number of chronic comorbid diseases, depressed patients had significantly higher costs than non-depressed patients, in a magnitude consistent across 11 chronic comorbid diseases. (Psychosomatics 2009; 50: 392-401) C1 [Welch, Charles A.] Massachusetts Gen Hosp, Somat Therapies Consultat Serv, Boston, MA 02114 USA. MIT, Ctr Operat Res, Cambridge, MA 02139 USA. D2 Hawkeye Inc, Waltham, MA USA. RP Welch, CA (reprint author), Massachusetts Gen Hosp, Somat Therapies Consultat Serv, Warren 601, Boston, MA 02114 USA. EM cwelch1@partners.org NR 37 TC 26 Z9 26 U1 0 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 2009 VL 50 IS 4 BP 392 EP 401 PG 10 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 484NJ UT WOS:000269052200012 PM 19687180 ER PT J AU Chakraborty, A Held, KD Prise, KM Liber, HL Redmond, RW AF Chakraborty, Asima Held, Kathryn D. Prise, Kevin M. Liber, Howard L. Redmond, Robert W. TI Bystander Effects Induced by Diffusing Mediators after Photodynamic Stress SO RADIATION RESEARCH LA English DT Article ID SISTER-CHROMATID EXCHANGES; LYMPHOBLASTOID CELL-LINES; ALPHA-PARTICLES; HUMAN FIBROBLASTS; DNA-DAMAGE; INTERCELLULAR COMMUNICATION; CHROMOSOMAL INSTABILITY; OXIDATIVE-METABOLISM; IONIZING-RADIATION; MAMMALIAN-CELLS AB The bystander effect, whereby cells that are not traversed by ionizing radiation exhibit various responses when in proximity to irradiated cells, is well documented in the field of radiation biology, Here we demonstrate that considerable bystander responses are also observed after photodynamic stress using the membrane-localizing dye deuteroporphyrin (DP). Using cells of a WTK1 human lymphoblastoid cell line in suspension and a transwell insert system that precludes contact between targeted and bystander cells, we have shown that the bystander signaling is mediated by diffusing species. The extranuclear localization of the photosensitizer used suggests that primary DNA damage is not the trigger for initiating these bystander responses, which include elevated oxidative stress, DNA damage (micronucleus formation), mutagenesis and decreased clonogenic survival. In addition, oxidative stress in the bystander population was reduced by the presence of the membrane antioxidant vitamin E in the targeted cells, suggesting that lipid peroxidation may play a key role in mediating these bystander effects. The fluence responses for these bystander effects are non-linear, with larger effects seen at lower fluences and toxicity to the target cell population. Hence, when considering outcomes of photodynamic action in cells and tissue, bystander effects may be significant, especially at sublethal fluences. (C) 2009 by Radiation Research Society C1 [Chakraborty, Asima; Redmond, Robert W.] Harvard Univ, Wellman Ctr Photomed, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chakraborty, Asima; Held, Kathryn D.] Harvard Univ, Dept Radiat Oncol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Prise, Kevin M.] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7BL, Antrim, North Ireland. [Liber, Howard L.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Redmond, RW (reprint author), Harvard Univ, Wellman Ctr Photomed, Sch Med, Massachusetts Gen Hosp, Thier 224, Boston, MA 02114 USA. EM Redmond@helix.mgh.harvard.edu RI Prise, Kevin/N-7872-2015 OI Prise, Kevin/0000-0001-6134-7946 FU NCI NIH HHS [T32 CA009078-30, P01 CA095227, P01 CA095227-01A2, P01 CA095227-01A20002, P01 CA095227-01A29002, P01 CA095227-02, P01 CA095227-020002, P01 CA095227-03, P01 CA095227-030002, P01 CA095227-04, P01 CA095227-040002, T32 CA009078, T32 CA009078-26, T32 CA009078-27, T32 CA009078-28, T32 CA009078-29, T32 CA009078-31, T32 CA009078-32, T32 CA009078-33, T32 CA009078-34] NR 58 TC 25 Z9 27 U1 0 U2 5 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2009 VL 172 IS 1 BP 74 EP 81 DI 10.1667/RR1669.1 PG 8 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 465WF UT WOS:000267619200008 PM 19580509 ER PT J AU Pomerantz, SR Choy, G AF Pomerantz, Stuart R. Choy, Garry TI Net Assets: The Social Web for Radiology. Part I. Social Bookmarking to Social Citation SO RADIOLOGY LA English DT Editorial Material C1 [Pomerantz, Stuart R.] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Choy, Garry] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Pomerantz, SR (reprint author), Massachusetts Gen Hosp, Dept Neuroradiol, 55 Fruit St,Gray 2-B285, Boston, MA 02114 USA. EM netassets@rsna.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2009 VL 252 IS 1 BP 23 EP 28 DI 10.1148/radiol.2521090515 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 475ME UT WOS:000268362900004 PM 19561248 ER PT J AU Wu, O Sorensen, AG Benner, T Singhal, AB Furie, KL Greer, DM AF Wu, Ona Sorensen, A. Gregory Benner, Thomas Singhal, Aneesh B. Furie, Karen L. Greer, David M. TI Comatose Patients with Cardiac Arrest: Predicting Clinical Outcome with Diffusion-weighted MR Imaging SO RADIOLOGY LA English DT Article ID CEREBRAL-ISCHEMIA; CARDIOPULMONARY-RESUSCITATION; HUMAN BRAIN; INJURY; COEFFICIENT; SURVIVORS; PERFUSION; ENCEPHALOPATHY; HYPOTHERMIA; HYPOXIA AB Purpose: To examine whether the severity and spatial distribution of reductions in apparent diffusion coefficient ( ADC) are associated with clinical outcomes in patients who become comatose after cardiac arrest. Materials and Methods: This was an institutional review board-approved, HIPAA-compliant retrospective study of 80 comatose patients with cardiac arrest who underwent diffusion-weighted magnetic resonance imaging. The need to obtain informed consent was waived except when follow-up phone calls were required; in those cases, informed consent was obtained from the families. Mean patient age was 57 years +/- 16 (standard deviation); 31 (39%) patients were women. ADC maps were semiautomatically segmented into the following regions: subcortical white matter; cerebellum; insula; frontal, occipital, parietal, and temporal lobes; caudate nucleus; putamen; and thalamus. Median ADCs were measured in these regions and in the whole brain and were compared ( with a two-tailed Wilcoxon test) as a function of clinical outcome. Outcome was defined by both early eye opening in the 1st week after arrest ( either spontaneously or in response to external stimuli) and 6-month modified Rankin scale score. Results: Whole-brain median ADC was a significant predictor of poor outcome as measured by no eye opening (specificity, 100% [95% confidence interval {CI}: 86%, 100%]; sensitivity, 30% [ 95% CI: 18%, 45%]) or 6-month modified Rankin scale score greater than 3 ( specificity, 100% [ 95% CI: 73%, 100%]; sensitivity, 41% [95% CI: 29%, 54%]), with patients with poor outcomes having significantly lower ADCs for both outcome measures (P <= .001). Differences in ADC between patients with good and those with poor outcomes varied according to brain region, involving predominantly the occipital and parietal lobes and the putamen, and were dependent on the timing of imaging. Conclusion: Spatial and temporal differences in ADCs may provide insight into mechanisms of hypoxic-ischemic brain injury and, hence, recovery. C1 [Wu, Ona; Sorensen, A. Gregory; Benner, Thomas] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Singhal, Aneesh B.; Furie, Karen L.; Greer, David M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Wu, O (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,CNY 2301, Charlestown, MA 02129 USA. EM ona@nmr.mgh.harvard.edu NR 36 TC 83 Z9 84 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2009 VL 252 IS 1 BP 173 EP 181 DI 10.1148/radiol.2521081232 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 475ME UT WOS:000268362900021 PM 19420318 ER PT J AU Singh, S Kalra, MK Moore, MA Shailam, R Liu, B Toth, TL Grant, E Westra, SJ AF Singh, Sarabjeet Kalra, Mannudeep K. Moore, Michael A. Shailam, Randheer Liu, Bob Toth, Thomas L. Grant, Ellen Westra, Sjirk J. TI Dose Reduction and Compliance with Pediatric CT Protocols Adapted to Patient Size, Clinical Indication, and Number of Prior Studies SO RADIOLOGY LA English DT Article ID TUBE CURRENT MODULATION; IMAGE QUALITY; FOLLOW-UP; ROW CT; RADIATION; CHILDREN; ABDOMEN; PELVIS; OPTIMIZATION; UK AB Purpose: To assess compliance and resultant radiation dose reduction with new pediatric chest and abdominal computed tomographic (CT) protocols based on patient weight, clinical indication, number of prior CT studies, and automatic exposure control. Materials and Methods: The study was institutional review board approved and HIPAA compliant. Informed consent was waived. The new pediatric CT protocols, which were organized into six color zones based on clinical indications and number of prior CT examinations in a given patient, were retrospectively assessed. Scanning parameters were adjusted on the basis of patient weight. For gradual dose reduction, pediatric CT (n = 692) examinations were performed in three phases of incremental stepwise dose reduction during a 17-month period. There were 245 male patients and 193 female patients (mean age, 12.6 years). Two radiologists independently reviewed CT images for image quality. Data were analyzed by using multivariate analysis of variance. Results: Compliance with the new protocols in the early stage of implementation ( chest CT, 58.9%; abdominal CT, 65.2%) was lower than in the later stage ( chest CT, 88%; abdominal CT, 82%) ( P < .001). For chest CT, there was 52.6% (9.1 vs 19.2 mGy) to 85.4% (2.8 vs 19.2 mGy) dose reduction in the early stage of implementation and 73.5% (4.9 vs 18.5 mGy) to 83.2% (3.1 vs 18.5 mGy) dose reduction in the later stages compared with dose at noncompliant examinations (P < .001); there was no loss of clinically relevant image quality. For abdominal CT, there was 34.3% (9.0 vs 13.7 mGy) to 80.2% (2.7 vs 13.7 mGy) dose reduction in the early stage of implementation and 62.4% (6.5 vs 17.3) to 83.8% ( 2.8 vs 17.3 mGy) dose reduction in the later stage ( P < .001). Conclusion: Substantial dose reduction and high compliance can be obtained with pediatric CT protocols tailored to clinical indications, patient weight, and number of prior studies. C1 [Singh, Sarabjeet; Kalra, Mannudeep K.; Moore, Michael A.; Shailam, Randheer; Liu, Bob; Grant, Ellen; Westra, Sjirk J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Toth, Thomas L.] GE Healthcare, Waukesha, WI USA. RP Singh, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, 25 New Chardon St,4th Floor, Boston, MA 02114 USA. EM ssingh6@partners.org NR 21 TC 104 Z9 115 U1 0 U2 9 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2009 VL 252 IS 1 BP 200 EP 208 DI 10.1148/radiol.2521081554 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 475ME UT WOS:000268362900024 PM 19435938 ER PT J AU Lewis, SL Miner-Williams, D Novian, A Escamilla, MI Blackwell, PH Kretzschmar, JH Arevalo-Flechas, LC Bonner, PN AF Lewis, Sharon L. Miner-Williams, Denise Novian, Allen Escamilla, Monica I. Blackwell, Paula H. Kretzschmar, Jennifer Hale Arevalo-Flechas, Lyda C. Bonner, Peter N. TI A Stress-Busting Program for Family Caregivers SO REHABILITATION NURSING LA English DT Article DE Alzheimer's disease; Alzheimer's disease and related dementias; caregiving.; intervention; stress ID RELAXATION THERAPY; SYMPTOM QUESTIONNAIRE; HEALTH; DEPRESSION; SPOUSAL; IMPACT AB Aging baby boomers, longer life spans, and rising levels of Alzheimer's disease and related dementias (ADRD) will result in a caregiver crisis in the near future. The ways in which caregivers deal with stresses related to caregiving will be critical to both their own well-being and their ability to care for others. The purpose of this article is to describe the Stress-Busting Program (SBP) for family caregivers and its effectiveness. The essential components of the SBP are education, stress management, problem solving, and support delivered in a group setting for 9 weeks. Results of the SBP indicate that throughout the program, caregivers experienced significant improvements in general health, vitality, social function, and mental health scores and decreases in anxiety anger/hostility, depression, perceived stress, and caregiver burden. The SBP is a cost-effective health-promotion strategy for caregivers who have substantial ongoing stress. C1 [Lewis, Sharon L.] Univ Texas Hlth Sci Ctr San Antonio, Sch Nursing & Med, San Antonio, TX 78229 USA. [Lewis, Sharon L.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Miner-Williams, Denise; Novian, Allen; Escamilla, Monica I.; Blackwell, Paula H.; Kretzschmar, Jennifer Hale; Arevalo-Flechas, Lyda C.] Univ Texas Hlth Sci Ctr San Antonio, Sch Nursing, San Antonio, TX 78229 USA. [Bonner, Peter N.] Data & Stat Inc, Boerne, TX USA. RP Lewis, SL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sch Nursing & Med, San Antonio, TX 78229 USA. EM lewissl@uthscsa.edu NR 32 TC 6 Z9 6 U1 1 U2 17 PU ASSOC REHABILITATION NURSES PI GLENVIEW PA 4700 W LAKE AVE, GLENVIEW, IL 60025-1485 USA SN 0278-4807 J9 REHABIL NURS JI Rehabil. Nurs. PD JUL-AUG PY 2009 VL 34 IS 4 BP 151 EP 159 PG 9 WC Nursing; Rehabilitation SC Nursing; Rehabilitation GA 461AK UT WOS:000267235300004 PM 19583056 ER PT J AU Maciejewski, ML Chen, SY Au, DH AF Maciejewski, Matthew L. Chen, Shih-Yin Au, David H. TI Adult Asthma Disease Management: An Analysis of Studies, Approaches, Outcomes, and Methods SO RESPIRATORY CARE LA English DT Review DE asthma; disease management; outcomes; study design; study quality ID GENERAL-PRACTICE; CARE POPULATION; NURSE PRACTICE; MEDICATION USE; HEALTH-CARE; PROGRAM; MORBIDITY; INTERVENTIONS; REGRESSION; EMERGENCY AB BACKGROUND: Disease management has been implemented for patients with asthma in various ways. We describe the approaches to and components of adult asthma disease-management interventions, examine the outcomes evaluated, and assess the quality of published studies. METHODS: We searched the MEDLINE, EMBASE, CINAHL, PsychInfo, and Cochrane databases for studies published in 1986 through 2008, on adult asthma management. With the studies that met our inclusion criteria, we examined the clinical, process, medication, economic, and patient-reported outcomes reported, and the study designs, provider collaboration during the studies, and statistical methods. RESULTS: Twenty-nine articles describing 27 studies satisfied our inclusion criteria. There was great variation in the content, extent of collaboration between physician and non-physician providers responsible for intervention delivery, and outcomes examined across the 27 studies. Because of limitations in the design of 22 of the 27 studies, the differences in outcomes assessed, and the lack of rigorous statistical adjustment, we could not draw definitive conclusions about the effectiveness or cost-effectiveness of the asthma disease-management programs or which approach was most effective. CONCLUSIONS: Few well-designed studies with rigorous evaluations have been conducted to evaluate disease-management interventions for adults with asthma. Current evidence is insufficient to recommend any particular intervention. C1 [Maciejewski, Matthew L.] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC 27701 USA. [Maciejewski, Matthew L.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Maciejewski, Matthew L.] Univ N Carolina, Sch Pharm, Div Pharmaceut Outcomes & Policy, Chapel Hill, NC USA. [Chen, Shih-Yin] Abt Biopharma Solut, Lexington, MA USA. [Au, David H.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Au, David H.] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA. RP Maciejewski, ML (reprint author), Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Legacy Tower,411 W Chapel Hill St, Durham, NC 27701 USA. EM mlm34@duke.edu NR 40 TC 9 Z9 9 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 J9 RESP CARE JI Respir. Care PD JUL PY 2009 VL 54 IS 7 BP 878 EP 886 DI 10.4187/002013209793800385 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 471DX UT WOS:000268036400008 PM 19558739 ER PT J AU Luk, AJ Levin, GP Moore, EE Zhou, XH Kestenbaum, BR Choi, HK AF Luk, Andrew J. Levin, Gregory P. Moore, Elya E. Zhou, Xiao-Hua Kestenbaum, Bryan R. Choi, Hyon K. TI Allopurinol and mortality in hyperuricaemic patients SO RHEUMATOLOGY LA English DT Article DE Allopurinol; Mortality; Hyperuricaemia; Gout ID XANTHINE-OXIDASE INHIBITION; CHRONIC HEART-FAILURE; ENDOTHELIAL DYSFUNCTION; URIC-ACID; CARDIOVASCULAR RISK; HYPERTENSION; GOUT; DISEASE AB Methods. From a population of hyperuricaemic veterans of [serum urate level 416 mol/l (7.0 mg/dl)] at least 40 years of age, we compared the risk of death between incident allopurinol users (n 2483) and non-users (n 7441). We estimated the multivariate mortality hazard ratio (HR) of allopurinol use with Cox proportional hazards models. Results. Of the 9924 veterans (males, 98 and mean age 62.7 years), 1021 died during the follow-up. Patients who began treatment with allopurinol had worse prognostic factors for mortality, including higher BMI and comorbidities. After adjusting for baseline urate levels, allopurinol treatment was associated with a lower risk of all-cause mortality (HR 0.78; 95 CI 0.67, 0.91). Further adjustment with other prognostic factors did not appreciably alter this estimate (HR 0.77; 95 CI 0.65, 0.91). The mean change from baseline in serum urate within the allopurinol group was 111 mol/l (1.86 mg/dl). Adjusting for baseline urate level, allopurinol users had a 40 mol/l (0.68 mg/dl) lower follow-up serum urate value than controls (95 CI 0.55, 0.81). Conclusion. Our findings indicate that allopurinol treatment may provide a survival benefit among patients with hyperuricaemia. C1 [Choi, Hyon K.] Univ British Columbia, Dept Med, Div Rheumatol, Arthrit Res Ctr Canada, Vancouver, BC V5Z 1L7, Canada. [Luk, Andrew J.; Zhou, Xiao-Hua] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Levin, Gregory P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Moore, Elya E.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kestenbaum, Bryan R.] Univ Washington, Dept Med, Seattle, WA USA. RP Choi, HK (reprint author), Univ British Columbia, Dept Med, Div Rheumatol, Arthrit Res Ctr Canada, 895 W 10th Ave, Vancouver, BC V5Z 1L7, Canada. EM hchoi@arthritisresearch.ca FU Takeda Pharmaceuticals North America, Inc FX Supported by a grant from Takeda Pharmaceuticals North America, Inc. NR 18 TC 43 Z9 43 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD JUL PY 2009 VL 48 IS 7 BP 804 EP 806 DI 10.1093/rheumatology/kep069 PG 3 WC Rheumatology SC Rheumatology GA 460XY UT WOS:000267227400018 PM 19447769 ER PT J AU Petrocca, F Lieberman, J AF Petrocca, Fabio Lieberman, Judy TI Micromanipulating cancer microRNA-based therapeutics? SO RNA BIOLOGY LA English DT Review DE cancer; microRNA; RNAi; delivery; therapeutics; oncomir ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CELL-CYCLE ARREST; LET-7 MICRORNA; MIR-200 FAMILY; BREAST-CANCER; IN-VIVO; MESENCHYMAL TRANSITION; REPRESSORS ZEB1; DOWN-REGULATION; MESSENGER-RNAS AB Because microRNAs regulate cancer cell differentiation, proliferation, survival and metastasis, manipulating microRNA function, either by mimicking or inhibiting miRNAs implicated in cancer, could provide a powerful therapeutic strategy to interfere with key pathways for cancer progression. This review will explore some of the opportunities and obstacles to harnessing microRNA biology for cancer therapy. C1 [Lieberman, Judy] Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst,Program Cellular & Mol Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA USA. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst,Program Cellular & Mol Med, Boston, MA 02115 USA. EM lieberman@idi.harvard.edu RI Lieberman, Judy/A-2717-2015 NR 59 TC 20 Z9 20 U1 1 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1547-6286 J9 RNA BIOL JI RNA Biol. PD JUL-AUG PY 2009 VL 6 IS 3 BP 335 EP 340 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545FA UT WOS:000273716700020 PM 19535911 ER PT J AU Goldstein, KE Hazlett, EA New, AS Haznedar, MM Newmark, RE Zelmanova, Y Passarelli, V Weinstein, SR Canfield, EL Meyerson, DA Tang, CY Buchsbaum, MS Siever, LJ AF Goldstein, Kim E. Hazlett, Erin A. New, Antonia S. Haznedar, M. Mehmet Newmark, Randall E. Zelmanova, Yuliya Passarelli, Vincent Weinstein, Shauna R. Canfield, Emily L. Meyerson, David A. Tang, Cheuk Y. Buchsbaum, Monte S. Siever, Larry J. TI Smaller superior temporal gyrus volume specificity in schizotypal personality disorder SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizotypal personality disorder; Borderline personality disorder; Schizophrenia; MRI; Brodmann area 22; Auditory cortex ID VOXEL-BASED MORPHOMETRY; BORDERLINE PERSONALITY; SCHIZOPHRENIA SPECTRUM; BRAIN ABNORMALITIES; MRI ABNORMALITIES; CINGULATE GYRUS; AUDITORY-CORTEX; GRAY-MATTER; AMYGDALA; WOMEN AB Background: Superior temporal gyrus (STG/BA22) volume is reduced in schizophrenia and to a milder degree in schizotypal personality disorder (SPD), representing a less severe disorder in the schizophrenia spectrum. SPD and Borderline personality disorder (BPD) are severe personality disorders characterized by social and cognitive dysfunction. However, while SPD is characterized by social withdrawal/anhedonia, BPD is marked by hyper-reactivity to interpersonal stimuli and hyper-emotionality. This is the first morphometric study to directly compare SPD and BPD patients in temporal lobe volume. Methods: We compared three age-, sex-, and education-matched groups: 27 unmedicated SPD individuals with no BPD traits, 52 unmedicated BPD individuals with no SPD traits, and 45 healthy controls. We examined gray matter volume of frontal and temporal lobe Brodmann areas (BAs), and dorsal/ventral amygdala from 3-T magnetic resonance imaging. Results: In the STG, an auditory association area reported to be dysfunctional in SPD and BPD, the SPD patients had significantly smaller volume than healthy controls and BPD patients. No group differences were found between BPD patients and controls. Smaller BA22 volume was associated with greater symptom severity in SPD patients. Reduced STG volume may be an important endophenotype for schizophrenia-spectrum disorders. SPD is distinct from BPD in terms of STG volume abnormalities which may reflect different underlying pathophysiological mechanisms and could help discriminate between them. (C) 2009 Elsevier B.V. All rights reserved. C1 [Goldstein, Kim E.; Hazlett, Erin A.; New, Antonia S.; Haznedar, M. Mehmet; Newmark, Randall E.; Zelmanova, Yuliya; Passarelli, Vincent; Weinstein, Shauna R.; Canfield, Emily L.; Meyerson, David A.; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [New, Antonia S.; Weinstein, Shauna R.; Siever, Larry J.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [New, Antonia S.; Weinstein, Shauna R.; Siever, Larry J.] MIRECC, Bronx, NY USA. [Tang, Cheuk Y.] Mt Sinai Sch Med, Dept Radiol, New York, NY USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Neurol, San Diego, CA 92103 USA. RP Hazlett, EA (reprint author), Mt Sinai Sch Med, Dept Psychiat, Box 1505, New York, NY 10029 USA. EM erin.hazlett@mssm.edu FU NIMH [MH073911, MH067918]; VA MERIT [7609-28]; National Center for Research Resources (NCRR) [RR-00071]; NIH; Mental Illness Research Education and Clinical Center; VISN 3 Veterans Health Administration FX This work was supported by NIMH grants MH073911 to Dr. Hazlett, MH067918 to Dr. New, and VA MERIT grant 7609-28 to Dr. Siever. Other support came from Grant Number M01 - Patient Care RR-00071 from the National Center for Research Resources (NCRR), a component of the NIH and the Mental Illness Research Education and Clinical Center, VISN 3 Veterans Health Administration. NR 60 TC 29 Z9 29 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2009 VL 112 IS 1-3 BP 14 EP 23 DI 10.1016/j.schres.2009.04.027 PG 10 WC Psychiatry SC Psychiatry GA 472TA UT WOS:000268153900003 PM 19473820 ER PT J AU Noda, SE El-Jawahri, A Patel, D Lautenschlaeger, T Siedow, M Chakravarti, A AF Noda, Shin-ei El-Jawahri, Areej Patel, Disha Lautenschlaeger, Tim Siedow, Michael Chakravarti, Arnab TI Molecular Advances of Brain Tumors in Radiation Oncology SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; FARNESYL TRANSFERASE INHIBITORS; PRIMARY GLIOBLASTOMA-MULTIFORME; RADIOTHERAPY PLUS CONCOMITANT; HISTONE DEACETYLASE INHIBITOR; HUMAN-MALIGNANT GLIOMAS; ADJUVANT TEMOZOLOMIDE; IN-VITRO; GENETIC ALTERATIONS; IONIZING-RADIATION AB Glioblastoma, grade IV malignant glioma based on the World Health Organization classification, is the most common primary brain tumor in adults. The average survival time of less than 1 year has not improved notably over the last 3 decades. Surgery and radiotherapy, the traditional cornerstones of therapy, provide palliative benefit, whereas the value of chemotherapy has been marginal and controversial. The dismal prognosis of glioblastoma patients is largely caused by the striking radioresistance of these tumors. A better understanding of the molecular mechanisms that underlie the malignant phenotype of glioblastomas and plausible mechanisms of radiation resistance can provide new possibilities in terms of targeted therapeutic strategies. Despite the genetic heterogeneity of malignant gliomas, common aberrations in the signaling elements of the growth and survival pathways are found. New treatments have emerged to target molecules in these signaling pathways with the goal to increase specific efficacy and minimize toxicity. Monoclonal antibodies and low molecular-weight kinase inhibitors are the most common classes of agents in targeted cancer treatment. This review introduces these new targeted therapies in the context of current treatment options for patients with glioblastoma. It is hoped that this combined approach will overcome the current limitations in the treatment of patients with glioblastoma and result in a better prognosis for these patients. Semin Radiat Oncol 19:171-178 (C) 2009 Elsevier Inc. All rights reserved. C1 [Chakravarti, Arnab] Ohio State Univ, Dept Radiat Oncol, Sch Med, Columbus, OH 43210 USA. [Noda, Shin-ei; El-Jawahri, Areej; Patel, Disha; Lautenschlaeger, Tim; Siedow, Michael] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Chakravarti, A (reprint author), Ohio State Univ, Dept Radiat Oncol, Sch Med, 300 W 10th Ave,Room 080B, Columbus, OH 43210 USA. EM arnab.chakravarti@osumc.edu FU Ohio State Urnversity-James Cancer Center FX This article is supported by funds from the Ohio State Urnversity-James Cancer Center. NR 86 TC 42 Z9 42 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2009 VL 19 IS 3 BP 171 EP 178 DI 10.1016/j.semradonc.2009.02.005 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 454JF UT WOS:000266677500006 PM 19464632 ER PT J AU Noda, SE Lautenschlaeger, T Siedow, MR Patel, DR El-Jawahri, A Suzuki, Y Loeffler, JS Bussiere, MR Chakravarti, A AF Noda, Shin-ei Lautenschlaeger, Tim Siedow, Michael R. Patel, Disha R. El-Jawahri, Areej Suzuki, Yoshiyuki Loeffler, Jay S. Bussiere, Marc R. Chakravarti, Arnab TI Technological Advances in Radiation Oncology for Central Nervous System Tumors SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID NEUTRON-CAPTURE THERAPY; INTENSITY-MODULATED RADIOTHERAPY; RECURRENT MALIGNANT GLIOMAS; WHOLE-BRAIN RADIOTHERAPY; HIGH-GRADE GLIOMAS; GLIOBLASTOMA-MULTIFORME; STEREOTACTIC RADIOSURGERY; RANDOMIZED-TRIAL; DOSE-ESCALATION; HYPOFRACTIONATED RADIOTHERAPY AB Advances in computer software technology have led to enormous progress that has enabled increasing levels of complexity to be incorporated into radiotherapy treatment planning systems. Because of these changes, the delivery of radiotherapy evolved from therapy designed primarily on plain 2-dimensional X-ray images and hand calculations to therapy based on 3-dimensional images incorporating increasingly complex computer algorithms in the planning process. In addition, challenges in treatment planning and radiation delivery, such as problems with setup error and organ movement, have begun to be systematically addressed, ushering in an era of so-called 4-dimensional radiotherapy. This review article discusses how these advances have changed the way in which many common neoplasms of the central nervous system are being treated at present. Semin Radiat Oncol 19:179-186 (C) 2009 Elsevier Inc. All rights reserved. C1 [Chakravarti, Arnab] Ohio State Univ, Sch Med, Dept Radiat Oncol, Columbus, OH 43210 USA. [Noda, Shin-ei; Lautenschlaeger, Tim; Siedow, Michael R.; Patel, Disha R.; El-Jawahri, Areej; Loeffler, Jay S.; Bussiere, Marc R.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Suzuki, Yoshiyuki] Gunma Univ, Dept Radiat Oncol, Grad Sch Med, Gunma, Japan. RP Chakravarti, A (reprint author), Ohio State Univ, Sch Med, Dept Radiat Oncol, 300W 10th Ave,Room 0808, Columbus, OH 43210 USA. EM arnab.chakravarti@osumc.edu FU Ohio State University-James Cancer Center FX This article is supported by funds from the Ohio State University-James Cancer Center. NR 75 TC 6 Z9 7 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 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2009 VL 19 IS 3 BP 179 EP 186 DI 10.1016/j.semradonc.2009.02.006 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 454JF UT WOS:000266677500007 PM 19464633 ER PT J AU Burns, SM Hough, S Boyd, BL Hill, J AF Burns, Shaun Michael Hough, Sigmund Boyd, Briana L. Hill, Justin TI Sexual Desire and Depression Following Spinal Cord Injury: Masculine Sexual Prowess as a Moderator SO SEX ROLES LA English DT Article DE Gender roles; Masculinity; Mental health; Sexual functioning; Spinal cord injury ID QUALITY-OF-LIFE; ADJUSTMENT FOLLOWING TREATMENT; ERECTILE DYSFUNCTION; PROSTATE-CANCER; MENS ADJUSTMENT; RELATIONSHIP QUESTIONNAIRE; UNMITIGATED AGENCY; SOCIAL SUPPORT; SELF-ESTEEM; SATISFACTION AB Men's adherence to masculine norms stressing sexual prowess may contribute to their adjustment to changes in sexual functioning following spinal cord injury. The authors test this hypothesis by examining the moderating role of men's conformity to gender norms for sexual prowess on the relationship between sexual desire and depression. One hundred and sixteen male citizens of the United States with spinal cord injuries were recruited for participation in the internet-based survey. Results indicated that participants with strong sexual desire evinced higher rates of depression when they conformed to masculine norms emphasizing sexual prowess. Men with little reported sexual desire, by contrast, demonstrated lower rates of depression when they endorsed norms for prowess. Directions for future research and treatment interventions are offered. C1 [Burns, Shaun Michael; Hough, Sigmund; Hill, Justin] Boston Univ, Sch Med, Harvard Univ, VA Boston Healthcare Syst, Boston, MA 02118 USA. [Boyd, Briana L.] Hartford Hosp, Inst Living, Hartford, CT 06115 USA. RP Burns, SM (reprint author), Boston Univ, Sch Med, Harvard Univ, VA Boston Healthcare Syst, Boston, MA 02118 USA. EM shaun.burns@va.gov NR 55 TC 4 Z9 4 U1 3 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-0025 J9 SEX ROLES JI Sex Roles PD JUL PY 2009 VL 61 IS 1-2 BP 120 EP 129 DI 10.1007/s11199-009-9615-7 PG 10 WC Psychology, Developmental; Psychology, Social; Women's Studies SC Psychology; Women's Studies GA 460XC UT WOS:000267224000010 ER PT J AU Vartanians, VM Karchmer, AW Giurini, JM Rosenthal, DI AF Vartanians, Vartan M. Karchmer, Adolf W. Giurini, John M. Rosenthal, Daniel I. TI Is there a role for imaging in the management of patients with diabetic foot? SO SKELETAL RADIOLOGY LA English DT Article ID CHRONIC OSTEOMYELITIS; DIAGNOSIS; SCINTIGRAPHY; METAANALYSIS; INFECTIONS; ULCERS; BONE; MRI; ABNORMALITIES; ACCURACY C1 [Vartanians, Vartan M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Karchmer, Adolf W.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Giurini, John M.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Podiatr Surg, Boston, MA 02215 USA. [Rosenthal, Daniel I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Vartanians, VM (reprint author), Massachusetts Gen Hosp, Dept Radiol, 25 New Chardon St,Suite 427-B, Boston, MA 02114 USA. EM vvartanians@partners.org NR 27 TC 9 Z9 9 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 JUL PY 2009 VL 38 IS 7 BP 633 EP 636 DI 10.1007/s00256-009-0663-4 PG 4 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 450IT UT WOS:000266394900001 PM 19241076 ER PT J AU Thomas, RJ Weiss, MD Mietus, JE Peng, CK Goldberger, AL Gottlieb, DJ AF Thomas, Robert Joseph Weiss, Matthew D. Mietus, Joseph E. Peng, Chung-Kang Goldberger, Ary L. Gottlieb, Daniel J. TI Prevalent Hypertension and Stroke in the Sleep Heart Health Study: Association with an ECG-derived Spectrographic Marker of Cardiopulmonary Coupling SO SLEEP LA English DT Article DE ECG; cardiopulmonary coupling; Sleep Heart Health Study; sleep spectrogram; hypertension stroke ID CHEMICAL CONTROL STABILITY; UPPER AIRWAY MECHANICS; APNEA; INSTABILITY; RESPIRATION; BYPASS AB Study Objectives: The electrocardiogram (ECG)-based sleep spectrogram generates a map of cardiopulmonary coupling based on heart rate variability and respiration derived from QRS amplitude variations. A distinct spectrographic phenotype, designated as narrow-band elevated low frequency coupling (e-LFC(NB)), has been associated with central apneas and periodic breathing and predicts sleep laboratory failure of continuous positive airway pressure therapy. This study assesses, at a population level, the associations of this spectrographic biomarker with prevalent cardiovascular disease using the Sleep Heart Health Study (SHHS)-I dataset. Design: Retrospective analysis of the Sleep Heart Health Study-I dataset. Setting: Laboratory for complex physiologic signals analysis. Measurements and Results: The fully-automated ECG-derived sleep spectrogram technique was applied to 5247 (of the original 6441) polysomnograms from the SHHS-I. Associations were estimated with use of various drugs and pathologies including prevalent hypertension and cardiovascular and cerebrovascular disease. Increasing with age and more common in males, e-LFC(NB) is also associated with greater severity of sleep apnea and fragmented sleep. After adjustment for potential confounders, an independent association with prevalent hypertension and stroke was found. Conclusions: An ECG-derived spectrographic marker related to low frequency cardiopulmonary coupling is associated with greater sleep apnea severity. Whether this biomarker is solely a sign of more severe disease or whether it reflects primary alterations in sleep apnea pathophysiology (which may either cause or result from sleep apnea) is unknown. This ECG-based spectral marker is associated with a higher prevalence of hypertension and stroke. C1 [Thomas, Robert Joseph] Beth Israel Deaconess Med Ctr, Pulm Off, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA. [Mietus, Joseph E.; Peng, Chung-Kang; Goldberger, Ary L.] Beth Israel Deaconess Med Ctr, Div Interdisciplinary Med & Biotechnol, Boston, MA 02215 USA. [Gottlieb, Daniel J.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, W Roxbury, MA USA. RP Thomas, RJ (reprint author), Beth Israel Deaconess Med Ctr, Pulm Off, Div Pulm Crit Care & Sleep Med, KB 023, Boston, MA 02215 USA. EM rthomas1@bidmc.harvard.edu RI Peng, Chung-Kang/E-1489-2011 OI Peng, Chung-Kang/0000-0003-3666-9833 FU National Heart, Lung and Blood Institute [R-21 HL079248]; Periodic Breathing Foundation; G. Harold and Leila Y. Mathers Foundation; James S. McDonnell Foundation; NIH [UOIEB008577]; Wyss Institute FX This work was supported in part by the grants from the National Heart, Lung and Blood Institute R-21 HL079248 (RJT), the Periodic Breathing Foundation, and following to ALG: G. Harold and Leila Y. Mathers Foundation, the James S. McDonnell Foundation, the NIH-sponsored Research Resource for Complex Physiologic Signals (UOIEB008577), and the Wyss Institute for Biologically Inspired Engineering. NR 24 TC 23 Z9 25 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 JUL 1 PY 2009 VL 32 IS 7 BP 897 EP 904 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 472JG UT WOS:000268126000009 PM 19639752 ER PT J AU Prasad, A Cevallos, ME Riosa, S Darouiche, RO Trautner, BW AF Prasad, A. Cevallos, M. E. Riosa, S. Darouiche, R. O. Trautner, B. W. TI A bacterial interference strategy for prevention of UTI in persons practicing intermittent catheterization SO SPINAL CORD LA English DT Article DE urinary tract infection; spinal cord injury; Escherichia coli ID BLADDER MANAGEMENT; URETHRAL CATHETERS; URINARY CATHETERS; ESCHERICHIA-COLI; PILOT TRIAL; COLONIZATION; INFECTION; ADHERENCE AB Study design: Non-randomized pilot trial. Objectives: To determine whether Escherichia coli 83972-coated urinary catheters in persons with spinal cord injury (SCI) practicing an intermittent catheterization program (ICP) could (1) achieve bladder colonization with this benign organism and (2) decrease the rate of symptomatic urinary tract infection (UTI). Setting: Outpatient SCI clinic in a Veterans Affairs hospital (USA). Methods: Participants had neurogenic bladders secondary to SCI, were practicing ICP, had experienced at least one UTI and had documented bacteruria within the past year. All participants received a urinary catheter that had been pre-inoculated with E. coli 83972. The catheter was left in place for 3 days and then removed. Participants were followed with urine cultures and telephone calls weekly for 28 days and then monthly until E. coli 83972 was lost from the urine. Outcome measures were (1) the rate of successful bladder colonization, defined as the detection (>= 10(2) cfu ml(-1)) of E. coli 83972 in urine cultures for >3 days after catheter removal and (2) the rate of symptomatic UTI during colonization with E. coli 83972. Results: Thirteen participants underwent 19 insertions of study catheters. Eight participants (62%) became successfully colonized for 43 days after catheter removal. In these 8 participants, the rate of UTI during colonization was 0.77 per patient-year, in comparison with the rate of 2.27 UTI per patient-year before enrollment. Conclusions: E. coli 83972-coated urinary catheters are a viable means of achieving bladder colonization with this potentially protective strain in persons practicing ICP. Spinal Cord (2009) 47, 565-569; doi: 10.1038/sc.2008.166; published online 13 January 2009 C1 [Cevallos, M. E.; Riosa, S.; Darouiche, R. O.; Trautner, B. W.] Baylor Coll Med, Dept Med, Div Infect Dis, Houston, TX 77030 USA. [Prasad, A.] New York Med Coll, Westchester Med Ctr, Dept Internal Med, Westchester, NY USA. [Cevallos, M. E.; Riosa, S.; Darouiche, R. O.; Trautner, B. W.] Baylor Coll Med, Ctr Prosthesis Infect, Dept Phys Med & Rehabil, Houston, TX 77030 USA. [Darouiche, R. O.; Trautner, B. W.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Trautner, BW (reprint author), Baylor Coll Med, Dept Med, Div Infect Dis, 1 Baylor Plaza,BCM 286,N1319, Houston, TX 77030 USA. EM trautner@bcm.edu FU Department of Veterans Affairs Rehabilitation Research and Development Service [B4623R, B4087R, B4387P]; NIH [HD42014, DK77313] FX This study was supported by Department of Veterans Affairs Rehabilitation Research and Development Service grants B4623R, B4087R and B4387P as well as by NIH grants HD42014 and DK77313. NR 20 TC 17 Z9 18 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD JUL PY 2009 VL 47 IS 7 BP 565 EP 569 DI 10.1038/sc.2008.166 PG 5 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 465QV UT WOS:000267602800011 PM 19139758 ER PT J AU Li, Y Tang, HC Lin, XH AF Li, Yi Tang, Haicheng Lin, Xihong TI SPATIAL LINEAR MIXED MODELS WITH COVARIATE MEASUREMENT ERRORS SO STATISTICA SINICA LA English DT Article DE Asymptotic bias; consistency and asymptotic normality; EM algorithmMeasurement error; increasing domain asymptotics; spatial data; structural modeling; variance components ID DISEASE RATES; REGRESSION AB Spatial data with covariate measurement errors have been commonly observed in public health studies. Existing work mainly concentrates on parameter estimation using Gibbs sampling, and no work has been conducted to understand and quantify the theoretical impact of ignoring measurement error on spatial data analysis in the form of the asymptotic biases in regression coefficients and variance components when measurement error is ignored. Plausible implementations, from frequentist perspectives, of maximum likelihood estimation in spatial covariate measurement error models are also elusive. In this paper, we propose a new class of linear mixed models for spatial data in the presence of covariate measurement errors. We show that the naive estimators of the regression coefficients are attenuated while the naive estimators of the variance components are inflated, if measurement error is ignored. We further develop a structural modeling approach to obtaining the maximum likelihood estimator by accounting for the measurement error. We study the large sample properties of the proposed maximum likelihood estimator, and propose an EM algorithm to draw inference. All the asymptotic properties are shown tinder the increasing-domain asymptotic framework. We illustrate the method by analyzing the Scottish lip cancer data, and evaluate its performance through a simulation study, all of which elucidate the importance of adjusting for covariate measurement errors. C1 [Li, Yi] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Yi; Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Tang, Haicheng] Amer Express, New York, NY 10285 USA. RP Li, Y (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 44 Binney St, Boston, MA 02115 USA. EM yili@hsph.harvard.edu; haicheng.k.tang@aexp.com; xlin@hsph.harvard.edu FU NCI NIH HHS [R37 CA076404, P01 CA134294-01, P01 CA134294, R37 CA076404-12] NR 22 TC 8 Z9 8 U1 0 U2 2 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD JUL PY 2009 VL 19 IS 3 BP 1077 EP 1093 PG 17 WC Statistics & Probability SC Mathematics GA 465SY UT WOS:000267608900011 PM 20046975 ER PT J AU Lee, HJ Teixeira, J AF Lee, Ho-Joon Teixeira, Jose TI Parthenogenesis in Human Oocytes that Were Collected From Resected Ovarian Tissue and Matured In Vitro SO STEM CELLS AND DEVELOPMENT LA English DT Article ID STEM-CELL LINES; MULLERIAN-INHIBITING SUBSTANCE; MOUSE OVARY; MATURATION; BLASTOCYSTS; DERIVATION; HORMONE; CULTURE; CRYOPRESERVATION; ESTABLISHMENT AB Currently, a major hurdle in the progress of human embryonic stem (hES) cell research is the lack of human oocytes with which to perform experiments. The collection process is a logistical and ethical challenge and usually involves the use of excess oocytes donated after assisted reproduction procedures. We collected resected human ovarian tissue after routine surgical procedures. Oocytes were isolated from the tissue and matured in vitro to the meiosis II (MII) stage, when the first polar body is extruded. With the large antral and smaller preantral follicles, the efficiencies of the maturation were nearly 50% and 25%, respectively. The quality of the matured oocytes was assessed by inducing parthenogenesis and > 50% of the in vitro matured oocytes were competent enough to develop pronuclei and 33% developed at least to the two-cell stage 48 h after activation. Parthenotes continued to develop by 72 h but with significant blastomere fragmentation. These results provide evidence that resected ovarian tissue, which is normally discarded, may be a suitable alternative source for oocytes in hES cell research. C1 Massachusetts Gen Hosp, Vincent Mem Hosp, Dept Obstet Gynecol & Reprod, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Teixeira, J (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol Thier 913, 55 Fruit St, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064 NR 34 TC 2 Z9 2 U1 0 U2 15 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUL PY 2009 VL 18 IS 6 BP 941 EP 946 DI 10.1089/scd.2009.0004 PG 6 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 464ET UT WOS:000267488800014 PM 19249941 ER PT J AU Romero, JR Frey, JL Schwamm, LH Demaerschalk, BM Chaliki, HP Parikh, G Burke, RF Babikian, VL AF Romero, Jose R. Frey, James L. Schwamm, Lee H. Demaerschalk, Bart M. Chaliki, Hari P. Parikh, Gunjan Burke, Robert F. Babikian, Viken L. TI Cerebral Ischemic Events Associated With 'Bubble Study' for Identification of Right to Left Shunts SO STROKE LA English DT Article DE atrial heart septal defects; arteriovenous fistula; echocardiography; patent foramen ovale; stroke; transcranial Doppler ultrasonography; transesophageal echocardiography; transient ischemic attack ID CONTRAST ECHOCARDIOGRAPHY; AIR-EMBOLISM; STROKE; COMMITTEE AB Background and Purpose-Detection of an intracardiac shunt is frequently sought during the evaluation of patients with cryptogenic ischemic stroke and agitated saline intravenous injection, or "bubble study" (BS), is performed in most cases. We present the first attempt to identify the clinical features in patients who had cerebral ischemic events with BS. Methods-Using a list serve established by the American Academy of Neurology, a member posted a question regarding the safety of BS in patients with patent foramen ovale. A standardized questionnaire was used to gather data about patients with cerebral ischemic events, details of each case were reviewed, and the findings pooled. Results-Five patients with ischemic complications of BS (all female, aged 42 to 90 years) were identified from 4 institutions, 3 ischemic strokes and 2 transient ischemic attacks. Events occurred either during or within 5 minutes of BS. Early brain MRIs confirmed acute infarction in 3, including one who had transient symptoms. MRI infarct volumes were small, and deficits were mild in those who developed stroke. Diagnostic evaluation revealed a patent foramen ovale alone in one case, a pulmonary arteriovenous malformation in one case, and a patent foramen ovale and/or pulmonary shunt in 3 cases. Conclusions-Ischemic cerebrovascular complications can occur in patients who undergo BS and are associated with the presence of cardiac or pulmonary shunts. The true incidence and degree of disability remains unknown, and further study is indicated to assess the impact of technical differences in BS methodology. Novel methods to promote physician communication such as the use of electronic list serves may reduce barriers to reporting of drug, technique, or device complications and should be explored to identify rare complications that otherwise will likely go unappreciated. (Stroke. 2009; 40: 2343-2348.) C1 [Romero, Jose R.; Babikian, Viken L.] Boston Univ, Dept Neurol, Sch Med, Med Ctr, Boston, MA 02118 USA. [Romero, Jose R.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Frey, James L.; Parikh, Gunjan] Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA. [Schwamm, Lee H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Demaerschalk, Bart M.] Mayo Clin Hosp, Dept Neurol, Phoenix, AZ USA. [Chaliki, Hari P.; Burke, Robert F.] Mayo Clin, Dept Cardiol, Scottsdale, AZ USA. RP Romero, JR (reprint author), Boston Univ, Dept Neurol, Sch Med, Med Ctr, 72 E Concord St,C-329, Boston, MA 02118 USA. EM joromero@bmc.org OI Schwamm, Lee/0000-0003-0592-9145 FU St Jude Medical; RESPECT Trial; AGA FX J.L.F. is on the speakers bureaus for Bristol Myers Squibb, EKT Pharma, Genentech, and Sanofi-Aventis. B. M. D. is the ESCAPE Trial site principal investigator sponsored by St Jude Medical and the RESPECT Trial site principal investigator sponsored by AGA. V. L. B. is a consultant for Boston Scientific and is on the speakers Bureau for Boehringer Ingelheim. NR 16 TC 34 Z9 36 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 JUL PY 2009 VL 40 IS 7 BP 2343 EP 2348 DI 10.1161/STROKEAHA.109.549683 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 463XR UT WOS:000267467900010 PM 19498192 ER PT J AU Greenberg, SM Nandigam, RNK Delgado, P Betensky, RA Rosand, J Viswanathan, A Frosch, MP Smith, EE AF Greenberg, Steven M. Nandigam, R. N. Kaveer Delgado, Pilar Betensky, Rebecca A. Rosand, Jonathan Viswanathan, Anand Frosch, Matthew P. Smith, Eric E. TI Microbleeds Versus Macrobleeds Evidence for Distinct Entities SO STROKE LA English DT Article DE cerebral amyloid angiopathy; intracerebral hemorrhage; microbleeds ID CEREBRAL AMYLOID ANGIOPATHY; INTRACEREBRAL HEMORRHAGE; ISCHEMIC-STROKE; RISK-FACTORS; ECHO MRI; PREVALENCE; CADASIL; ASSOCIATIONS; VALIDATION; DEMENTIA AB Background and Purpose-Small, asymptomatic microbleeds commonly accompany larger symptomatic macrobleeds. It is unclear whether microbleeds and macrobleeds represent arbitrary categories within a single continuum versus truly distinct events with separate pathophysiologies. Methods-We performed 2 complementary retrospective analyses. In a radiographic analysis, we measured and plotted the volumes of all hemorrhagic lesions detected by gradient-echo MRI among 46 consecutive patients with symptomatic primary lobar intracerebral hemorrhage diagnosed as probable or possible cerebral amyloid angiopathy. In a second neuropathologic analysis, we performed blinded qualitative and quantitative examinations of amyloid-positive vessel segments in 6 autopsied subjects whose MRI scans demonstrated particularly high microbleed counts (>50 microbleeds on MRI, n=3) or low microbleed counts (<3 microbleeds, n=3). Results-Plotted on a logarithmic scale, the volumes of 163 hemorrhagic lesions identified on scans from the 46 subjects fell in a distinctly bimodal distribution with mean volumes for the 2 modes of 0.009 cm(3) and 27.5 cm3. The optimal cut point for separating the 2 peaks (determined by receiver operating characteristics) corresponded to a lesion diameter of 0.57 cm. On neuropathologic analysis, the high microbleed-count autopsied subjects showed significantly thicker amyloid-positive vessel walls than the low microbleed-count subjects (proportional wall thickness 0.53 +/- 0.01 versus 0.37 +/- 0.01; P<0.0001; n=333 vessel segments analyzed). Conclusions-These findings suggest that cerebral amyloid angiopathy-associated microbleeds and macrobleeds comprise distinct entities. Increased vessel wall thickness may predispose to formation of microbleeds relative to macrobleeds. (Stroke. 2009; 40: 2382-2386.) C1 [Greenberg, Steven M.; Nandigam, R. N. Kaveer; Delgado, Pilar; Rosand, Jonathan; Viswanathan, Anand; Smith, Eric E.] Massachusetts Gen Hosp, Dept Neurol, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Greenberg, SM (reprint author), MGH Stroke Res Ctr, 55 Fruit St,CPZ 175,Suite 300, Boston, MA 02114 USA. EM sgreenberg@partners.org RI Smith, Eric/C-5443-2012 OI Smith, Eric/0000-0003-3956-1668 FU NCI NIH HHS [R29 CA075971]; NIA NIH HHS [P50 AG005134, R01 AG026484, R01 AG026484-04]; NINDS NIH HHS [K24 NS056207, K24 NS056207-03, T32 NS048005] NR 24 TC 72 Z9 79 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 JUL PY 2009 VL 40 IS 7 BP 2382 EP 2386 DI 10.1161/STROKEAHA.109.548974 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 463XR UT WOS:000267467900016 PM 19443797 ER PT J AU Oleinik, A Romero, JM Schwab, K Lev, MH Jhawar, N Almandoz, JED Smith, EE Greenberg, SM Rosand, J Goldstein, JN AF Oleinik, Alexandra Romero, Javier M. Schwab, Kristin Lev, Michael H. Jhawar, Nupur Almandoz, Josser E. Delgado Smith, Eric E. Greenberg, Steven M. Rosand, Jonathan Goldstein, Joshua N. TI CT Angiography for Intracerebral Hemorrhage Does Not Increase Risk of Acute Nephropathy SO STROKE LA English DT Article DE cerebral hemorrhage; tomography; X-ray computed; contrast media ID CONTRAST-INDUCED NEPHROPATHY; PREDICTS HEMATOMA EXPANSION; ACUTE STROKE; TOMOGRAPHY ANGIOGRAPHY; COMPUTED-TOMOGRAPHY; SAFETY; TRIAL; EXTRAVASATION; PERFUSION; WARFARIN AB Background and Purpose-CT angiography (CTA) is receiving increased attention in intracerebral hemorrhage (ICH) for its role in ruling out vascular abnormalities and potentially predicting ongoing bleeding. Its use is limited by the concern for contrast induced nephropathy (CIN); however, the magnitude of this risk is not known. Methods-We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with ICH presenting to a single tertiary care hospital from 2002 to 2007. Demographic, clinical, and radiographic data were prospectively collected for all patients. Laboratory data and clinical course over the first 48 hours were retrospectively reviewed. Acute nephropathy was defined as any rise in creatinine of >25% or >0.5 mg/dL, such that the highest creatinine value was above 1.5 mg/dL. Results-539 patients presented during the study period and had at least 2 creatinine measurements. 348 (65%) received a CTA. Acute nephropathy developed in 6% of patients who received a CTA and in 10% of those who did not (P=0.1). Risk of nephropathy was 14% in those receiving no contrast (130 patients), 5% in those receiving 1 contrast study (124 patients), and 6% in those receiving >1 contrast study (244 patients). Neither CTA nor any use of contrast predicted nephropathy in univariate or multivariate analysis. Conclusion-The risk of acute nephropathy after ICH was not increased by use of CTA. Studies of CIN that do not include a control group may overestimate the influence of contrast. Patients with ICH appear to have an 8% risk of developing "Hospital-Acquired Nephropathy." (Stroke. 2009; 40: 2393-2397.) C1 [Jhawar, Nupur; Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Oleinik, Alexandra; Schwab, Kristin; Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Romero, Javier M.; Lev, Michael H.; Almandoz, Josser E. Delgado] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary Stroke Program, Calgary, AB T2N 1N4, Canada. RP Goldstein, JN (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM jgoldstein@partners.org RI Smith, Eric/C-5443-2012; Goldstein, Joshua/H-8953-2016 OI Smith, Eric/0000-0003-3956-1668; FU National Institute of Neurological Disorders and Stroke [NIH R01NS059727]; Deane Institute for Integrative Study of Atrial Fibrillation and Stroke FX This work was supported by a grant from the National Institute of Neurological Disorders and Stroke (NIH R01NS059727), an American Heart Association Grant-in-Aid Award, and the Deane Institute for Integrative Study of Atrial Fibrillation and Stroke. NR 31 TC 41 Z9 42 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2009 VL 40 IS 7 BP 2393 EP 2397 DI 10.1161/STROKEAHA.108.546127 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 463XR UT WOS:000267467900018 PM 19461032 ER PT J AU Saver, JL Gornbein, J Grotta, J Liebeskind, D Lutsep, H Schwamm, L Scott, P Starkman, S AF Saver, Jeffrey L. Gornbein, Jeffrey Grotta, James Liebeskind, David Lutsep, Helmi Schwamm, Lee Scott, Phillip Starkman, Sidney TI Number Needed to Treat to Benefit and to Harm for Intravenous Tissue Plasminogen Activator Therapy in the 3-to 4.5-Hour Window SO STROKE LA English DT Article DE cerebral infarction; clinical trial; fibrinolysis; ischemic stroke; thrombolysis ID ACUTE ISCHEMIC-STROKE; QUALITY-OF-LIFE; RT-PA STROKE; ENTIRE RANGE; THROMBOLYTIC THERAPY; TRIALS; DISABILITY; DERIVATION; SHIFTS; TIME AB Background and Purpose-Measures of a therapy's effect size are important guides to clinicians, patients, and policy-makers on treatment decisions in clinical practice. The ECASS 3 trial demonstrated a statistically significant benefit of intravenous tissue plasminogen activator for acute cerebral ischemia in the 3- to 4.5-hour window, but an effect size estimate incorporating benefit and harm across all levels of poststroke disability has not previously been derived. Methods-Joint outcome table specification was used to derive number needed to treat to benefit (NNTB) and number needed to treat to harm (NNTH) values summarizing treatment impact over the entire outcome range on the modified Rankin scale of global disability, including both expert-dependent and expert-independent (algorithmic and repeated random sampling) array generation. Results-For the full 7-category modified Rankin scale, algorithmic analysis demonstrated that the NNTB for 1 additional patient to have a better outcome by >= 1 grades than with placebo must lie between 4.0 and 13.0. In bootstrap simulations, the mean NNTB was 7.1. Expert joint outcome table analyses indicated that the NNTB for improved final outcome was 6.1 (95% CI, 5.6-6.7) and the NNTH 37.5 (95% CI, 34.6-40.5). Benefit per 100 patients treated was 16.3 and harm per 100 was 2.7. The likelihood of help to harm ratio was 6.0. Conclusions-Treatment with tissue plasminogen activator in the 3- to 4.5-hour window confers benefit on approximately half as many patients as treatment <3 hours, with no increase in the conferral of harm. Approximately 1 in 6 patients has a better and 1 in 35 has a worse outcome as a result of therapy. (Stroke. 2009; 40: 2433-2437.) C1 [Saver, Jeffrey L.; Liebeskind, David; Starkman, Sidney] Univ Calif Los Angeles, David Geffen Sch Med, Stroke Ctr, Los Angeles, CA 90095 USA. [Saver, Jeffrey L.; Liebeskind, David; Starkman, Sidney] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Gornbein, Jeffrey] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Starkman, Sidney] Univ Calif Los Angeles, David Geffen Sch Med, Dept Emergency Med, Los Angeles, CA 90095 USA. [Grotta, James] Univ Texas Houston, Dept Neurol, Sch Med, Houston, TX USA. [Lutsep, Helmi] Oregon Hlth & Sci Univ, Oregon Stroke Ctr, Portland, OR 97201 USA. [Schwamm, Lee] Massachusetts Gen Hosp, Div Neurol, Boston, MA 02114 USA. [Scott, Phillip] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. RP Saver, JL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Stroke Ctr, 710 Westwood Plaza, Los Angeles, CA 90095 USA. EM jsaver@ucla.edu FU NIH-NINDS Awards [U01 NS 44364, P50 NS044378] FX This work was supported in part by NIH-NINDS Awards NIH-NINDS U01 NS 44364 and NIH-NINDS P50 NS044378. NR 22 TC 55 Z9 56 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2009 VL 40 IS 7 BP 2433 EP 2437 DI 10.1161/STROKEAHA.108.543561 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 463XR UT WOS:000267467900025 PM 19498197 ER PT J AU Subramanian, S Zhang, B Kosaka, Y Burrows, GG Grafe, MR Vandenbark, AA Hurn, PD Offner, H AF Subramanian, Sandhya Zhang, Bing Kosaka, Yasuharu Burrows, Gregory G. Grafe, Marjorie R. Vandenbark, Arthur A. Hurn, Patricia D. Offner, Halina TI Recombinant T Cell Receptor Ligand Treats Experimental Stroke SO STROKE LA English DT Article DE autoreactive T cells; immunotherapy; recombinant TCR ligands; stroke ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ISCHEMIC-STROKE; MULTIPLE-SCLEROSIS; TRANSGENIC MICE; ACTIVATION; INJURY; LYMPHOCYTES; SYSTEM; ASSOCIATION; INDUCTION AB Background and Purpose-Experimental stroke induces a biphasic effect on the immune response that involves early activation of peripheral leukocytes followed by severe immunodepression and atrophy of the spleen and thymus. In tandem, the developing infarct is exacerbated by influx of numerous inflammatory cell types, including T and B lymphocytes. These features of stroke prompted our use of recombinant T cell receptor ligands (RTL), partial major histocompatibility complex Class II molecules covalently bound to myelin peptides. We tested the hypothesis that RTL would improve ischemic outcome in the brain without exacerbating defects in the peripheral immune system function. Methods-Four daily doses of RTL were administered subcutaneously to C57BL/6 mice after middle cerebral artery occlusion, and lesion size and cellular composition were assessed in the brain and cell numbers were assessed in the spleen and thymus. Results-Treatment with RTL551 (I-A(b) molecule linked to MOG-35-55 peptide) reduced cortical and total stroke lesion size by approximately 50%, inhibited the accumulation of inflammatory cells, particularly macrophages/activated microglial cells and dendritic cells, and mitigated splenic atrophy. Treatment with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide) similarly reduced the stroke lesion size in HLA-DR2 transgenic mice. In contrast, control RTL with a nonneuroantigen peptide or a mismatched major histocompatibility complex Class II moiety had no effect on stroke lesion size. Conclusions-These data are the first to demonstrate successful treatment of experimental stroke using a neuroantigen-specific immunomodulatory agent administered after ischemia, suggesting therapeutic potential in human stroke. (Stroke. 2009; 40: 2539-2545.) C1 [Subramanian, Sandhya; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Vet Affairs Med Ctr, Portland, OR 97201 USA. [Zhang, Bing; Kosaka, Yasuharu; Grafe, Marjorie R.; Hurn, Patricia D.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA. [Burrows, Gregory G.; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Grafe, Marjorie R.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. RP Offner, H (reprint author), Portland VA Med Ctr, R&D 31,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU US Public Health Service National Institutes of Health [NS33668, NRO3521, NS49210, AI43960, NS47661]; National Multiple Sclerosis Society [RG379-A-4]; The Nancy Davis Center Without Walls; Biomedical Laboratory R&D Service, Department of Veterans' Affairs FX This work was supported by US Public Health Service National Institutes of Health grants NS33668, NRO3521, NS49210, AI43960, and NS47661; National Multiple Sclerosis Society grant RG379-A-4; The Nancy Davis Center Without Walls; and the Biomedical Laboratory R&D Service, Department of Veterans' Affairs. NR 34 TC 46 Z9 49 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2009 VL 40 IS 7 BP 2539 EP 2545 DI 10.1161/STROKEAHA.108.543991 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 463XR UT WOS:000267467900041 PM 19443805 ER PT J AU Smith, EE Greenberg, SM AF Smith, Eric E. Greenberg, Steven M. TI beta-Amyloid, Blood Vessels, and Brain Function SO STROKE LA English DT Review DE Alzheimer disease; cerebral amyloid angiopathy; vascular cognitive impairment ID LOBAR INTRACEREBRAL HEMORRHAGE; ALZHEIMERS-DISEASE PATHOLOGY; TRANSGENIC MOUSE MODEL; PITTSBURGH COMPOUND-B; WHITE-MATTER LESIONS; SMOOTH-MUSCLE-CELLS; PRECURSOR PROTEIN; COGNITIVE IMPAIRMENT; A-BETA; CEREBROVASCULAR DYSFUNCTION AB Cerebrovascular disease and Alzheimer disease are common diseases of aging and frequently coexist in the same brain. Accumulating evidence suggests that the presence of brain infarction, including silent infarction, influences the course of Alzheimer disease. Conversely, there is evidence that beta-amyloid can impair blood vessel function. Vascular beta-amyloid deposition, also known as cerebral amyloid angiopathy, is associated with vascular dysfunction in animal and human studies. Alzheimer disease is associated with morphological changes in capillary networks, and soluble beta-amyloid produces abnormal vascular responses to physiological and pharmacological stimuli. In this review, we discuss current evidence linking beta-amyloid metabolism with vascular function and morphological changes in animals and humans. (Stroke. 2009; 40: 2601-2606.) C1 [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Div Neurol, Calgary, AB, Canada. [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. RP Greenberg, SM (reprint author), Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM sgreenberg@partners.org OI Smith, Eric/0000-0003-3956-1668 FU National Institute of Neurological Disorders and Stroke [R01 NS062028, K24 NS056207, R01 NS042147]; Canadian Stroke Network; National Institute of Aging [R01 AG026484, R01 AG021084]; Alzheimer's Association FX E. E. S. has received funding from the National Institute of Neurological Disorders and Stroke ( R01 NS062028) and the Canadian Stroke Network. S. M. G. has received funding from the National Institute of Neurological Disorders and Stroke ( K24 NS056207, R01 NS042147), National Institute of Aging ( R01 AG026484, R01 AG021084), and the Alzheimer's Association. NR 72 TC 119 Z9 123 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2009 VL 40 IS 7 BP 2601 EP 2606 DI 10.1161/STROKEAHA.108.536839 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 463XR UT WOS:000267467900057 PM 19443808 ER PT J AU Kvale, EA Murthy, R Taylor, R Lee, JY Nabors, LB AF Kvale, Elizabeth A. Murthy, Rashmi Taylor, Richard Lee, Jeannette Y. Nabors, L. B. TI Distress and quality of life in primary high-grade brain tumor patients SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Glioblastoma multiforme; Brain tumor; Quality of life; Distress ID FUNCTIONAL OUTCOMES; CANCER-PATIENTS; GLIOMAS; ADULTS; SCALE; DETERMINANTS; RECOGNITION; DEPRESSION; SURVIVAL; THERAPY AB We report on the routine use of the NCCN Distress Thermometer and the Functional Assessment of Cancer Therapy-Brain (FACT-Br) to assess patient distress and quality of life in GBM patients. The purpose of this study was to examine the relationship between patient quality of life and distress. Data from 50 GBM patients presenting to a neuro-oncology clinic were evaluated. Descriptive statistics and correlations between the distress score and the FACT-Br subscale scores were generated. The mean distress score was 2.15 (std 2.66), and 28.9% of brain tumor patients identified a distress score of 4 or above. The mean FACT-Br total was 127.34 (std 21.29), with patients scoring lowest in the EWB (18.95 std 4.4) and FWB (15.06 std 6.80) subscales. No differences between demographic groups were identified with regard to distress or quality of life. Statistically significant correlations were identified between the distress score and the SWB (R = -0.46, P = 0.001) and EWB (R = -0.56, P = 0.001) subscales of the FACT-Br. Fifty percent of participants who did not complete the FACT-Br reported clinically significant distress, but this did not differ significantly from participants who completed it. Assessment of distress in brain tumor patients provides clinically relevant information and suggests interventions that may support quality of life. Further research is needed to explore the relationship between distress and quality of life. Current approaches to measuring quality of life in brain tumor patients may systematically undersample patients with advanced illness or significant psychosocial distress. C1 [Kvale, Elizabeth A.] Univ Alabama, Birmingham VA Med Ctr, Birmingham, AL USA. [Murthy, Rashmi] Baylor Coll Med, Houston, TX 77030 USA. [Lee, Jeannette Y.] Univ Arkansas Med Sci, Fayetteville, AR USA. RP Kvale, EA (reprint author), Univ Alabama, Birmingham VA Med Ctr, Birmingham, AL USA. EM ekvale@aging.uab.edu NR 25 TC 24 Z9 24 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUL PY 2009 VL 17 IS 7 BP 793 EP 799 DI 10.1007/s00520-008-0551-9 PG 7 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 456FK UT WOS:000266827000006 PM 19421789 ER PT J AU Serebruany, VL Kogushi, M Dastros-Pitei, D Flather, M Bhatt, DL AF Serebruany, Victor L. Kogushi, Motoji Dastros-Pitei, Daniela Flather, Marcus Bhatt, Deepak L. TI The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE E5555; PAR-1; thrombin receptor antagonists; platelets; aspirin; clopidogrel; in vitro; coronary artery disease ID ACUTE MYOCARDIAL-INFARCTION; THROMBIN RECEPTOR; CLOPIDOGREL; RESISTANCE; ASPIRIN AB E5555 is a potent protease-activated receptor (PAR-1) antagonist targeting the G-coupled receptor and modulating thrombinplatelet-endothelial interactions. The drug is currently being tested in phase 11 trials in patients with coronary artery disease (CAD) and has potential antithrombotic and anti-inflammatory benefits. We investigated the in-vitro effects of E5555 on platelet function beyond PAR-1 blockade in healthy volunteers and CAD patients treated with aspirin (ASA) with or without clopidogrel. Conventional aggregation induced by 5 mu M ADP, 1 mu g/ml collagen, 10 mu M TRAP, whole blood aggregation with 1 mu g/ml collagen, and expression of 14 intact, and TRAP-stimulated receptors by flow cytometry were utilised to assess platelet activity after preincubation with escalating concentrations of E5555 (20 ng/ml, 50 ng/ml, and 100 ng/ml) in healthy volunteers, CAD patients treated with ASA, and CAD patients treated with ASA and clopidogrel combination (n= 10,for each group). E5555 inhibited a number of platelet biomarkers. Platelet inhibition was usually moderate, present already at 20 ng/ml, and was not seemingly dose-dependent without TRAP stimulation. E5555 caused 10-15% inhibition of ADP- and collagen-induced platelet aggregation in plasma, but not in whole blood. TRAP-induced aggregation was inhibited almost completely. PECAM-1, GP IIb/IIIa antigen, and activity with PAC-1, GPIb, thrombospondin, vitronectin receptor expression, and formation of platelet-monocyte aggregates were also significantly reduced by E5555. TRAP stimulation caused dose-dependent effects between 20 and 50 ng/ml E5555 doses. P-selectin, LAMP-1, LAMP, and CD40-ligand were not affected by E5555. In conclusion, E5555 in vitro moderately but significantly inhibits platelet activity beyond PAR-1 blockade. Antiplatelet potency of ASA alone, and the combination of ASA and clopidogrel may be enhanced by E5555 providing rationale for their synergistic use. Selective blockade of platelet receptors suggests unique antiplatelet properties of E5555 as a potential addition to current antithrombotic regimens. C1 [Serebruany, Victor L.] Johns Hopkins Univ, HeartDrug Res Labs, Baltimore, MD USA. [Kogushi, Motoji] Eisai & Co Ltd, Innovat Biol Labs, Tsukuba, Ibaraki, Japan. [Dastros-Pitei, Daniela] Eisai Ltd, Eisai Global Clin Dev, London, England. [Flather, Marcus] Royal Brompton Hosp, London SW3 6LY, England. [Flather, Marcus] Univ London Imperial Coll Sci Technol & Med, London, England. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Serebruany, VL (reprint author), Osler Med Ctr, 7600 Osler Dr,St 307, Towson, MD 21204 USA. EM Heartdrug@aol.com NR 18 TC 58 Z9 61 U1 0 U2 4 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 2009 VL 102 IS 1 BP 111 EP 119 DI 10.1160/TH08-12-0805 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 474XJ UT WOS:000268317900018 PM 19572075 ER PT J AU Lewis, CM Chang, KP Pitman, M Faquin, WC Randolph, GW AF Lewis, Carol M. Chang, Kuo-Ping Pitman, Martha Faquin, William C. Randolph, Gregory W. TI Thyroid Fine-Needle Aspiration Biopsy: Variability in Reporting SO THYROID LA English DT Article; Proceedings Paper CT 111th Annual Meeting of the American-Academy-of-Otolaryngology-Head-and-Neck-Surgery-Foundation CY SEP 16-19, 2007 CL Washington, DC SP Amer Acad Otolaryngol Head & Neck Surg Fdn ID FROZEN-SECTION ANALYSIS; SURGICAL-MANAGEMENT; CYTOLOGY; NODULES; EXPERIENCE; DIAGNOSIS; ACCURACY; CANCER; ULTRASONOGRAPHY; GUIDELINES AB Background: The low incidence of thyroid cancer despite the high prevalence of thyroid nodules necessitates a screening tool to determine which patients require surgical management. The utility of fine-needle aspiration biopsy (FNAB) for this purpose requires a low false-negative (FN) rate and an acceptable sensitivity and specificity for the detection of malignancy. While reviewing our institution's experience with thyroid FNAB, we found significant discrepancies in how statistics of thyroid FNAB were tabulated and reported in the literature. Here we examine the sources of these discrepancies by evaluating large series of thyroid FNAB with regard to cytopathologic reporting and statistical calculation. Methods: Published series of thyroid FNAB with >200 FNAB and available histological data with sufficient raw data to recalculate statistics were analyzed. Considering indeterminate and malignant results to be positive FNAB results, since, in a four-tier system, both lead to surgical management, specificity, sensitivity, accuracy, positive predictive value, negative predictive value, FN, and false-positive (FP) rates were recalculated. Differences between reported and recalculated statistics were then evaluated for significance. Results: Nineteen studies and 20 series were identified. The following are reported and recalculated means, respectively: for sensitivity, 81% and 86%; for specificity, 81% and 62%; for accuracy, 77% and 71%; for positive predictive value, 65% and 50%; for negative predictive value, 84% and 93%; for FN rates, 13% and 14%; for FP rates, 10% and 38%. FP rates had a mean of 1.4% when recalculated considering only malignant FNAB as positive tests. Specificity and FP rates had statistically significant differences between the means of reported and recalculated values. Conclusions: Thyroid FNAB remains the screening tool of choice in the evaluation of thyroid nodules. However, the variability in the calculation of reported thyroid FNAB statistics highlights the need for uniformity in statistical reporting for accurate understanding of thyroid FNAB's clinical utility. C1 [Lewis, Carol M.; Chang, Kuo-Ping; Randolph, Gregory W.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Lewis, Carol M.; Chang, Kuo-Ping; Randolph, Gregory W.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Pitman, Martha; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Pitman, Martha; Faquin, William C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM gregory_randolph@meei.harvard.edu NR 31 TC 76 Z9 78 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD JUL PY 2009 VL 19 IS 7 BP 717 EP 723 DI 10.1089/thy.2008.0425 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467SO UT WOS:000267762900006 PM 19485775 ER PT J AU Mintz, PD Dzik, WH AF Mintz, Paul D. Dzik, Walter H. TI Double standard for double ABO grouping? SO TRANSFUSION LA English DT Editorial Material ID SAMPLE COLLECTION; TRANSFUSION SAFETY; BLOOD; PATIENT; PERFORMANCE C1 [Mintz, Paul D.] Univ Virginia Hlth Syst, Div Clin Pathol Clin Labs & Transfus Serv, Charlottesville, VA USA. [Dzik, Walter H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Blood Transfus Serv, Boston, MA USA. RP Mintz, PD (reprint author), Univ Virginia Hlth Syst, Div Clin Pathol Clin Labs & Transfus Serv, Charlottesville, VA USA. EM mintz@virginia.edu NR 18 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2009 VL 49 IS 7 BP 1282 EP 1285 PN 1 PG 4 WC Hematology SC Hematology GA 467CX UT WOS:000267715300003 PM 19602208 ER PT J AU Steiner, ME Stowell, C AF Steiner, Marie E. Stowell, Christopher TI Does red blood cell storage affect clinical outcome? When in doubt, do the experiment SO TRANSFUSION LA English DT Editorial Material ID CRITICALLY-ILL; TRANSFUSION PRACTICES; TRIAL; GUIDELINES; CARE C1 [Steiner, Marie E.] Univ Minnesota, Minneapolis, MN 55455 USA. [Stowell, Christopher] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Steiner, ME (reprint author), Univ Minnesota, Minneapolis, MN 55455 USA. EM stein083@umn.edu NR 26 TC 30 Z9 31 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2009 VL 49 IS 7 BP 1286 EP 1290 PG 5 WC Hematology SC Hematology GA 467CX UT WOS:000267715300004 PM 19602209 ER PT J AU Driver, J Blankenburg, F Bestmann, S Vanduffel, W Ruff, CC AF Driver, Jon Blankenburg, Felix Bestmann, Sven Vanduffel, Wim Ruff, Christian C. TI Concurrent brain-stimulation and neuroimaging for studies of cognition SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID TRANSCRANIAL MAGNETIC STIMULATION; THETA-BURST-STIMULATION; FRONTAL EYE FIELD; VISUAL-CORTEX; TMS-FMRI; EVOKED-POTENTIALS; MOTOR CORTEX; POSTERIOR PARIETAL; PREFRONTAL CORTEX; SPATIAL ATTENTION AB Neuroimaging can address activity across the entire brain in relation to cognition, but is typically correlative rather than causal. Brain stimulation can target a local brain area causally, but without revealing the entire network affected. Combining brain stimulation with concurrent neuroimaging allows a new causal approach to how interplay between extended networks of brain regions can support cognition. Brain stimulation does not affect only the targeted local region but also activity in remote interconnected regions. These remote effects depend on cognitive factors (e.g. task-condition), revealing dynamic changes in interplay between brain areas. We illustrate this with examples from top-down modulation of visual cortex, response-competition, interhemispheric rivalry and motor tasks; but the new approach should be applicable to many domains of cognition. C1 [Driver, Jon; Blankenburg, Felix; Bestmann, Sven; Ruff, Christian C.] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Driver, Jon; Ruff, Christian C.] UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Blankenburg, Felix] Humboldt Univ, Bernstein Ctr Computat Neurosci, D-10115 Berlin, Germany. [Bestmann, Sven] UCL, Sobell Dept Motor Neurosci, London WC1N 3BG, England. [Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Vanduffel, Wim] Katholieke Univ Leuven, Sch Med, Lab Neurofysiol & Psychofysiol, B-3000 Louvain, Belgium. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. [Ruff, Christian C.] Univ Zurich, Lab Social & Neural Syst Res, Inst Empir Res Econ, CH-8006 Zurich, Switzerland. RP Ruff, CC (reprint author), UCL, Inst Cognit Neurosci, London WC1N 3AR, England. EM ruff@iew.uzh.ch OI Ruff, Christian/0000-0002-3964-2364 FU European Commission [HEALTH-F2-2008-200728]; Wellcome Trust; Medical Research Council FX Our research was funded in London and Leuven by the European Commission, 7th Framework Programme (BrainSync: HEALTH-F2-2008-200728) and in London by the Wellcome Trust and the Medical Research Council. NR 49 TC 64 Z9 66 U1 1 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD JUL PY 2009 VL 13 IS 7 BP 319 EP 327 DI 10.1016/j.tics.2009.04.007 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 475RW UT WOS:000268379400008 PM 19540793 ER PT J AU Ji, RR Xu, ZZ Wang, XY Lo, EH AF Ji, Ru-Rong Xu, Zhen-Zhong Wang, Xiaoying Lo, Eng H. TI Matrix metalloprotease regulation of neuropathic pain SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID SPINAL NERVE LIGATION; PRIMARY SENSORY NEURONS; NECROSIS-FACTOR-ALPHA; MECHANICAL ALLODYNIA; PERIPHERAL NEUROPATHY; CENTRAL SENSITIZATION; PERSISTENT PAIN; RAT MODEL; GLIA; ACTIVATION AB Neuropathic pain affects millions of people globally and could be a disease on its own right. Current treatments focus on blocking neurotransmission and have resulted in limited success. Recent progress points to an important role of neuroinflammation in the pathogenesis of neuropathic pain. Matrix metalloproteases (MMPs) comprise a large family of zinc endopeptidases that have been implicated in the generation of neuroinflammation via cleavage of extracellular matrix proteins and activation of proinflammatory cytokines and chemokines. However, little is known about the role of MMPs in chronic pain regulation. Our recent study has shown that neuropathic pain development in the early and late phase requires MMP-9 and MMP-2, respectively. Inhibition of MMP-9 or MMP-2 might provide a new strategy for the prevention and treatment of neuropathic pain. C1 [Ji, Ru-Rong; Xu, Zhen-Zhong] Brigham & Womens Hosp, Dept Anesthesiol, Pain Res Ctr, Boston, MA 02115 USA. [Ji, Ru-Rong; Xu, Zhen-Zhong] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wang, Xiaoying; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. [Wang, Xiaoying; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Hillsborough, 02129, North Ireland. [Wang, Xiaoying; Lo, Eng H.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Ji, RR (reprint author), Brigham & Womens Hosp, Dept Anesthesiol, Pain Res Ctr, Boston, MA 02115 USA. EM rrji@zeus.bwh.harvard.edu OI Ji, Ru-Rong/0000-0002-9355-3688 FU National Institutes of Health [R01-NS54932, R01-DE17794, R01-NS48422, R01-NS56458, R37-NS37074, P01-NS55104] FX This work was supported by National Institutes of Health grants R01-NS54932 and R01-DE17794 to R-R.J. and R01-NS48422, R01-NS56458, R37-NS37074 and P01-NS55104 to E.H.L and X.W. NR 49 TC 45 Z9 47 U1 0 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUL PY 2009 VL 30 IS 7 BP 336 EP 340 DI 10.1016/j.tips.2009.04.002 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 475RQ UT WOS:000268378700005 PM 19523695 ER PT J AU Morris, KR Lutz, RD Bai, XY McGibney, MT Cook, D Ordway, D Chan, ED AF Morris, Kristin R. Lutz, Ryan D. Bai, Xiyuan McGibney, Mischa T. Cook, Danielle Ordway, Diane Chan, Edward D. TI Suppression of IFN gamma plus mycobacterial lipoarabinomannan-induced NO by IL-4 is due to decreased IRF-1 expression SO TUBERCULOSIS LA English DT Article DE Lipoarabinomannan; Nitric oxide; Interleukin-4; Inducible nitric oxide synthase; Interferon-gamma; Transcriptional regulation ID NITRIC-OXIDE SYNTHASE; TUMOR-NECROSIS-FACTOR; GROWTH-FACTOR-BETA; NF-KAPPA-B; HUMAN PULMONARY TUBERCULOSIS; RAT-LIVER ARGINASE; INTERFERON-GAMMA; FACTOR-ALPHA; ALTERNATIVE ACTIVATION; MURINE MACROPHAGES AB In mice, and possibly in humans, nitric oxide (NO) is an important host-defense molecule against Mycobacterium tuberculosis. Inducible nitric oxide synthase (iNOS) and NO are upregulated in murine macrophages stimulated with interferon-gamma (IFN gamma) and mannose-capped lipoarabinomannan (ManLAM), a major lipoglycan in the cell wall of M. tuberculosis. Interleukin-4 (IL-4) can inhibit NO expression and may impair host immune response to M. tuberculosis. Therefore, we sought to determine the mechanism by which IL-4 inhibits IFN gamma + ManLAM-induced NO production. Since L-arginine is the substrate for both iNOS and arginase, and IL-4 increases arginase activity by inducing its production, a plausible mechanism of IL-4 inhibition of NO expression is via depletion of L-arginine through increased arginase activity. Herein, we show that IL-4 inhibited iNOS gene expression at the transcriptional level, suggesting an inhibitory mechanism that is independent of the competition for L-arginine between iNOS and arginase. Furthermore, pharmacologic inhibition of IL-4-induced arginase activity did not abrogate IL-4 inhibition of IFN gamma + ManLAM-induced NO expression. Instead, inhibition by IL-4 was mediated principally by the ability of IL-4 to inhibit the production of IFN gamma-induced interferon-gamma response factor-1 (IRF-1) protein, a critically important transcriptional element that enhances expression of IFN gamma-inducible genes such as iNOS. Published by Elsevier Ltd. C1 [Chan, Edward D.] Univ Colorado, Hlth Sci Ctr, Resp Dept, Denver Vet Affairs Med Ctr, Denver, CO USA. [Morris, Kristin R.; Lutz, Ryan D.; Cook, Danielle; Chan, Edward D.] Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. [Chan, Edward D.] Univ Colorado, Hlth Sci Ctr, Cell Biol Program, Denver, CO USA. [Bai, Xiyuan; McGibney, Mischa T.; Chan, Edward D.] Univ Colorado, Hlth Sci Ctr, Div Pulm Sci & Crit Care Med, Denver, CO USA. [Ordway, Diane] Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. RP Chan, ED (reprint author), K720,Goodman Bldg,1400 Jackson St, Denver, CO 80206 USA. EM chane@njhealth.org FU Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development (EDC); [N01-Al-75320] FX This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (EDC). The authors wish to thank Drs. Patrick Brennan, John Belisle, and Karen Dobos of Colorado State University in Ft. Collins, Colorado for the ManLAM, the procurement of which is supported by N01-Al-75320. NR 47 TC 11 Z9 11 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD JUL PY 2009 VL 89 IS 4 BP 294 EP 303 DI 10.1016/j.tube.2009.03.004 PG 10 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 484NG UT WOS:000269051800009 PM 19556165 ER PT J AU Benacerraf, BR Shipp, TD Bromley, B AF Benacerraf, B. R. Shipp, T. D. Bromley, B. TI Three-dimensional ultrasound detection of abnormally located intrauterine contraceptive devices which are a source of pelvic pain and abnormal bleeding SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE 3D ultrasound; IUD; pelvic pain ID SONOGRAPHY; UTERUS AB Objective To determine whether intrauterine contraceptive devices (IUDs) that are located abnormally within the myometrium or cervix cause a higher incidence of pelvic pain and abnormal bleeding compared with normally positioned devices. Methods Over a period of 9 months, all patients with an IUD presenting at our unit for two-dimensional pelvic ultrasound underwent a three-dimensional (3D) volume reconstruction of the coronal view, to visualize the entire IUD within the cavity. The IUD was deemed malpositioned if any part extended past the cavity, into the myometrium or cervix. The indications for ultrasound were recorded at presentation for the exam. The presenting symptoms of patients with an abnormally located IUD were compared with those with normally positioned ones. Results Among 167 consecutive patients with an IUD evaluated using the 3D reconstructed coronal view, 28 (16.8%) bad an IUD with side arms abnormally located within the myometrium. The abnormal positioning of the IUD arms was only detected using the 3D coronal view. A higher proportion of patients with an abnormally located IUD presented with bleeding (35.7%) or pain (39.3%) compared with those with normally positioned IUDs (15.1% with bleeding and 19.4% with pain) (P = 0.02 and 0.03, respectively). Seventy-five Percent of Patients with an abnormally located IUD presented with bleeding or pain compared with 34.5% of those whose IUD was normally placed (P = 0.0001). Twenty of 21 patients with an abnormally located IUD presenting with pelvic pain or bleeding reported improvement in their symptoms after IUD removal. Conclusion A 3D coronal view of the uterus is useful in the visualization of IUDs. The coronal view showing the entire device and its position within the uterus may help in identifying the cause of pelvic pain and bleeding in patients with an embedded IUD. Copyright (c) 2009 ISUOG. Published by John Wiley & Sons, Ltd. C1 [Benacerraf, B. R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Benacerraf, B. R.; Shipp, T. D.; Bromley, B.] Brigham & Womens Hosp, Dept OB GYN, Boston, MA 02115 USA. [Benacerraf, B. R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Benacerraf, B. R.; Shipp, T. D.; Bromley, B.] Massachusetts Gen Hosp, Dept OB GYN, Boston, MA 02114 USA. [Benacerraf, B. R.; Shipp, T. D.; Bromley, B.] Harvard Univ, Med Scbool, Boston, MA USA. RP Benacerraf, BR (reprint author), Diagnost Ultrasound Associates, 333 Longwood Ave, Boston, MA 02115 USA. EM bbsono@aol.com NR 10 TC 34 Z9 34 U1 2 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD JUL PY 2009 VL 34 IS 1 BP 110 EP 115 DI 10.1002/uog.6421 PG 6 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 473OT UT WOS:000268217800020 PM 19565532 ER PT J AU Exadaktylos, AK Alam, HB AF Exadaktylos, A. K. Alam, H. B. TI The war on (too many) fluids SO UNFALLCHIRURG LA German DT Article DE Fluids; Review; Bleeding; Trauma ID RESUSCITATION; CASUALTIES; UPDATE; BLOOD; MODEL AB In the coming years, our approach to the bleeding patient will have to change radically. The inevitable knowledge from the wars in Iraq and Afghanistan permits the prediction that conventional crystalloids will sooner or later disappear from volume replacement therapy. The dogma that fluids must always be given will be abandoned, to be replaced by the practice of careful and goal-directed resuscitation. In the near future, we would rely on designer fluids and sophisticated pharmacological agents to deliver personalized resuscitation based upon the specific needs of the individual patient. C1 [Exadaktylos, A. K.] Univ Bern, Dept Acad Emergency Med, Inselspital, CH-3010 Bern, Switzerland. [Alam, H. B.] Harvard Univ, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA USA. RP Exadaktylos, AK (reprint author), Univ Bern, Dept Acad Emergency Med, Inselspital, CH-3010 Bern, Switzerland. EM aristomenis@exadaktylos.ch NR 12 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0177-5537 J9 UNFALLCHIRURG JI Unfallchirurg PD JUL PY 2009 VL 112 IS 7 BP 670 EP + DI 10.1007/s00113-008-1562-1 PG 3 WC Emergency Medicine; Surgery SC Emergency Medicine; Surgery GA 471KN UT WOS:000268056600007 PM 19603217 ER PT J AU Saenz, AJ Koreishi, AF Rosenberg, AE Kradin, RL AF Saenz, A. J. Koreishi, A. F. Rosenberg, A. E. Kradin, R. L. TI Immune cell subsets in necrotizing fasciitis: an immunohistochemical analysis SO VIRCHOWS ARCHIV LA English DT Article DE Skin; Immunohistochemistry; Toxic shock; Streptococci ID TUMOR-NECROSIS-FACTOR; TOXIC SHOCK SYNDROME; STREPTOCOCCUS-PYOGENES; INFECTIONS; SUPERANTIGEN AB Current concepts of the pathophysiology of necrotizing fasciitis (NF), a life-threatening infection of soft tissues associated with a toxic shock syndrome, emphasizes the role of bacterial superantigens as mediators of cytokine release by immune lymphocytes. In order to assess the cellular basis of immune activation, immunohistochemistry was applied to the analysis of inflammatory cell subsets in situ in 13 patients with NF. The percentage of inflammatory cells in skin and soft tissue was scored from 0 to 3+ (> 50%). Substantial numbers of CD15+ polymorphonuclear leukocytes were present in 12 of 13 patients. CD3+ T-lymphocytes accounted for > 10%, CD68+ macrophages for > 50%, and Factor XIIIa+ mononuclear cells for > 10% of the mononuclear cell infiltrates, respectively, in 10 of 13 patients, whereas CD1a+ cells were present in only 3 of 13 cases and accounted for < 10% of mononuclear inflammatory cells. We conclude that immune lymphocytes and accessory immune cells are represented in substantial numbers in the early lesions of NF, and their presence supports current concepts with respect to the pathophysiology of this disorder. C1 [Saenz, A. J.; Koreishi, A. F.; Rosenberg, A. E.; Kradin, R. L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Saenz, A. J.; Koreishi, A. F.; Rosenberg, A. E.; Kradin, R. L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Saenz, A. J.; Koreishi, A. F.; Rosenberg, A. E.; Kradin, R. L.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Kradin, R. L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Kradin, RL (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM rlkradin@partners.org NR 19 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD JUL PY 2009 VL 455 IS 1 BP 87 EP 92 DI 10.1007/s00428-009-0781-3 PG 6 WC Pathology SC Pathology GA 466UJ UT WOS:000267688100010 PM 19529958 ER PT J AU Cozzi, E Tallacchini, M Flanagan, EB Pierson, RN Sykes, M Vanderpool, HY AF Cozzi, Emanuele Tallacchini, Mariachiara Flanagan, Enda B. Pierson, Richard N., III Sykes, Megan Vanderpool, Harold Y. TI The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes - Chapter 1: Key ethical requirements and progress toward the definition of an international regulatory framework SO XENOTRANSPLANTATION LA English DT Article DE ethics; islets of Langerhans; regulation; xenotransplantation ID NONHUMAN-PRIMATES; SELECTION AB The outstanding results recently obtained in islet xenotransplantation suggest that porcine islet clinical trials may soon be scientifically appropriate. Before the initiation of such clinical studies, however, it is essential that a series of key ethical and regulatory conditions are satisfied. As far as ethics is concerned, the fundamental requirements have been previously reported in a position paper of the Ethics Committee of the International Xenotransplantation Association. These include aspects related to the selection of adequately informed, appropriate recipients; animal breeding and welfare; safety issues and the need for a favorable risk/benefit assessment based on strong efficacy data in relevant xenotransplantation studies in the primate. As most diabetic patients are not at risk of short-term mortality without islet transplantation, only a small subset of patients could currently be considered for any type of islet transplant. However, there are potential advantages to xenotransplantation that could result in a favorable benefit-over-harm determination for islet xenotransplantation in this subpopulation and ultimately in a broader population of diabetic patients. With regard to regulatory aspects, the key concepts underlying the development of the regulatory models in existence in the United States, Europe and New Zealand are discussed. Each of these models provides an example of a well-defined regulatory approach to ensure the initiation of well-regulated and ethically acceptable clinical islet xenotransplantation trials. At this stage, it becomes apparent that only a well-coordinated international effort such as that initiated by the World Health Organization, aimed at harmonizing xenotransplantation procedures according to the highest ethical and regulatory standards on a global scale, will enable the initiation of clinical xenotransplantation trials under the best auspices for its success and minimize any risk of failure. C1 [Cozzi, Emanuele] Univ Padua, Dept Surg & Gastroenterol Sci Pier Giuseppe Ceves, Clin Chirurg 3, I-35128 Padua, Italy. [Cozzi, Emanuele] Padua Hosp, Direz Sanit, Padua, Italy. [Cozzi, Emanuele] Consortium Res Organ Transplantat CORIT, Padua, Italy. [Tallacchini, Mariachiara] Univ Milan, Biotechnol Fac, Catholic Univ Piacenza, Fac Law, Milan, Italy. [Flanagan, Enda B.] Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN USA. [Flanagan, Enda B.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. [Pierson, Richard N., III] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA. [Pierson, Richard N., III] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Sykes, Megan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr,Surg Serv, Boston, MA USA. [Vanderpool, Harold Y.] Univ Texas Med Branch, Inst Med Humanities, Galveston, TX USA. RP Cozzi, E (reprint author), Univ Padua, Dept Surg & Gastroenterol Sci Pier Giuseppe Ceves, Clin Chirurg 3, Via Giustiniani 2, I-35128 Padua, Italy. EM emanuele.cozzi@unipd.it FU CORIT (Consorzio per la Ricerca sul Trapianto d'Organi, Padua, Italy); Italian Ministry of Health; Veneto Region; EU [LSHB-CT-2006-037377] FX This study was supported by CORIT (Consorzio per la Ricerca sul Trapianto d'Organi, Padua, Italy), the Italian Ministry of Health, the Veneto Region, and the EU FP6 Integrated Project "Xenome," contract # LSHB-CT-2006-037377. The authors wish to thank Dr. Stewart Jessamine (Medsafe, Ministry of Health, New Zealand) for providing information on the regulatory framework related to xenotransplantation in New Zealand, Niketa Walawalkar for assistance with references, and Suzanne Schoenfelt for editing the manuscript. NR 25 TC 23 Z9 23 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD JUL-AUG PY 2009 VL 16 IS 4 BP 203 EP 214 DI 10.1111/j.1399-3089.2009.00540.x PG 12 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 499QG UT WOS:000270238900003 PM 19799760 ER PT J AU Mukerji, S Brown, MC Lee, DJ AF Mukerji, Sudeep Brown, M. Christian Lee, Daniel J. TI A morphologic study of Fluorogold labeled tensor tympani motoneurons in mice SO BRAIN RESEARCH LA English DT Article DE Middle ear; Pons; Auditory reflex; Trigerminal nucleus; Dendrite; Retrograde tracer; Synaptic input ID VENTRAL COCHLEAR NUCLEUS; MIDDLE-EAR MUSCLES; HORSERADISH-PEROXIDASE; GUINEA-PIG; OLIVOCOCHLEAR NEURONS; MOTOR NEURONS; BRAIN-STEM; CAT; RAT; MOUSE AB The tensor tympani is one of two middle ear muscles that regulates the transmission of sound through the middle ear. Contraction of the tensor tympani in response to both auditory and non-auditory stimulation is mediated by the tensor tympani motoneurons (TTMNs). There are interesting differences among species in the acoustic thresholds for contraction of the middle ear muscles, which may be a reflection of underlying anatomical differences such as the number of TTMNs. However anatomical data for mice are lacking, even though the mouse is becoming the most common animal model for auditory and neuroscience research. We investigated the number and morphology of TTMNs in mice using Fluorogold, a retrograde neuronal tracer. After injections of Fluorogold into the tensor tympani muscle, a column of labeled TTMNs was identified ventro-lateral to the ipsilateral trigeminal nucleus. The labeled TTMNs were classified according to their morphological characteristics into three subtypes: "octopus-like", "fusiform" and "stellate", suggesting underlying differences in function. All three subtypes formed sparsely branched and radiating dendrites, some longer than 600 mu m. Dendrites were longest and most numerous in the dorso-medial direction. In 18 cases, the mean number of mouse TTMNs was 51; the largest numbers were 70, 74 and 90 (n = 3 injections). The mean size of mouse TTMNs was 13.0 mu m (minor axis) and 23.5 mu m (major axis). Compared with studies of TTMNs in larger species (cats and rats), mouse TTMNs are both fewer in number and smaller in size. (C) 2009 Elsevier B.V. All rights reserved. C1 [Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lee, DJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM daniel_lee@meei.harvard.edu FU NIDCD [RO1 DC01089, K08 DC06285]; Norwegian State Lending Agency FX This study was supported by NIDCD grants RO1 DC01089, K08 DC06285 and The Norwegian State Lending Agency. NR 49 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 30 PY 2009 VL 1278 BP 59 EP 65 DI 10.1016/j.brainres.2009.04.035 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 466PJ UT WOS:000267674200006 PM 19397898 ER PT J AU Kutcher, MA Klein, LW Ou, FS Wharton, TP Dehmer, GJ Singh, M Anderson, HV Rumsfeld, JS Weintraub, WS Shaw, RE Sacrinty, MT Woodward, A Peterson, ED Brindis, RG AF Kutcher, Michael A. Klein, Lloyd W. Ou, Fang-Shu Wharton, Thomas P., Jr. Dehmer, Gregory J. Singh, Mandeep Anderson, H. Vernon Rumsfeld, John S. Weintraub, William S. Shaw, Richard E. Sacrinty, Matthew T. Woodward, Albert Peterson, Eric D. Brindis, Ralph G. CA NCDR TI Percutaneous Coronary Interventions in Facilities Without Cardiac Surgery On Site: A Report From the National Cardiovascular Data Registry (NCDR) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE percutaneous coronary intervention; cardiac surgery; outcomes analysis ID ACUTE MYOCARDIAL-INFARCTION; ARTERY-BYPASS-SURGERY; ON-SITE; PRIMARY ANGIOPLASTY; AMERICAN-COLLEGE; SURGICAL BACKUP; ACC-NCDR; THROMBOLYTIC THERAPY; HOSPITALS; COMMUNITY C1 [Kutcher, Michael A.; Sacrinty, Matthew T.] Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. [Klein, Lloyd W.] Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. [Ou, Fang-Shu; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Wharton, Thomas P., Jr.] Royal Devon & Exeter Hosp, Exeter, NH USA. [Dehmer, Gregory J.] Texas A&M Univ, Coll Med, Scott & White HealthCare, Temple, TX 76508 USA. [Singh, Mandeep] Mayo Clin, Rochester, MN USA. [Anderson, H. Vernon] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. [Weintraub, William S.] Christiana Care Hlth Syst, Newark, DE USA. [Shaw, Richard E.] Sutter Pacific Heart Ctr, San Francisco, CA USA. [Woodward, Albert] Natl Cardiovasc Data Registry, Washington, DC USA. [Brindis, Ralph G.] No Calif Kaiser Permanente, San Francisco, CA USA. RP Kutcher, MA (reprint author), Wake Forest Univ, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mkutcher@wfubmc.edu NR 30 TC 49 Z9 50 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 30 PY 2009 VL 54 IS 1 BP 16 EP 24 DI 10.1016/j.jacc.2009.03.038 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465AJ UT WOS:000267552000002 PM 19555835 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Noninvasive Detection of Vulnerable Coronary Plaques Locking the Barn Door Before the Horse Is Stolen SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE coronary artery disease; atherosclerosis; acute coronary syndrome; computed tomography; primary prevention ID ROW COMPUTED-TOMOGRAPHY; ANGIOGRAPHY; PREDICTION; ULTRASOUND C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Off Floor, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 13 TC 16 Z9 17 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 JUN 30 PY 2009 VL 54 IS 1 BP 58 EP 59 DI 10.1016/j.jacc.2009.03.040 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465AJ UT WOS:000267552000008 PM 19555841 ER PT J AU Prescot, A Becerra, L Pendse, G Tully, S Jensen, E Hargreaves, R Renshaw, P Burstein, R Borsook, D AF Prescot, Andrew Becerra, Lino Pendse, Gautam Tully, Shannon Jensen, Eric Hargreaves, Richard Renshaw, Perry Burstein, Rami Borsook, David TI Excitatory neurotransmitters in brain regions in interictal migraine patients SO MOLECULAR PAIN LA English DT Article ID ANTERIOR CINGULATE CORTEX; EVOKED CORTICAL POTENTIALS; CENTRAL-NERVOUS-SYSTEM; IN-VIVO; MAGNETIC-RESONANCE; N-ACETYLASPARTYLGLUTAMATE; CENTRAL SENSITIZATION; MATTER ABNORMALITIES; CUTANEOUS ALLODYNIA; VISUAL-STIMULATION AB Objective: To examine biochemical differences in the anterior cingulate cortex (ACC) and insula during the interictal phase of migraine patients. We hypothesized that there may be differences in levels of excitatory amino acid neurotransmitters and/or their derivatives in migraine group based on their increased sensitivity to pain. Methods: 2D J-resolved proton magnetic resonance spectroscopy ((1)H-MRS) data were acquired at 4.0 Tesla (T) from the ACC and insula in 10 migraine patients (7 women, 3 men, age 43 +/- 11 years) and 8 age gender matched controls (7 women, 3 men, age 41 +/- 9 years). Results: Standard statistical analyses including analysis of variance (ANOVA) showed no significant metabolite differences between the two subject cohorts in the ACC nor the insula. However, linear discriminant analysis (LDA) introduced a clear separation between subject cohorts based on N-acetyl aspartylglutamate (NAAG) and glutamine (Gln) in the ACC and insula. Conclusion: These results are consistent with glutamatergic abnormalities in the ACC and insula in migraine patients during their interictal period compared to healthy controls. An alteration in excitatory amino acid neurotransmitters and their derivatives may be a contributing factor for migraineurs for a decrease in sensitivity for migraine or a consequence of the chronic migraine state. Such findings, if extrapolated to other regions of the brain would offer new opportunities to modulate central system as interictal or preemptive medications in these patients. C1 [Prescot, Andrew; Becerra, Lino; Jensen, Eric; Renshaw, Perry; Borsook, David] McLean Hosp, Brain Imaging Ctr, Belmont, MA 02478 USA. [Becerra, Lino; Pendse, Gautam; Tully, Shannon; Borsook, David] McLean Hosp, PAIN Grp, Belmont, MA 02478 USA. [Becerra, Lino; Borsook, David] Massachusetts Gen Hosp, Martinos Ctr, PAIN Grp, Charlestown, MA USA. [Hargreaves, Richard] Merck & Co Inc, Imaging, West Point, PA USA. [Burstein, Rami] Harvard Univ, Sch Med, Dept Anesthesia, Beth Israel Deaconess Hosp, Boston, MA 02115 USA. RP Prescot, A (reprint author), McLean Hosp, Brain Imaging Ctr, Belmont, MA 02478 USA. EM andrew.prescot@utah.edu; lbecerra@mclean.harvard.edu; gpendse@mclean.harvard.edu; stully@mclean.harvard.edu; ejensen@bicserve.mclean.harvard.edu; richard_hargreaves@merck.com; perry_renshaw@yahoo.com; rburstei@bidmc.harvard.edu; dborsook@partners.org FU NIDA NIH HHS [K24 DA015116, DA015116]; NINDS NIH HHS [NS056195, R01 NS051484, NS051484, R01 NS056195] NR 95 TC 47 Z9 48 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD JUN 30 PY 2009 VL 5 AR 34 DI 10.1186/1744-8069-5-34 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 475DS UT WOS:000268339200002 PM 19566960 ER PT J AU Adelson, D Lao, L Zhang, G Kim, W Marvizon, JCG AF Adelson, D. Lao, L. Zhang, G. Kim, W. Marvizon, J. C. G. TI SUBSTANCE P RELEASE AND NEUROKININ 1 RECEPTOR ACTIVATION IN THE RAT SPINAL CORD INCREASE WITH THE FIRING FREQUENCY OF C-FIBERS SO NEUROSCIENCE LA English DT Article DE A delta-fiber; neurokinin A; neuropeptide; pain; presynaptic terminal; tachykinins ID LONG-TERM POTENTIATION; PRIMARY AFFERENT-FIBERS; DORSAL-HORN NEURONS; METHYL-D-ASPARTATE; PRIMARY SENSORY NEURONS; UNITS IN-VITRO; LAMINA-I; EVOKED POTENTIALS; CONDUCTION-VELOCITY; NEUROTROPHIC FACTOR AB Both the firing frequency of primary afferents and neurokinin I receptor (NK1R) internalization in dorsal horn neurons increase with the intensity of noxious stimulus. Accordingly, we studied how the pattern of firing of primary afferent influences NK1R internalization. In rat spinal cord slices, electrical stimulation of the dorsal root evoked NK1R internalization in lamina I neurons by inducing substance P release from primary afferents. The stimulation frequency had pronounced effects on NK1R internalization, which increased up to 100 Hz and then diminished abruptly at 200 Hz. Peptidase inhibitors increased NK1R internalization at frequencies below 30 Hz, indicating that peptidases limit the access of substance P to the receptor at moderate firing rates. NK1R internalization increased with number of pulses at all frequencies, but maximal internalization was substantially lower at 1-10 Hz than at 30 Hz. Pulses organized into bursts produced the same NK1R internalization as sustained 30 Hz stimulation. To determine whether substance P release induced at high stimulation frequencies was from C-fibers, we recorded compound action potentials in the sciatic nerve of anesthetized rats. We observed substantial NK1R internalization when stimulating at intensities evoking a C-elevation, but not at intensities evoking only an A delta-elevation. Each pulse in trains at frequencies up to 100 Hz evoked a C-elevation, demonstrating that C-fibers can follow these high frequencies. C-elevation amplitudes declined progressively with increasing stimulation frequency, which was likely caused by a combination of factors including temporal dispersion. In conclusion, the instantaneous firing frequency in C-fibers determines the amount of substance P released by noxious stimuli. Published by Elsevier Ltd on behalf of IBRO. C1 [Adelson, D.; Marvizon, J. C. G.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Adelson, D.; Lao, L.; Zhang, G.; Kim, W.; Marvizon, J. C. G.] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobiol Stress, CURE Digest Dis Res Ctr,Div Digest Dis,Dept Med, Los Angeles, CA 90095 USA. RP Marvizon, JCG (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Bldg 115,Room 119,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM marvizon@ucla.edu OI Adelson, David/0000-0002-4623-6030 FU Rehabilitation Research and Development Service [B47661]; Department of Veteran Affairs; National Institutes of Health [1R01DA012609] FX Supported by grants B47661 from the Rehabilitation Research and Development Service, Department of Veteran Affairs and 1R01DA012609 from the National Institutes of Health to J.C.G.M. Confocal images were acquired at Carol Moss Spivak Cell Imaging Facility of the Brain Research Institute at UCLA, with the assistance of Dr. Matthew J. Schibler. NR 59 TC 14 Z9 14 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUN 30 PY 2009 VL 161 IS 2 BP 538 EP 553 DI 10.1016/j.neuroscience.2009.03.058 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 455VC UT WOS:000266794100020 PM 19336248 ER PT J AU Brunet, E Simsek, D Tomishima, M DeKelver, R Choi, VM Gregory, P Urnov, F Weinstock, DM Jasin, M AF Brunet, Erika Simsek, Deniz Tomishima, Mark DeKelver, Russell Choi, Vivian M. Gregory, Philip Urnov, Fyodor Weinstock, David M. Jasin, Maria TI Chromosomal translocations induced at specified loci in human stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE double-strand break repair (DSB repair); zinc finger nucleases; mesenchymal cells; gene targeting; nonhomologous end-joining (NHEJ) ID ZINC-FINGER NUCLEASES; DOUBLE-STRAND BREAKS; MAMMALIAN-CELLS; DNA-RECOGNITION; REPAIR; GENOME; GENE; CANCER; RECOMBINATION; FUSION AB The precise genetic manipulation of stem and precursor cells offers extraordinary potential for the analysis, prevention, and treatment of human malignancies. Chromosomal translocations are hallmarks of several tumor types where they are thought to have arisen in stem or precursor cells. Although approaches exist to study factors involved in translocation formation in mouse cells, approaches in human cells have been lacking, especially in relevant cell types. The technology of zinc finger nucleases (ZFNs) allows DNA double-strand breaks (DSBs) to be introduced into specified chromosomal loci. We harnessed this technology to induce chromosomal translocations in human cells by generating concurrent DSBs at 2 endogenous loci, the PPP1R12C/p84 gene on chromosome 19 and the IL2R gamma gene on the X chromosome. Translocation breakpoint junctions for t(19;X) were detected with nested quantitative PCR in a high throughput 96-well format using denaturation curves and DNA sequencing in a variety of human cell types, including embryonic stem (hES) cells and hES cell-derived mesenchymal precursor cells. Although readily detected, translocations were less frequent than repair of a single DSB by gene targeting or nonhomologous end-joining, neither of which leads to gross chromosomal rearrangements. While previous studies have relied on laborious genetic modification of cells and extensive growth in culture, the approach described in this report is readily applicable to primary human cells, including mutipotent and pluripotent cells, to uncover both the underlying mechanisms and phenotypic consequences of targeted translocations and other genomic rearrangements. C1 [Brunet, Erika; Simsek, Deniz; Tomishima, Mark; Jasin, Maria] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10021 USA. [Tomishima, Mark] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst Stem Cell Res Facil, New York, NY 10021 USA. [Weinstock, David M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [DeKelver, Russell; Choi, Vivian M.; Gregory, Philip; Urnov, Fyodor] Sangamo BioSci Inc, Richmond, CA USA. [Weinstock, David M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Jasin, M (reprint author), Mem Sloan Kettering Canc Ctr, Dev Biol Program, 1275 York Ave, New York, NY 10021 USA. EM m-jasin@ski.mskcc.org FU Byrne Fund; Heckscher Foundation for Children; National Institutes of Health [GM54668] FX We thank Margaret Leversha and Lei Zhang at the Memorial Sloan-Kettering Cancer Center Molecular Cytogenetics Core Facility for performing the FISH analysis, Yufuko Akamatsu, Francesca Cole, and other members of Jasin laboratory for helpful discussions, and Gene Bryant and Daniel Spagna in Mark Ptashne's laboratory for technical assistance. This work was supported by the Byrne Fund, the Heckscher Foundation for Children, and Grant R01 National Institutes of Health GM54668 (to M. J.). NR 39 TC 101 Z9 105 U1 2 U2 18 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 JUN 30 PY 2009 VL 106 IS 26 BP 10620 EP 10625 DI 10.1073/pnas.0902076106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465EI UT WOS:000267564300043 PM 19549848 ER PT J AU Zhou, EH Trepat, X Park, CY Lenormand, G Oliver, MN Mijailovich, SM Hardin, C Weitz, DA Butler, JP Fredberg, JJ AF Zhou, E. H. Trepat, X. Park, C. Y. Lenormand, G. Oliver, M. N. Mijailovich, S. M. Hardin, C. Weitz, D. A. Butler, J. P. Fredberg, J. J. TI Universal behavior of the osmotically compressed cell and its analogy to the colloidal glass transition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE compression; cytoplasm; cytoskeleton; mechanotransduction; stiffness ID AIRWAY SMOOTH-MUSCLE; LIVING CELL; VOLUME; STIFFNESS; LIQUIDS; STRESS; VISCOELASTICITY; CYTOSKELETON; MECHANICS; DYNAMICS AB Mechanical robustness of the cell under different modes of stress and deformation is essential to its survival and function. Under tension, mechanical rigidity is provided by the cytoskeletal network; with increasing stress, this network stiffens, providing increased resistance to deformation. However, a cell must also resist compression, which will inevitably occur whenever cell volume is decreased during such biologically important processes as anhydrobiosis and apoptosis. Under compression, individual filaments can buckle, thereby reducing the stiffness and weakening the cytoskeletal network. However, the intracellular space is crowded with macromolecules and organelles that can resist compression. A simple picture describing their behavior is that of colloidal particles; colloids exhibit a sharp increase in viscosity with increasing volume fraction, ultimately undergoing a glass transition and becoming a solid. We investigate the consequences of these 2 competing effects and show that as a cell is compressed by hyperosmotic stress it becomes progressively more rigid. Although this stiffening behavior depends somewhat on cell type, starting conditions, molecular motors, and cytoskeletal contributions, its dependence on solid volume fraction is exponential in every instance. This universal behavior suggests that compression-induced weakening of the network is overwhelmed by crowding-induced stiffening of the cytoplasm. We also show that compression dramatically slows intracellular relaxation processes. The increase in stiffness, combined with the slowing of relaxation processes, is reminiscent of a glass transition of colloidal suspensions, but only when comprised of deformable particles. Our work provides a means to probe the physical nature of the cytoplasm under compression, and leads to results that are universal across cell type. C1 [Zhou, E. H.; Trepat, X.; Park, C. Y.; Lenormand, G.; Oliver, M. N.; Mijailovich, S. M.; Butler, J. P.; Fredberg, J. J.] Harvard Univ, Sch Publ Hlth, Program Mol & Integrat Physiol Sci, Boston, MA 02115 USA. [Hardin, C.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Weitz, D. A.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Butler, J. P.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Trepat, X.] Univ Barcelona, Inst Bioengn Catalonia & Ciber Enfermedades Resp, E-08036 Barcelona, Spain. RP Fredberg, JJ (reprint author), Harvard Univ, Sch Publ Hlth, Program Mol & Integrat Physiol Sci, 665 Huntington Ave, Boston, MA 02115 USA. EM jeffrey_fredberg@harvard.edu FU National Institutes of Health FX We thank Michael Wasserman and Emil Millet for technical assistance; Karen Kasza and Dhananjay Tambe for discussions; Reynold Panettieri (University of Pennsylvania Medical Center, Philadelphia), Tao Lu (Harvard Medical School, Boston), Daniel Tschumperlin (Harvard School of Public Health, Boston), and Fei Liu (Harvard School of Public Health, Boston) for providing cells; and Nenad Filipovic, Milos Kojic, and Velibor Isailovic for performing the finite element calculations. This work was supported by grants from National Institutes of Health. The AFM experiments were performed at the Center for Nanoscale Systems (CNS) at Harvard University. NR 42 TC 79 Z9 80 U1 0 U2 28 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 JUN 30 PY 2009 VL 106 IS 26 BP 10632 EP 10637 DI 10.1073/pnas.0901462106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465EI UT WOS:000267564300045 PM 19520830 ER PT J AU Yuan, XL Ansari, MJ D'Addio, F Paez-Cortez, J Schmitt, I Donnarumma, M Boenisch, O Zhao, XZ Popoola, J Clarkson, MR Yagita, H Akiba, H Freeman, GJ Iacomini, J Turka, LA Glimcher, LH Sayegh, MH AF Yuan, Xueli Ansari, M. Javeed D'Addio, Francesca Paez-Cortez, Jesus Schmitt, Isabella Donnarumma, Michela Boenisch, Olaf Zhao, Xiaozhi Popoola, Joyce Clarkson, Michael R. Yagita, Hideo Akiba, Hisaya Freeman, Gordon J. Iacomini, John Turka, Laurence A. Glimcher, Laurie H. Sayegh, Mohamed H. TI Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE costimulation; IL-17; rejection; immunosuppression ID CARDIAC ALLOGRAFT-REJECTION; T-CELLS; IFN-GAMMA; TH17 CELLS; BLOCKADE-RESISTANT; TUMOR-GROWTH; IN-VIVO; IL-17; INTERLEUKIN-17; MICE AB The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-costimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation. C1 [Yuan, Xueli; Ansari, M. Javeed; D'Addio, Francesca; Paez-Cortez, Jesus; Schmitt, Isabella; Donnarumma, Michela; Boenisch, Olaf; Zhao, Xiaozhi; Popoola, Joyce; Clarkson, Michael R.; Iacomini, John; Sayegh, Mohamed H.] Brigham & Womens Hosp, Transplantat Res Ctr, Div Renal, Boston, MA 02115 USA. [Yuan, Xueli; Ansari, M. Javeed; D'Addio, Francesca; Paez-Cortez, Jesus; Schmitt, Isabella; Donnarumma, Michela; Boenisch, Olaf; Zhao, Xiaozhi; Popoola, Joyce; Clarkson, Michael R.; Iacomini, John; Sayegh, Mohamed H.] Childrens Hosp Boston, Boston, MA USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ansari, M. Javeed] Northwestern Univ, Div Nephrol & Organ Transplantat, Feinberg Sch Med, Chicago, IL 60611 USA. [Yagita, Hideo; Akiba, Hisaya] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 1138421, Japan. [Turka, Laurence A.] Hosp Univ Penn, Renal Elect & Hypertens Div, Philadelphia, PA 19104 USA. [Glimcher, Laurie H.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sayegh, MH (reprint author), Brigham & Womens Hosp, Transplantat Res Ctr, Div Renal, Boston, MA 02115 USA. EM msayegh@rics.bwh.harvard.edu RI D'Addio, Francesca/F-3417-2017 OI D'Addio, Francesca/0000-0002-0345-0694 FU National Institutes of Health (NIH) [RO1 AI-51559, R01AI-37691, R01 AI-70820, P01 AI-41521, CA112663, NS038037, K08 AI080836-01]; American Society of Transplantation (AST) Basic Science Faculty Development; AST-Wyeth Basic Science Faculty Development FX This work was supported by National Institutes of Health (NIH) Grants: RO1 AI-51559, R01AI-37691, R01 AI-70820, and P01 AI-41521 (to M. H. S.) and CA112663 and NS038037 (to L. H. G.). X. Y. was supported in part by American Society of Transplantation (AST) Basic Science Faculty Development Grant Award. M. J. A. is supported in part by the AST-Wyeth Basic Science Faculty Development Grant Award and NIH Grant K08 AI080836-01. NR 39 TC 46 Z9 47 U1 1 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 JUN 30 PY 2009 VL 106 IS 26 BP 10734 EP 10739 DI 10.1073/pnas.0812538106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465EI UT WOS:000267564300063 PM 19528638 ER PT J AU Koenigsberg, HW Siever, LJ Lee, H Pizzarello, S New, AS Goodman, M Cheng, H Flory, J Prohovnik, I AF Koenigsberg, Harold W. Siever, Larry J. Lee, Hedok Pizzarello, Scott New, Antonia S. Goodman, Marianne Cheng, Hu Flory, Janine Prohovnik, Isak TI Neural correlates of emotion processing in borderline personality disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Affective instability; Emotion; fMRI; Social-emotional cues; Borderline personality disorder ID POSITRON-EMISSION-TOMOGRAPHY; AFFECTIVE INSTABILITY; AMYGDALA; ACTIVATION; STIMULI; PERCEPTION; WOMEN; FMRI; FACE; CUES AB Emotional instability is a hallmark feature of borderline personality disorder (BPD), yet its biological underpinnings are poorly understood. We employed functional magnetic resonance imaging (fMRI) to compare patterns of regional brain activation in BPD patients and healthy volunteers as they process positive and negative social emotional stimuli. fMRI images were acquired while 19 BPD patients and 17 healthy controls (HC) viewed emotion-inducing pictures from the International Affective Pictures System set. Activation data were analyzed with SPM5 ANCOVA models to derive the effects of diagnosis and stimulus type. BPD patients demonstrated greater differences in activation than controls, when viewing negative pictures compared with rest, in the amygdala, fusiform gyrus, primary visual areas, superior temporal gyrus (STG), and premotor areas, while healthy controls showed greater differences than BPD patients in the insula, middle temporal gyrus and dorsolateral prefrontal cortex (BA46). When viewing positive pictures compared with rest, BPD patients showed greater differences in the STG, premotor cortex, and ventrolateral prefrontal cortex. These findings suggest that BPD patients show greater amygdala activity and heightened activity of visual processing regions relative to findings for HC subjects in the processing of negative social emotional pictures compared with rest. The patients activate neural networks in emotion processing that are phylogeneticall older and more reflexive than those activated by HC subjects. Published by Elsevier Ireland Ltd. C1 [Koenigsberg, Harold W.; Siever, Larry J.; Lee, Hedok; New, Antonia S.; Goodman, Marianne; Prohovnik, Isak] Mt Sinai Sch Med, James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Koenigsberg, Harold W.; Siever, Larry J.; New, Antonia S.; Goodman, Marianne; Prohovnik, Isak] Mt Sinai Sch Med, New York, NY USA. [Cheng, Hu] Indiana Univ, Bloomington, IN 47405 USA. [Flory, Janine] CUNY Queens Coll, Dept Psychol, Flushing, NY 11367 USA. [Pizzarello, Scott] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. RP Koenigsberg, HW (reprint author), Mt Sinai Sch Med, James J Peters VA Med Ctr, 116A,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM HWarrenK@nyc.rr.com FU National Center for Research Resources (NCRR) [MO1-RR-00071]; National Institutes of Health (NIH); Mental Illness Research Education and Clinical Center; Siemens Medical Systems, Inc FX This work was supported by Grant Number MO1-RR-00071 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and the Mental Illness Research Education and Clinical Center, VISN 3 Veterans Health Administration, and an educational grant from the Siemens Medical Systems, Inc. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR, NIH, or the VA. We thank Dr. Sergei Pakhomov (Institute of the Human Brain, St. Petersburg, Russia) for the MSU software. NR 54 TC 96 Z9 96 U1 3 U2 18 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUN 30 PY 2009 VL 172 IS 3 BP 192 EP 199 DI 10.1016/j.pscychresns.2008.07.010 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 452ZX UT WOS:000266580800004 PM 19394205 ER PT J AU El-Din, MAA Hughes, KS Raad, RA Goldberg, SI Aisenberg, AC Niemierko, A Taghian, AG AF El-Din, Mohamed A. Alm Hughes, Kevin S. Raad, Rita A. Goldberg, Saveli I. Aisenberg, Alan C. Niemierko, Andrzej Taghian, Alphonse G. TI Clinical outcome of breast cancer occurring after treatment for Hodgkin's lymphoma: case-control analysis SO RADIATION ONCOLOGY LA English DT Article ID ATOMIC-BOMB SURVIVORS; CONTRALATERAL BREAST; RISK-FACTORS; PATHOLOGICAL ANALYSIS; MANTLE IRRADIATION; RADIATION-THERAPY; 2ND MALIGNANCY; DISEASE; RADIOTHERAPY; CARCINOMA AB Background: To evaluate diagnosis, management and outcome of breast cancer (BC) occurring after irradiation for Hodgkin's lymphoma (HL). Methods: 39 cases of BC in 28 HL survivors were retrospectively reviewed. 21 patients were included in a case-control analysis. Results: The median age at diagnosis of HL and BC was 25.3 and 45.3 years, respectively. The median interval to develop BC was 16.1 years. Eleven women (39.2%) had bilateral disease. Mode of detection of the index breast cancers was by mammographic screening in 17 patients (60.7%), palpable lump in 8 patients (28.6%), clinical examination in two patients (7.1%), and unknown in one patient (3.6%). Case-control analysis showed that histological features and prognosis of BC after HL were similar to those of primary BC, however, for BC after HL, mastectomy was the predominant surgery (P = .001) and adjuvant radiotherapy and anthracycline-based chemotherapy were less frequently used as compared to primary BC (P < .001 and .003, respectively). Conclusion: The previous history of HL does not appear to be a poor prognostic factor for BC occurring thereafter. C1 [El-Din, Mohamed A. Alm; Raad, Rita A.; Goldberg, Saveli I.; Niemierko, Andrzej; Taghian, Alphonse G.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Sch Med, Boston, MA 02114 USA. [Hughes, Kevin S.] Harvard Univ, Massachusetts Gen Hosp, Dept Surg Oncol, Sch Med, Boston, MA 02114 USA. [Aisenberg, Alan C.] Harvard Univ, Massachusetts Gen Hosp, Dept Med Oncol, Sch Med, Boston, MA 02114 USA. [El-Din, Mohamed A. Alm] Tanta Univ Hosp, Tanta Fac Med, Dept Radiat Oncol, Tanta, Egypt. RP Taghian, AG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Sch Med, Boston, MA 02114 USA. EM almeldin@gmail.com; kshughes@partners.org; rabiraad@partners.org; sigoldberg@partners.org; aaisenberg@partners.org; aniemierko@partners.org; ataghian@partners.org OI Hughes, Kevin/0000-0003-4084-6484 FU Jane Mailloux fund; Blanche Montesi fund; Tim Levy fund for breast cancer research; National Institutes of Health [CA50628] FX Results of this study were published in part at the 43rd annual meeting of the American Society of Clinical Oncology (ASCO), June 2007, Chicago, IL. Supported in part by the Jane Mailloux fund, the Blanche Montesi fund, the Tim Levy fund for breast cancer research (AGT) and grant CA50628 from the National Institutes of Health (AN). NR 43 TC 8 Z9 8 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND J9 RADIAT ONCOL JI Radiat. Oncol. PD JUN 30 PY 2009 VL 4 AR 19 DI 10.1186/1748-717X-4-19 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 475SI UT WOS:000268380600001 ER PT J AU Pinne, M Haake, DA AF Pinne, Marija Haake, David A. TI A Comprehensive Approach to Identification of Surface-Exposed, Outer Membrane-Spanning Proteins of Leptospira interrogans SO PLOS ONE LA English DT Article AB Leptospirosis is a zoonosis with worldwide distribution caused by pathogenic spirochetes belonging to the genus Leptospira. The leptospiral life cycle involves transmission via fresh water and colonization of the renal tubules of their reservoir hosts or infection of accidental hosts, including humans. Bacterial outer membrane proteins (OMPs), particularly those with surface-exposed regions, play crucial roles in virulence mechanisms of pathogens and the adaptation to various environmental conditions, including those of the mammalian host. Little is known about the surface-exposed OMPs in Leptospira, particularly those with outer membrane-spanning domains. Herein, we describe a comprehensive strategy for identification and characterization of leptospiral transmembrane OMPs. The genomic sequence of L. interrogans serovar Copenhageni strain Fiocruz L1-130 allowed us to employ the beta-barrel prediction programs, PRED-TMBB and TMBETA-NET, to identify potential transmembrane OMPs. Several complementary methods were used to characterize four novel OMPs, designated OmpL36, OmpL37, OmpL47 and OmpL54. In addition to surface immunofluorescence and surface biotinylation, we describe surface proteolysis of intact leptospires as an improved method for determining the surface exposure of leptospiral proteins. Membrane integration was confirmed using techniques for removal of peripheral membrane proteins. We also demonstrate deficiencies in the Triton X-114 fractionation method for assessing the outer membrane localization of transmembrane OMPs. Our results establish a broadly applicable strategy for the elucidation of novel surface-exposed outer membrane-spanning proteins of Leptospira, an essential step in the discovery of potential virulence factors, diagnostic antigens and vaccine candidates. RP Pinne, M (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. EM mpinne@ucla.edu FU NIAID NIH HHS [AI-34431, R01 AI034431, R01 AI034431-12, R21 AI034431, R29 AI034431] NR 84 TC 38 Z9 38 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 JUN 29 PY 2009 VL 4 IS 6 AR e6071 DI 10.1371/journal.pone.0006071 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 463XB UT WOS:000267465900007 PM 19562037 ER PT J AU Okpara, N Aswad, B Baffy, G AF Okpara, Nnenna Aswad, Bassam Baffy, Gyorgy TI Eosinophilic colitis SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Eosinophilia; Colitis; Gastrointestinal disease; Ascites ID GASTROINTESTINAL DISORDERS; ENTEROBIUS-VERMICULARIS; FOOD ALLERGIES; ACUTE ABDOMEN; GASTROENTERITIS; ESOPHAGITIS; DIAGNOSIS; PATIENT; INTUSSUSCEPTION; ENTEROCOLITIS AB Eosinophilic colitis (EC) is a rare form of primary eosinophilic gastrointestinal disease with a bimodal peak of prevalence in neonates and young adults. EC remains a little understood condition in contrast to the increasingly recognized eosinophilic esophagitis. Clinical presentation of EC is highly variable according to mucosal, transmural, or serosal predominance of inflammation. EC has a broad differential diagnosis because colon tissue eosinophilia often occurs in parasitic infection, drug-induced allergic reactions, inflammatory bowel disease, and various connective tissue disorders, which require thorough searching for secondary causes that may be specifically treated with antibiotics or dietary and drug elimination. Like eosinophilic gastrointestinal disease involving other segments of the gastrointestinal tract, EC responds very well to steroids that may be spared by using antihistamines, leukotriene inhibitors and biologics. (c) 2009 The WJG Press and Baishideng. All rights reserved. C1 [Okpara, Nnenna; Baffy, Gyorgy] Rhode Isl Hosp, Div Gastroenterol, Dept Med, Providence, RI 02130 USA. [Okpara, Nnenna; Aswad, Bassam; Baffy, Gyorgy] Brown Univ, Alpert Med Sch, Providence, RI 02130 USA. [Aswad, Bassam] Rhode Isl Hosp, Dept Pathol, Providence, RI 02130 USA. RP Baffy, G (reprint author), VA Boston Healthcare Syst, Gastroenterol Sect, 150 S Huntington Ave,Rm A6-46, Boston, MA 02130 USA. EM gbaffy@partners.org NR 51 TC 31 Z9 36 U1 0 U2 2 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUN 28 PY 2009 VL 15 IS 24 BP 2975 EP 2979 DI 10.3748/wig.15.2975 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 464HN UT WOS:000267496100003 PM 19554649 ER PT J AU Surman, OS Cosimi, AB DiMartini, A AF Surman, Owen S. Cosimi, A. Benedict DiMartini, Andrea TI Psychiatric Care of Patients Undergoing Organ Transplantation SO TRANSPLANTATION LA English DT Review DE Transplantation; Psychiatry; Selection; Consent; Compliance ID ALCOHOLIC LIVER-DISEASE; DRUG-DRUG INTERACTIONS; RENAL-TRANSPLANTATION; HEPATITIS-C; NONADHERENCE; DEPRESSION; RISK; COMPLICATIONS; PREDICTORS; MEDICATION AB Transplantation provides life-saving therapy to critically ill patients with end-stage organ failure. We found that the specialized knowledge of mental health clinicians and physicians, committed to the evaluation and management of transplant recipients, is essential for the optimal care of these patients who require a life-long regimen of immunosuppressive medication and dependency on the transplant team. Critical issues requiring psychiatric input are frequently encountered in the following areas (1) patient selection and informed consent; (2) recognition and pretransplant treatment of psychiatric disorders; (3) substance or alcohol abuse; (4) compliance with medical regimens; (5) posttransplant psychosis; and (6) immunosuppressive/psychiatric drug-drug interactions. This review focuses on the priorities in psychological and psychiatric care of these unique patients. C1 [Surman, Owen S.; Cosimi, A. Benedict] Massachusetts Gen Hosp, Dept Psychiat & Surg, Boston, MA 02114 USA. [Surman, Owen S.; DiMartini, Andrea] Univ Pittsburgh, Med Ctr, Dept Psychiat & Surg, Pittsburgh, PA USA. RP Surman, OS (reprint author), WANG Ambulatory Care Ctr, Suite 812,15 Parkman St, Boston, MA 02114 USA. EM osurman@partners.org NR 49 TC 19 Z9 20 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN 27 PY 2009 VL 87 IS 12 BP 1753 EP 1761 DI 10.1097/TP.0b013e3181a754d4 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 462NO UT WOS:000267361000001 PM 19543050 ER PT J AU Xia, Y Ongusaha, P Lee, SW Liou, YC AF Xia, Yun Ongusaha, Pat Lee, Sam W. Liou, Yih-Cherng TI Loss of Wip1 Sensitizes Cells to Stress- and DNA Damage-induced Apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-JUN; SIGNAL-TRANSDUCTION; TRANSCRIPTION FACTOR; PROTEIN PHOSPHATASE; KINASE; P53; ACTIVATION; PATHWAYS; PPM1D; PHOSPHORYLATION AB In response to various environmental stresses, the stress-responsive MAPKs p38 and JNK are activated and phosphorylate ATF2 and c-Jun transcription factors, thereby affecting cell-fate decision. Targeted gene disruption studies have established that JNK-c-Jun signaling plays a vital role in stress-induced apoptosis. The oncogenic phosphatase Wip1 acts as an important regulator in DNA damage pathway by dephosphorylating a spectrum of proteins including p53, p38, Chk1, Chk2, and ATM. In this study we show that Wip1 negatively regulates the activation of MKK4-JNK-c-Jun signaling during stress-induced apoptosis. The loss of Wip1 function sensitizes mouse embryonic fibroblasts to stress-induced apoptosis via the activation of both p38-ATF2 and JNK-c-Jun signaling. Here we reveal that Wip1 has dual roles in alternatively regulating stress- and DNA damage-induced apoptosis through p38/JNK MAPKs and p38/p53-dependent pathways, respectively. Our results point to Wip1 as a general regulator of apoptosis, which further supports its role in tumorigenesis. C1 [Xia, Yun; Liou, Yih-Cherng] Natl Univ Singapore, Fac Sci, Dept Biol Sci, Singapore 117543, Singapore. [Ongusaha, Pat; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. [Ongusaha, Pat; Lee, Sam W.] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Liou, YC (reprint author), 14 Sci Dr 4, Singapore 117543, Singapore. EM dbslyc@nus.edu.sg RI Xia, Yun/K-4128-2015 OI Xia, Yun/0000-0003-2184-4870 FU Biomedical Research Council [06/1/21/19/473]; Agency for Science, Research and Technology, Singapore FX This work was supported, in whole or in part, by Grant 06/1/21/19/473 from the Biomedical Research Council, the Agency for Science, Research and Technology, Singapore (to Y.C.L.). NR 49 TC 22 Z9 23 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 26 PY 2009 VL 284 IS 26 BP 17428 EP 17437 DI 10.1074/jbc.M109.007823 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 460QP UT WOS:000267202500009 PM 19395378 ER PT J AU Zarei, S Schwenter, F Luy, P Aurrand-Lions, M Morel, P Kopf, M Dranoff, G Mach, N AF Zarei, Shohreh Schwenter, Frank Luy, Patricia Aurrand-Lions, Michel Morel, Philippe Kopf, Manfred Dranoff, Glenn Mach, Nicolas TI Role of GM-CSF signaling in cell-based tumor immunization SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; REFRACTORY PROSTATE-CANCER; POTENT ANTITUMOR IMMUNITY; MYELOID SUPPRESSOR-CELLS; DENDRITIC CELLS; IN-VIVO; DEFICIENT MICE; T-CELLS; HEMATOPOIETIC-CELLS; MELANOMA-CELLS AB Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent adjuvant in cancer vaccination; however, the specific role of endogenous GM-CSF remains unknown. We performed cell-based vaccination in 2 tumor models. First, we vaccinated C57BL/6 mice lacking either GM-CSF, IL-5, or beta-common chain (beta c), a receptor subunit essential for GM-CSF and IL-5 signaling, with melanoma cells engineered to produce GM-CSF. Tumor vaccination was effective in both GM-CSF(-/-) and IL-5(-/-) mice, showing that protective immunization is independent of both endogenous cytokines. However, all beta c(-/-) animals developed tumor. Loss of tumor immunity in beta c(-/-) mice does not reflect global impairment in cell-mediated immunity, as contact hypersensitivity reaction to haptens is unaltered. The importance of tumor cell-derived GM-CSF was highlighted by recruitment of dendritic cells at the vaccination site in wildtype, GM-CSF(-/-), and IL-5(-/-) but not in beta c(-/-) mice. In the second model, vaccination with unmodified RENCA cells showed similar results with efficient immunization in BALB/c wild-type and GM-CSF(-/-), whereas all beta c(-/-) animals died. Altogether, our results strongly suggest that although endogenous GM-CSF and IL-5 are not required to induce tumor immunity, signaling through beta c receptor is critically needed for efficient cancer vaccination in both genetically modified GM-CSF-secreting tumor cells and a spontaneously immunogenic models. (Blood. 2009;113:6658-6668) C1 [Zarei, Shohreh; Schwenter, Frank; Luy, Patricia; Mach, Nicolas] Univ Hosp Geneva, Dept Internal Med, Div Oncol, CH-1205 Geneva, Switzerland. [Schwenter, Frank; Morel, Philippe] Univ Hosp Geneva, Dept Surg, Visceral & Transplantat Unit, CH-1205 Geneva, Switzerland. [Zarei, Shohreh; Schwenter, Frank; Luy, Patricia; Mach, Nicolas] Geneva Sch Med, Dept Internal Med, Div Oncol, Geneva, Switzerland. [Schwenter, Frank; Morel, Philippe] Geneva Sch Med, Dept Surg, Visceral & Transplantat Unit, Geneva, Switzerland. [Aurrand-Lions, Michel] Canc Res Ctr, INSERM, Inst J Paoli I Calmettes, Marseille, France. [Kopf, Manfred] Swiss Fed Inst Technol, Dept Environm Sci, Zurich, Switzerland. [Dranoff, Glenn] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Dranoff, Glenn] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Mach, N (reprint author), Univ Hosp Geneva, Dept Internal Med, Div Oncol, 24 Rue Micheli du Crest, CH-1205 Geneva, Switzerland. EM nicolas.mach@medecine.unige.ch RI Aurrand-Lions, Michel/O-9953-2016 OI Aurrand-Lions, Michel/0000-0002-8361-3034 FU Swiss National Science Foundation, Berne, Switzerland [PNR 37]; La Ligue genevoise contre le cancer (Geneva, Switzerland); la Fondation pour la lutte contre le cancer (Zurich, Switzerland; Cancer Research Institute/Partridge Foundation (New York, NY); Clinical Scholar of the Leukemia & Lymphoma Society (White Plains, NY); [CA 74886] FX This work was supported by the Swiss National Science Foundation (PNR 37) (Berne, Switzerland), La Ligue genevoise contre le cancer (Geneva, Switzerland), la Fondation pour la lutte contre le cancer (Zurich, Switzerland; N. M.), the Cancer Research Institute/Partridge Foundation (New York, NY), and CA 74886 (G. D). G. D. is a Clinical Scholar of the Leukemia & Lymphoma Society (White Plains, NY). NR 50 TC 20 Z9 24 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 JUN 25 PY 2009 VL 113 IS 26 BP 6658 EP 6668 DI 10.1182/blood-2008-06-161075 PG 11 WC Hematology SC Hematology GA 468BY UT WOS:000267789600026 PM 19282460 ER PT J AU Roccaro, AM Sacco, A Thompson, B Leleu, X Azab, AK Azab, F Runnels, J Jia, XY Ngo, HT Melhem, MR Lin, CP Ribatti, D Rollins, BJ Witzig, TE Anderson, KC Ghobrial, IM AF Roccaro, Aldo M. Sacco, Antonio Thompson, Brian Leleu, Xavier Azab, Abdel Kareem Azab, Feda Runnels, Judith Jia, Xiaoying Ngo, Hai T. Melhem, Molly R. Lin, Charles P. Ribatti, Domenico Rollins, Barrett J. Witzig, Thomas E. Anderson, Kenneth C. Ghobrial, Irene M. TI MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma SO BLOOD LA English DT Article ID NF-KAPPA-B; ENDOTHELIAL-CELLS; WALDENSTROM MACROGLOBULINEMIA; MALIGNANT-MELANOMA; PATHWAY; PROTEIN; GROWTH; EXPRESSION; INHIBITOR; FREQUENT AB Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138(+) MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P < .01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonineprotein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-kappa B-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM. (Blood. 2009;113:6669-6680) C1 [Roccaro, Aldo M.; Sacco, Antonio; Leleu, Xavier; Azab, Abdel Kareem; Azab, Feda; Runnels, Judith; Jia, Xiaoying; Ngo, Hai T.; Melhem, Molly R.; Rollins, Barrett J.; Anderson, Kenneth C.; Ghobrial, Irene M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Roccaro, Aldo M.; Sacco, Antonio; Leleu, Xavier; Azab, Abdel Kareem; Azab, Feda; Runnels, Judith; Jia, Xiaoying; Ngo, Hai T.; Melhem, Molly R.; Rollins, Barrett J.; Anderson, Kenneth C.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Boston, MA USA. [Roccaro, Aldo M.] Univ Brescia, Sch Med, Unit Blood Dis & Cell Therapies, Brescia, Italy. [Roccaro, Aldo M.] Univ Bari, Dept Internal Med & Clin Oncol, Sch Med, Bari, Italy. [Thompson, Brian; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Witzig, Thomas E.] Mayo Clin, Dept Hematol, Rochester, MN USA. [Ribatti, Domenico] Univ Bari, Dept Human Anat & Histol, Sch Med, Bari, Italy. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128 FU Claudia Adams Barr Foundation (Boston, MA) [RO1 CA125690-01]; Italian Association for Cancer Research (Milan, Italy); Doctors Cancer Foundation (New Rochelle, NY) FX This work was supported by in part by RO1 CA125690-01, Claudia Adams Barr Foundation (Boston, MA); Italian Association for Cancer Research (Milan, Italy); and The Doctors Cancer Foundation (New Rochelle, NY). NR 53 TC 141 Z9 155 U1 2 U2 15 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 25 PY 2009 VL 113 IS 26 BP 6669 EP 6680 DI 10.1182/blood-2009-01-198408 PG 12 WC Hematology SC Hematology GA 468BY UT WOS:000267789600027 PM 19401561 ER PT J AU Bongiovanni, M Bloom, L Krane, JF Baloch, ZW Powers, CN Hintermann, S Pache, JC Faquin, WC AF Bongiovanni, Massimo Bloom, Leonard Krane, Jeffrey F. Baloch, Zubair W. Powers, Celeste N. Hintermann, Suzanne Pache, Jean-Claude Faquin, William C. TI Cytomorphologic Features of Poorly Differentiated Thyroid Carcinoma A Multi-Institutional Analysis of 40 Cases SO CANCER CYTOPATHOLOGY LA English DT Article DE fine-needle aspiration; thyroid; insular; poorly differentiated; carcinoma ID FINE-NEEDLE-ASPIRATION; INSULAR CARCINOMA; CYTOLOGIC FEATURES; INTACT INSULAE; BIOPSY; GLAND; CYTOPATHOLOGY; STRUMA AB BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) is an uncommon and aggressive malignancy. Despite the significant clinical implications of a diagnosis of PDTC, its cytomorphologic features have not been well defined. Statistical analysis was applied to a series of 40 PDTCs to identify a specific set of cytomorphologic features that characterized these tumors on fine-needle aspiration biopsy (FNAB). METHODS: In total, 40 thyroid FNABs that were highly diagnosed histologically as PDTC (19 insular carcinomas and 21 noninsular carcinomas) comprised the study group. A control group of 40 well differentiated thyroid neoplasms were selected for comparison. All FNABs were reviewed and scored for a series of 32 cytomorphologic features. The results were evaluated using univariate and stepwise logistic regression (SLR) analyses. RESULTS: In univariate analysis, 17 cytomorphologic features were identified that characterized the 40 PDTCs: insular, solid, or trabecular cytoarchitecture (P < .001); high cellularity (P = .007); necrosis (P = .025) or background debris (P = .025); plasmacytoid appearance (P = .0007); single cells (P < .0001); high nuclear/cytoplasmic ratio (P < .0001); scant cytoplasm (P = .03); nuclear atypia (P < .0001), including nuclear pleomorphism (P = .0052) and anisokaryosis (P < .0001); granular/coarse chromatin (P = .026); naked nuclei (P = .01); mitotic activity (P = .0001) and apoptosis (P < .0001); endothelial wrapping (P = .0053); and severe crowding (P < .0001). In logistic regression analysis, severe crowding (P = .0008) and cytoarchitecture (P < .0001) were identified as the most significant cytomorphologic features of PDTCs, and the combination of cytoarchitecture, severe crowding, single cells, and high nuclear/cytoplasmic ratio was the most predictive of PDTC. CONCLUSIONS: PDTCs have characteristic cytomorphologic features. By using logistic regression analysis, the features that were identified as the most predictive of PDTC were severe crowding, insular/solid/trabecular morphology, single cells, and high nuclear/cytoplasmic ratio. Cancer (Cancer Cytopathol) 2009;117:185-94. (C) 2009 American Cancer Society. C1 [Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bongiovanni, Massimo; Pache, Jean-Claude] Univ Hosp Geneva, Dept Pathol, Geneva, Switzerland. [Bloom, Leonard] Univ Tennessee, Ctr Hlth Sci, Clin Sci Lab, Memphis, TN 38163 USA. [Krane, Jeffrey F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Baloch, Zubair W.] Univ Penn, Dept Pathol, Med Ctr, Philadelphia, PA 19104 USA. [Powers, Celeste N.] Virginia Commonwealth Univ, Dept Pathol, Richmond, VA USA. [Hintermann, Suzanne] Unilabs Cypa, Lausanne, Switzerland. RP Faquin, WC (reprint author), Massachusetts Gen Hosp, Dept Pathol, WRN 219,55 Fruit St, Boston, MA 02114 USA. EM wfaquin@partners.org RI Bongiovanni, Massimo/C-3144-2017 OI Bongiovanni, Massimo/0000-0001-9846-6682 NR 30 TC 23 Z9 28 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUN 25 PY 2009 VL 117 IS 3 BP 185 EP 194 DI 10.1002/cncy.20023 PG 10 WC Oncology; Pathology SC Oncology; Pathology GA 459IT UT WOS:000267095900007 PM 19365842 ER PT J AU Shen, J Brugge, WR DiMaio, CJ Pitman, MB AF Shen, Jian Brugge, William R. DiMaio, Christopher J. Pitman, Martha B. TI Molecular Analysis of Pancreatic Cyst Fluid A Comparative Analysis With Current Practice of Diagnosis SO CANCER CYTOPATHOLOGY LA English DT Article DE pancreatic neoplastic mucinous cysts; mucinous cystic neoplasm; intraductal papillary mucinous neoplasm; k-ras gene; loss of heterozygosity; molecular diagnosis; clinical consensus diagnosis ID FINE-NEEDLE-ASPIRATION; PAPILLARY MUCINOUS NEOPLASMS; ETHANOL LAVAGE; LESIONS; MANAGEMENT; CYTOLOGY; TUMORS; INJECTION; SAMPLES AB BACKGROUND: The management of patients with pancreatic cysts is based on the preoperative distinction of nonmucinous and mucinous cysts in general and of benign and malignant cysts in particular. An accurate diagnosis is challenging, because endoscopic ultrasound (EUS) and cyst fluid analysis for carcinoembryonic antigen (CEA) and cytology have low sensitivity and specificity. Currently, molecular analysis is a commercially available test that promises an accurate diagnosis. The objective of the current study was to correlate a commercially provided molecular diagnosis (MDx) with a clinical consensus diagnosis (CCD) in the general categories of malignant, benign mucinous, and benign nonmucinous pancreatic cysts. METHODS: Pancreatic cysts that had aspirated fluid submitted for a commercially available molecular test (PathFinderTG) were reviewed. The CCD, defined by histology, malignant cytology, or 2 concordant tests (such as EUS, cytology, or CEA >= 192 ng/mL for mucinous cysts), was categorized as malignant, benign mucinous, or benign nonmucinous cyst in 35 patients. Their MDx, based on the PathFinderTG report, including analysis of k-ras mutation, loss of heterozygosity, and quantity/quality of DNA, also was classified as malignant, benign mucinous, or benign nonmucinous cyst. These 2 diagnoses were compared and correlated. RESULTS: The concordance between CCD and MDx was 5 of 6 (83%),13 of 15 (87%), and 13 of 14 (93%), respectively, for malignant, benign mucinous, and benign nonmucinous cysts, with an overall Cohen kappa statistic of 0.816. The sensitivity, specificity, and positive predictive value of the MDx were 83%, 100%, and 100%, respectively, for a malignant cyst and 86%, 93%, and 95%, respectively for a benign mucinous cyst. CONCLUSIONS: Molecular analysis of pancreatic cyst fluid adds diagnostic value to the preoperative diagnosis with high sensitivity, specificity, and positive predictive value for the diagnosis of malignant and benign mucinous pancreatic cysts. Cancer (Cancer Cytopathol) 2009;117:217-27. (C) 2009 American Cancer Society. C1 [Pitman, Martha B.] Harvard Univ, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Sch Med,Dept Pathol, Boston, MA 02114 USA. [Brugge, William R.; DiMaio, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Dept Med, Sch Med, Boston, MA 02114 USA. RP Pitman, MB (reprint author), Harvard Univ, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Sch Med,Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM mpitman@partners.org FU RedPath IP FX This article was not supported financially by RedPath IP or any other entity. NR 29 TC 67 Z9 67 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUN 25 PY 2009 VL 117 IS 3 BP 217 EP 227 DI 10.1002/cncy.20027 PG 11 WC Oncology; Pathology SC Oncology; Pathology GA 459IT UT WOS:000267095900011 PM 19415731 ER PT J AU Curran, SP Wu, XY Riedel, CG Ruvkun, G AF Curran, Sean P. Wu, Xiaoyun Riedel, Christian G. Ruvkun, Gary TI A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants SO NATURE LA English DT Article ID OXIDATIVE-STRESS-RESPONSE; GENOME-WIDE RNAI; C-ELEGANS; LIFE-SPAN; POSTMITOTIC CELLS; GENE-EXPRESSION; FACTOR SKN-1; DNA-DAMAGE; DAF-16; IDENTIFICATION AB Unlike the soma, which ages during the lifespan of multicellular organisms, the germ line traces an essentially immortal lineage. Genomic instability in somatic cells increases with age, and this decline in somatic maintenance might be regulated to facilitate resource reallocation towards reproduction at the expense of cellular senescence. Here we show that Caenorhabditis elegans mutants with increased longevity exhibit a soma-to-germline transformation of gene expression programs normally limited to the germ line. Decreased insulin-like signalling causes the somatic misexpression of the germline-limited pie-1 and pgl family of genes in intestinal and ectodermal tissues. The forkhead boxO1A (FOXO) transcription factor DAF-16, the major transcriptional effector of insulin-like signalling, regulates pie-1 expression by directly binding to the pie-1 promoter. The somatic tissues of insulin-like mutants are more germline-like and protected from genotoxic stress. Gene inactivation of components of the cytosolic chaperonin complex that induce increased longevity also causes somatic misexpression of PGL-1. These results indicate that the acquisition of germline characteristics by the somatic cells of C. elegans mutants with increased longevity contributes to their increased health and survival. C1 [Curran, Sean P.; Wu, Xiaoyun; Riedel, Christian G.; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Curran, Sean P.; Wu, Xiaoyun; Riedel, Christian G.; Ruvkun, Gary] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Ruvkun, G (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM ruvkun@molbio.mgh.harvard.edu OI Riedel, Christian/0000-0002-3689-8022 FU National Institutes of Health; National Institute on Aging [F32-AG026207, R01-AG016636]; European Molecular Biology Organization; Human Frontier Science Program FX Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health National Center for Research Resources. We thank A. Conery, H. Gabel, J. Melo, E. O'Rourke, D. Simon, A. Soukas and M. Wang for reagents, discussion and reading of the manuscript; G. Seydoux and members of the Ruvkun, Ausubel and Kaplan laboratories for discussion; S. Strome for the pie-1p::gfp::pgl-1 strain and C. Mello for monoclonal antisera against PGL-1, S. S. Lee, S. Ercan and the Kingston laboratory for technical advice on ChIP. This work was supported by grants from the National Institutes of Health and the National Institute on Aging F32-AG026207 to S. P. C. and R01-AG016636 to G. R. and the European Molecular Biology Organization and the Human Frontier Science Program to C. G. R. NR 49 TC 68 Z9 92 U1 1 U2 17 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 JUN 25 PY 2009 VL 459 IS 7250 BP 1079 EP U60 DI 10.1038/nature08106 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 466BX UT WOS:000267636700033 PM 19506556 ER PT J AU Scott, KL Kabbarah, O Liang, MC Ivanova, E Anagnostou, V Wu, J Dhakal, S Wu, M Chen, SJ Feinberg, T Huang, J Saci, A Widlund, HR Fisher, DE Xiao, YH Rimm, DL Protopopov, A Wong, KK Chin, L AF Scott, Kenneth L. Kabbarah, Omar Liang, Mei-Chih Ivanova, Elena Anagnostou, Valsamo Wu, Joyce Dhakal, Sabin Wu, Min Chen, Shujuan Feinberg, Tamar Huang, Joseph Saci, Abdel Widlund, Hans R. Fisher, David E. Xiao, Yonghong Rimm, David L. Protopopov, Alexei Wong, Kwok-Kin Chin, Lynda TI GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer SO NATURE LA English DT Article ID P70 S6 KINASE; CELL-SIZE; GOLGI; TARGET; GROWTH; TOR; GLYCOSYLTRANSFERASES; PHOSPHORYLATION; LOCALIZATION; PROGRESSION AB Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma ( 32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans- Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin ( TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use. C1 [Scott, Kenneth L.; Kabbarah, Omar; Liang, Mei-Chih; Wu, Joyce; Dhakal, Sabin; Wu, Min; Chen, Shujuan; Feinberg, Tamar; Huang, Joseph; Wong, Kwok-Kin; Chin, Lynda] Harvard Univ, Ctr Canc, Dept Med Oncol, Boston, MA 02115 USA. [Ivanova, Elena; Xiao, Yonghong; Protopopov, Alexei; Chin, Lynda] Harvard Univ, Ctr Canc, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Widlund, Hans R.; Fisher, David E.] Harvard Univ, Ctr Canc, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wong, Kwok-Kin] Harvard Univ, Ctr Canc, Ludwig Ctr Dana Farber, Boston, MA 02115 USA. [Anagnostou, Valsamo; Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Saci, Abdel] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Widlund, Hans R.; Chin, Lynda] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Fisher, David E.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Chin, L (reprint author), Harvard Univ, Ctr Canc, Dept Med Oncol, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu OI wong, kwok kin/0000-0001-6323-235X FU American Cancer Society [PF-07-039-01-CSM]; National Institutes of Health (NIH) [5-T32-AR07098-31, R01 AG2400401, R01 CA122794, RO-1 CA 114277, RO1 CA93947, P50 CA93683]; Program of Research Excellence (SPORE) grant [P50 CA090578] FX We thank R. DePinho for critical reading of the manuscript, and L. Cantley, as well as members of the Chin laboratory, for helpful discussion. We thank H. Ying for assistance with confocal microscopy. The rabbit polyclonal antibody against human GOLPH3 was kindly provided by J. J. Bergeron of McGill University. Mouse monoclonal antibody against human GOLPH3, C19, was generated at the Dana-Farber/Harvard Cancer Center Monoclonal Antibody Core Facility. K. L. S. is at present supported by a Postdoctoral Fellowship from the American Cancer Society (PF-07-039-01-CSM), and K. L. S. and O. K. were previously supported by a National Institutes of Health (NIH) Training Grant appointment in the Department of Dermatology at Brigham and Women's Hospital (5-T32-AR07098-31). K.-K. W. was supported by a Program of Research Excellence (SPORE) grant (P50 CA090578) and NIH grants (R01 AG2400401; R01 CA122794). The AQUA immunofluorescence study was supported by a grant from the NIH to D. L. R. (RO-1 CA 114277). This work is primarily supported by grants from the NIH to L. C. (RO1 CA93947; P50 CA93683). NR 33 TC 146 Z9 163 U1 1 U2 19 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 JUN 25 PY 2009 VL 459 IS 7250 BP 1085 EP U68 DI 10.1038/nature08109 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 466BX UT WOS:000267636700034 PM 19553991 ER PT J AU Baek, KH Zaslavsky, A Lynch, RC Britt, C Okada, Y Siarey, RJ Lensch, MW Park, IH Yoon, SS Minami, T Korenberg, JR Folkman, J Daley, GQ Aird, WC Galdzicki, Z Ryeom, S AF Baek, Kwan-Hyuck Zaslavsky, Alexander Lynch, Ryan C. Britt, Carmella Okada, Yoshiaki Siarey, Richard J. Lensch, M. William Park, In-Hyun Yoon, Sam S. Minami, Takashi Korenberg, Julie R. Folkman, Judah Daley, George Q. Aird, William C. Galdzicki, Zygmunt Ryeom, Sandra TI Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1 SO NATURE LA English DT Article ID CRITICAL REGION; ENDOTHELIAL-CELLS; GENE-EXPRESSION; CYCLOSPORINE-A; MOUSE MODEL; ANGIOGENESIS; VEGF; TARGET; CHROMOSOME-21; REGRESSION AB The incidence of many cancer types is significantly reduced in individuals with Down's syndrome(1-4), and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor ( VEGF)mediated angiogenic signalling by the calcineurin pathway(5-10). Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals. C1 [Baek, Kwan-Hyuck; Zaslavsky, Alexander; Lynch, Ryan C.; Britt, Carmella; Folkman, Judah; Ryeom, Sandra] Childrens Hosp Boston, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA. [Okada, Yoshiaki; Aird, William C.] Beth Israel Deaconess Med Ctr, Div Mol & Vasc Med, Vasc Biol Res Ctr, Boston, MA 02115 USA. [Siarey, Richard J.; Galdzicki, Zygmunt] Uniformed Serv Univ Hlth Serv, Sch Med, Mol & Cellular Biol Program, Dept Anat Physiol & Genet Neurosci, Bethesda, MD 20814 USA. [Lensch, M. William; Park, In-Hyun; Daley, George Q.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Dept Med, Boston, MA 02115 USA. [Lensch, M. William; Park, In-Hyun; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Yoon, Sam S.] Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. [Minami, Takashi] Univ Tokyo, Adv Sci & Technol Res Ctr, Tokyo 1538904, Japan. [Korenberg, Julie R.] Univ Utah, Inst Brain, Salt Lake City, UT 84108 USA. [Korenberg, Julie R.] Univ Utah, Dept Pediat, Salt Lake City, UT 84108 USA. RP Ryeom, S (reprint author), Childrens Hosp Boston, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA. EM sandra.ryeom@childrens.harvard.edu FU Howard Hughes Medical Institute; Harvard Stem Cell Institute; National Institute of Health Director's Pioneer Award; NHLBI; Jerome Lejeune Foundation; USUHS; Smith Family Medical Foundation; Garrett B. Smith Foundation; Annie's Fun Foundation FX We thank G. Evan, C. Kim, K. Cichowski and J. Italiano for critical discussions and advice. This work was supported by the Howard Hughes Medical Institute ( G. Q. D.), Harvard Stem Cell Institute ( G. Q. D.), the National Institute of Health Director's Pioneer Award ( G. Q. D.), NHLBI ( W. C. A.), Jerome Lejeune Foundation ( Z. G.), USUHS ( Z. G.), the Smith Family Medical Foundation ( S. R.), the Garrett B. Smith Foundation ( S. R.) and Annie's Fun Foundation ( S. R.). NR 30 TC 178 Z9 183 U1 0 U2 38 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 JUN 25 PY 2009 VL 459 IS 7250 BP 1126 EP U113 DI 10.1038/nature08062 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 466BX UT WOS:000267636700043 PM 19458618 ER PT J AU Adamo, L Naveiras, O Wenzel, PL McKinney-Freeman, S Mack, PJ Gracia-Sancho, J Suchy-Dicey, A Yoshimoto, M Lensch, MW Yoder, MC Garcia-Cardena, G Daley, GQ AF Adamo, Luigi Naveiras, Olaia Wenzel, Pamela L. McKinney-Freeman, Shannon Mack, Peter J. Gracia-Sancho, Jorge Suchy-Dicey, Astrid Yoshimoto, Momoko Lensch, M. William Yoder, Mervin C. Garcia-Cardena, Guillermo Daley, George Q. TI Biomechanical forces promote embryonic haematopoiesis SO NATURE LA English DT Article ID NITRIC-OXIDE SYNTHASE; STEM-CELLS; MOUSE EMBRYO; DEFINITIVE HEMATOPOIESIS; IN-VITRO; YOLK-SAC; EXPRESSION DEFINES; ENDOTHELIAL-CELLS; PROGENITOR CELLS; FLOW AB Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system(1,2). After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3-5), a master regulator of haematopoiesis, and give rise to haematopoietic cells(4). It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential(6). Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in CD41(+)c-Kit(+) haematopoietic progenitor cells(7), concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta-gonads-mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling(8), compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development. C1 [Naveiras, Olaia; Wenzel, Pamela L.; McKinney-Freeman, Shannon; Lensch, M. William; Daley, George Q.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Adamo, Luigi; Mack, Peter J.; Gracia-Sancho, Jorge; Suchy-Dicey, Astrid; Garcia-Cardena, Guillermo] Brigham & Womens Hosp, Dept Pathol, Ctr Excellence Vasc Biol, Boston, MA 02115 USA. [Naveiras, Olaia; Wenzel, Pamela L.; McKinney-Freeman, Shannon; Lensch, M. William; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Naveiras, Olaia; Wenzel, Pamela L.; McKinney-Freeman, Shannon; Lensch, M. William; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Naveiras, Olaia; Wenzel, Pamela L.; McKinney-Freeman, Shannon; Lensch, M. William; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Naveiras, Olaia; Wenzel, Pamela L.; McKinney-Freeman, Shannon; Lensch, M. William; Daley, George Q.] Harvard Univ, Stem Cell Inst, Boston, MA 02115 USA. [Naveiras, Olaia; Wenzel, Pamela L.; McKinney-Freeman, Shannon; Lensch, M. William; Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Naveiras, Olaia; Wenzel, Pamela L.; McKinney-Freeman, Shannon; Lensch, M. William; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Yoshimoto, Momoko; Yoder, Mervin C.] Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. RP Daley, GQ (reprint author), Childrens Hosp Boston, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. EM guillermo_garcia-cardena@hms.harvard.edu; george.daley@childrens.harvard.edu RI Wenzel, Pamela/A-2992-2010; Gracia-Sancho, Jordi/C-8920-2014; Yoshimoto, Momoko/N-4238-2014; OI Gracia-Sancho, Jordi/0000-0001-7736-4089; Yoshimoto, Momoko/0000-0002-7272-6682; Suchy-Dicey, Astrid/0000-0002-5608-7817 FU Giovanni Armenise- Harvard Foundation; Barrie de la Maza Foundation; National Institutes of Health; NIH Director's Pioneer Award of the NIH Roadmap for Medical Research; Burroughs Wellcome Fund Clinical Scientist Award; Howard Hughes Medical Institute FX We thank G. Losyev for assistance with flow cytometry, S. Schmitt for critical help in optimizing AGM culture conditions, C. Lengerke and Y. Mukouyama for critical discussions. L. A. was partially funded by the Giovanni Armenise- Harvard Foundation. O. N. was partially funded by the Barrie de la Maza Foundation. G. G.-C. was supported by grants from the National Institutes of Health and G. Q. D was supported by grants from the National Institutes of Health ( NIH), and the NIH Director's Pioneer Award of the NIH Roadmap for Medical Research. G. Q. D. is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and is an Investigator of the Howard Hughes Medical Institute. NR 33 TC 239 Z9 247 U1 3 U2 39 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 JUN 25 PY 2009 VL 459 IS 7250 BP 1131 EP U120 DI 10.1038/nature08073 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 466BX UT WOS:000267636700044 PM 19440194 ER PT J AU Avram, MM Hoang, M AF Avram, Mathew M. Hoang, Mai TI A Woman with a Blistering Cutaneous Eruption Acute generalized exanthematous pustulosis due to hydroxychloroquine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EUROSCAR; AGEP C1 [Avram, Mathew M.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Hoang, Mai] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Avram, Mathew M.] Harvard Univ, Sch Med, Dept Dermatol, Cambridge, MA 02138 USA. [Hoang, Mai] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Avram, MM (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. NR 13 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 25 PY 2009 VL 360 IS 26 BP 2771 EP 2777 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 461RC UT WOS:000267286600013 PM 19553651 ER PT J AU Cheng, S Keyes, MJ Larson, MG McCabe, EL Newton-Cheh, C Levy, D Benjamin, EJ Vasan, RS Wang, TJ AF Cheng, Susan Keyes, Michelle J. Larson, Martin G. McCabe, Elizabeth L. Newton-Cheh, Christopher Levy, Daniel Benjamin, Emelia J. Vasan, Ramachandran S. Wang, Thomas J. TI Long-term Outcomes in Individuals With Prolonged PR Interval or First-Degree Atrioventricular Block SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY HEART-DISEASE; ATRIAL-FIBRILLATION; RISK-FACTORS; NATURAL-HISTORY; WAVE DURATION; CONDUCTION; REGURGITATION; POPULATION; PROGNOSIS; FEATURES AB Context Prolongation of the electrocardiographic PR interval, known as first-degree atrioventricular block when the PR interval exceeds 200 milliseconds, is frequently encountered in clinical practice. Objective To determine the clinical significance of PR prolongation in ambulatory individuals. Design, Setting, and Participants Prospective, community-based cohort including 7575 individuals from the Framingham Heart Study (mean age, 47 years; 54% women) who underwent routine 12-lead electrocardiography. The study cohort underwent prospective follow-up through 2007 from baseline examinations in 1968-1974. Multivariable-adjusted Cox proportional hazards models were used to examine the associations of PR interval with the incidence of arrhythmic events and death. Main Outcome Measures Incident atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. Results During follow-up, 481 participants developed AF, 124 required pacemaker implantation, and 1739 died. At the baseline examination, 124 individuals had PR intervals longer than 200 milliseconds. For those with PR intervals longer than 200 milliseconds compared with those with PR intervals of 200 milliseconds or shorter, incidence rates per 10 000 person-years were 140 (95% confidence interval [CI], 95-208) vs 36 (95% CI, 32-39) for AF, 59 (95% CI, 40-87) vs 6 (95% CI, 5-7) for pacemaker implantation, and 334 (95% CI, 260-428) vs 129 (95% CI, 123-135) for all-cause mortality. Corresponding absolute risk increases were 1.04% (AF), 0.53% (pacemaker implantation), and 2.05% (all-cause mortality) per year. In multivariable analyses, each 20-millisecond increment in PR was associated with an adjusted hazard ratio (HR) of 1.11 (95% CI, 1.02-1.22; P = .02) for AF, 1.22 (95% CI, 1.14-1.30; P < .001) for pacemaker implantation, and 1.08 (95% CI, 1.02-1.13; P = .005) for all-cause mortality. Individuals with first-degree atrioventricular block had a 2-fold adjusted risk of AF (HR, 2.06; 95% CI, 1.36-3.12; P < .001), 3-fold adjusted risk of pacemaker implantation (HR, 2.89; 95% CI, 1.83-4.57; P < .001), and 1.4-fold adjusted risk of all-cause mortality (HR, 1.44, 95% CI, 1.09-1.91; P = .01). Conclusion Prolongation of the PR interval is associated with increased risks of AF, pacemaker implantation, and all-cause mortality. JAMA. 2009; 301(24):2571-2577 C1 [Cheng, Susan; McCabe, Elizabeth L.; Newton-Cheh, Christopher; Wang, Thomas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cheng, Susan; Keyes, Michelle J.; Larson, Martin G.; McCabe, Elizabeth L.; Newton-Cheh, Christopher; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Newton-Cheh, Christopher] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cheng, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA 02114 USA. [Cheng, Susan] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Clin Investigator Training Program, Boston, MA 02114 USA. [Keyes, Michelle J.; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Wang, TJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health [N01-HC-25195]; [K24-HL-04334] FX Funding/Support: The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. Dr Vasan was supported in part by grant K24-HL-04334. NR 37 TC 197 Z9 202 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 24 PY 2009 VL 301 IS 24 BP 2571 EP 2577 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 461KU UT WOS:000267266500022 PM 19549974 ER PT J AU Strenzke, N Chanda, S Kopp-Scheinpflug, C Khimich, D Reim, K Bulankina, AV Neef, A Wolf, F Brose, N Xu-Friedman, MA Moser, T AF Strenzke, Nicola Chanda, Soham Kopp-Scheinpflug, Cornelia Khimich, Darina Reim, Kerstin Bulankina, Anna V. Neef, Andreas Wolf, Fred Brose, Nils Xu-Friedman, Matthew A. Moser, Tobias TI Complexin-I Is Required for High-Fidelity Transmission at the Endbulb of Held Auditory Synapse SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ANTEROVENTRAL COCHLEAR NUCLEUS; RETINAL RIBBON SYNAPSES; NEUROTRANSMITTER RELEASE; HAIR-CELLS; HEARING-LOSS; TRANSMITTER RELEASE; RECIPROCAL SYNAPSES; MEMBRANE-FUSION; NERVE FIBERS; SNARE AB Complexins (CPXs I-IV) presumably act as regulators of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, but their function in the intact mammalian nervous system is not well established. Here, we explored the role of CPXs in the mouse auditory system. Hearing was impaired in CPXI knock-out mice but normal in knock-out mice for CPXs II, III, IV, and III/IV as measured by auditory brainstem responses. Complexins were not detectable in cochlear hair cells but CPX I was expressed in spiral ganglion neurons (SGNs) that give rise to the auditory nerve. Ca(2+)-dependent exocytosis of inner hair cells and sound encoding by SGNs were unaffected in CPX I knock-out mice. In the absence of CPX I, the resting release probability in the endbulb of Held synapses of the auditory nerve fibers with bushy cells in the cochlear nucleus was reduced. As predicted by computational modeling, bushy cells had decreased spike rates at sound onset as well as longer and more variable first spike latencies explaining the abnormal auditory brainstem responses. In addition, we found synaptic transmission to outlast the stimulus at many endbulb of Held synapses in vitro and in vivo, suggesting impaired synchronization of release to stimulus offset. Although sound encoding in the cochlea proceeds in the absence of complexins, CPX I is required for faithful processing of sound onset and offset in the cochlear nucleus. C1 [Strenzke, Nicola; Khimich, Darina; Bulankina, Anna V.; Moser, Tobias] Univ Gottingen, Sch Med, InnerEarLab, Dept Otolaryngol, D-37099 Gottingen, Germany. [Strenzke, Nicola] Harvard Univ, Eaton Peabody Lab, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Chanda, Soham; Xu-Friedman, Matthew A.] SUNY Buffalo, Dept Biol Sci, Buffalo, NY 14260 USA. [Kopp-Scheinpflug, Cornelia] Univ Leipzig, Inst Zool, D-04103 Leipzig, Germany. [Reim, Kerstin; Brose, Nils] Max Planck Inst Expt Med, Dept Mol Neurobiol, D-37075 Gottingen, Germany. [Reim, Kerstin; Brose, Nils] Max Planck Inst Expt Med, Ctr Mol Physiol Brain, D-37075 Gottingen, Germany. [Neef, Andreas; Wolf, Fred; Moser, Tobias] Univ Gottingen, Bernstein Ctr Computat Neurosci, D-37073 Gottingen, Germany. [Wolf, Fred] Max Planck Inst Dynam & Self Org, D-37073 Gottingen, Germany. RP Moser, T (reprint author), Univ Gottingen, Sch Med, InnerEarLab, Dept Otolaryngol, D-37099 Gottingen, Germany. EM brose@em.mpg.de; tmoser@gwdg.de RI Wolf, Fred/D-5771-2011; Moser, Tobias/L-5068-2014 OI Wolf, Fred/0000-0002-7068-3762; Moser, Tobias/0000-0001-7145-0533 FU Max Planck Society; German Federal Ministry of Education and Research [01GQ0433]; German Research Foundation [FZT-103]; European Council; National Institutes of Health [DC008125]; Bernstein Center for Computational Neuroscience Gottingen FX This work was supported by a Max Planck Society Tandem-Project grant (N.B., T. M.); the German Federal Ministry of Education and Research [Bernstein Center Grant 01GQ0433 (T. M.)]; the German Research Foundation [ fellowship (N.S.); Center for Molecular Physiology of the Brain Grant FZT-103 (N.B., T. M.); a grant to Dr. R. Rubsamen, University of Leipzig, Leipzig, Germany (supporting C. K.-S.)]; a European Council Eurohear grant (T. M.); and National Institutes of Health Grant DC008125 (M. A. X.-F.). A.N. is a Fellow of the Bernstein Center for Computational Neuroscience Gottingen. We thank M. C. Liberman for ample mentoring concering auditory nerve fiber recordings and A. Gehrt, M. Koppler, M. Degenhardt, and C. Rudiger for expert technical assistance. This study was designed by T. M. and N.B. with contributions of N. S., M. A. X.-F., D. K., C. K.-S., and K. R. The experimental work was performed by N. S., D. K., K. R., C. K.-S., A. V. B., and S. C. A. N. performed the computational modeling, collaborating with M. A. X.-F. T. M., N. S., D. K., M. A. X.-F., C. K.-S., A. N., and N. B. prepared this manuscript. NR 52 TC 54 Z9 54 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 24 PY 2009 VL 29 IS 25 BP 7991 EP 8004 DI 10.1523/JNEUROSCI.0632-09.2009 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 462GL UT WOS:000267339000006 PM 19553439 ER PT J AU Scalapino, KJ Daikh, DI AF Scalapino, Kenneth J. Daikh, David I. TI Suppression of Glomerulonephritis in NZB/NZW Lupus Prone Mice by Adoptive Transfer of Ex Vivo Expanded Regulatory T Cells SO PLOS ONE LA English DT Article AB Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown cause characterized by expansion of autoreactive lymphocytes. Regulatory T cells (T(regs)) are a component of the normal immune system and contribute to the maintenance of peripheral tolerance. T(reg) abnormalities have been associated with several autoimmune diseases and there is interest in the role of T(regs) in SLE. We previously demonstrated that transfer of expanded CD4(+)CD25(+)CD62L(HI) T(regs) slows the development of lupus in (NZBxNZW)F(1) (B/W) mice. However in the absence of T(reg) specific surface antigens, cell purification remains a compromise between the breadth and purity of the population isolated. Importantly, purified populations always contain Foxp3(-) effector T cells (T(effs)) that theoretically could exacerbate autoimmunity in the recipient. Here we explore the impact of transferring the more comprehensive, but less pure T(reg) subset defined by CD4(+)CD25(+) expression on development of murine lupus. All cells were FACS sorted and expanded prior to adoptive transfer. Development of proteinuria and survival were measured. We found that exogenous expansion of CD4(+)CD25(+) cells produced a population containing 70-85% CD4(+)Foxp3(+) T(regs). Expanded T(regs) had higher CTLA-4 and Foxp3 expression, increased in vitro suppression capacity, and prolonged in vivo survival as compared to freshly isolated cells. Adoptive transfer of expanded CD4(+)CD25(+) T(regs) inhibited the onset of glomerulonephritis and prolonged survival in mice. Importantly the population of T(eff) contained within the adoptively transferred cells had reduced survival and proliferation capacity as compared to either co-transferred T(regs) or transferred T(effs) expanded in the absence of T(regs). These studies demonstrate that adoptive transfer of expanded CD4(+)CD25(+)Foxp3(+) T(regs) has the capacity to inhibit the onset of murine lupus and that this capacity is significant despite transfer of co-cultured T(eff) cells. These data indicate that when co-expanded with regulatory T cells, exogenously activated T(effs) from autoimmune patients may not pose a significant risk of promoting disease. RP Scalapino, KJ (reprint author), San Francisco VA Med Ctr, Arthrit Sect, San Francisco, CA USA. EM daikh@itsa.ucsf.edu NR 36 TC 21 Z9 23 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 JUN 24 PY 2009 VL 4 IS 6 AR e6031 DI 10.1371/journal.pone.0006031 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 462MF UT WOS:000267356500015 PM 19551149 ER PT J AU Rigotti, NA AF Rigotti, Nancy A. TI Helping smokers with cardiac disease to abstain from tobacco after a stay in hospital SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID SMOKING-CESSATION; MYOCARDIAL-INFARCTION; INTERVENTION; MORTALITY C1 [Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM nrigotti@partners.org NR 11 TC 10 Z9 10 U1 0 U2 2 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 JUN 23 PY 2009 VL 180 IS 13 BP 1283 EP 1284 DI 10.1503/cmaj.090729 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 458IH UT WOS:000267010200002 PM 19546446 ER PT J AU Lee, DS Gona, P Vasan, RS Larson, MG Benjamin, EJ Wang, TJ Tu, JV Levy, D AF Lee, Douglas S. Gona, Philimon Vasan, Ramachandran S. Larson, Martin G. Benjamin, Emelia J. Wang, Thomas J. Tu, Jack V. Levy, Daniel TI Relation of Disease Pathogenesis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction Insights From the Framingham Heart Study of the National Heart, Lung, and Blood Institute SO CIRCULATION LA English DT Article DE coronary disease; epidemiology; heart diseases; heart failure; hypertension; mortality; ventricles ID VENTRICULAR SYSTOLIC FUNCTION; CLINICAL DETERMINANTS; QRS DURATION; MORTALITY; POPULATION; CARDIOMYOPATHY; DYSFUNCTION; PREVALENCE; SURVIVAL; SPECTRUM AB Background-The contributions of risk factors and disease pathogenesis to heart failure with preserved ejection fraction (HFPEF) versus heart failure with reduced ejection fraction (HFREF) have not been fully explored. Methods and Results-We examined clinical characteristics and risk factors at time of heart failure onset and long-term survival in Framingham Heart Study participants according to left ventricular ejection fraction <= 45% (n = 314; 59%) versus >45% (n = 220; 41%) and hierarchical causal classification. Heart failure was attributed to coronary heart disease in 278 participants (52%), valvular heart disease in 42 (8%), hypertension in 140 (26%), or other/unknown causes in 74 (14%). Multivariable predictors of HFPEF (versus HFREF) included elevated systolic blood pressure (odds ratio [OR] = 1.13 per 10 mm Hg; 95% confidence interval [CI], 1.04 to 1.22), atrial fibrillation (OR = 4.23; 95% CI, 2.38 to 7.52), and female sex (OR = 2.29; 95% CI, 1.35 to 3.90). Conversely, prior myocardial infarction (OR = 0.32; 95% CI, 0.19 to 0.53) and left bundle-branch block QRS morphology (OR = 0.21; 95% CI, 0.10 to 0.46) reduced the odds of HFPEF. Long-term prognosis was grim, with a median survival of 2.1 years (5-year mortality rate, 74%), and was equally poor in men and women with HFREF or HFPEF. Conclusions-Among community patients with new-onset heart failure, there are differences in causes and time-of-onset clinical characteristics between those with HFPEF versus HFREF. In people with HFREF, mortality is increased when coronary heart disease is the underlying cause. These findings suggest that heart failure with reduced left ventricular systolic function and heart failure with preserved left ventricular systolic function are partially distinct entities, with potentially different approaches to early detection and prevention. (Circulation. 2009; 119: 3070-3077.) C1 [Gona, Philimon; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.; Wang, Thomas J.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Lee, Douglas S.; Tu, Jack V.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Lee, Douglas S.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Gona, Philimon; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Tu, Jack V.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nih.gov RI Lee, Douglas/J-4315-2014; OI Larson, Martin/0000-0002-9631-1254; Tu, Jack/0000-0003-0111-722X; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health [N01-HL-25195]; Canadian Institutes of Health Research Operating Grant [MOP 86718]; Team Grant; Canadian Institutes of Health Research clinician-scientist award; Canada Research Chair in Health Services Research; National Heart, Lung, and Blood Institute [2K24 H-04334] FX This study was supported by National Institutes of Health contract N01-HL-25195 to the Framingham Heart Study, a Canadian Institutes of Health Research Operating Grant (MOP 86718) and Team Grant in Cardiovascular Outcomes Research, a Canadian Institutes of Health Research clinician-scientist award (D. S. L.), and a Canada Research Chair in Health Services Research (J. V. T.). Dr Vasan was supported in part by 2K24 H-04334 (National Heart, Lung, and Blood Institute). NR 25 TC 231 Z9 237 U1 4 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 23 PY 2009 VL 119 IS 24 BP 3070 EP 3077 DI 10.1161/CIRCULATIONAHA.108.815944 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 461PI UT WOS:000267279900006 PM 19506115 ER PT J AU Goldman, S McCarren, M Morkin, E Ladenson, PW Edson, R Warren, S Ohm, J Thai, H Churby, L Barnhill, J O'Brien, T Anand, I Warner, A Hattler, B Dunlap, M Erikson, J Shih, MC Lavori, P AF Goldman, Steven McCarren, Madeline Morkin, Eugene Ladenson, Paul W. Edson, Robert Warren, Stuart Ohm, Janet Thai, Hoang Churby, Lori Barnhill, Jamie O'Brien, Terrence Anand, Inder Warner, Alberta Hattler, Brack Dunlap, Mark Erikson, John Shih, Mei-Chiung Lavori, Phil TI DITPA (3,5-Diiodothyropropionic Acid), a Thyroid Hormone Analog to Treat Heart Failure Phase II Trial Veterans Affairs Cooperative Study SO CIRCULATION LA English DT Article DE cardiac output; hemodynamics; thyroid; heart failure; pharmacology ID LEFT-VENTRICULAR PERFORMANCE; CHOLESTEROL; ACTIVATION; WEIGHT AB Background-In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results-This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2: 1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n = 57 to DITPA, n = 29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions-DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure. (Circulation. 2009; 119: 3093-3100.) C1 [Goldman, Steven] So Arizona VA Hlth Care Syst, Cardiol Sect 1 111C, Tucson, AZ 85723 USA. [McCarren, Madeline] VA Pharm Benefits Management, Hines, IL USA. [Morkin, Eugene] Univ Arizona, Tucson, AZ USA. [Ladenson, Paul W.] Johns Hopkins Univ, Baltimore, MD USA. [Edson, Robert; Churby, Lori; Shih, Mei-Chiung; Lavori, Phil] Vet Affairs Med Ctr, R&D Serv, Palo Alto, CA 94304 USA. [Warren, Stuart; Barnhill, Jamie] Vet Affairs Med Ctr, R&D Serv, Albuquerque, NM USA. [O'Brien, Terrence] Vet Affairs Med Ctr, Charleston, SC 29403 USA. [Anand, Inder] Vet Affairs Med Ctr, Minneapolis, MN USA. [Warner, Alberta] Vet Affairs Med Ctr, Los Angeles, CA USA. [Hattler, Brack] Vet Affairs Med Ctr, Denver, CO USA. [Dunlap, Mark] Vet Affairs Med Ctr, Cleveland, OH USA. [Erikson, John] Vet Affairs Med Ctr, San Antonio, TX USA. RP Goldman, S (reprint author), So Arizona VA Hlth Care Syst, Cardiol Sect 1 111C, 3601 S 6th Ave, Tucson, AZ 85723 USA. EM steven.goldman@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Science Research and Development Service, Cooperative Studies Program FX This study was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Science Research and Development Service, Cooperative Studies Program. NR 28 TC 50 Z9 52 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 23 PY 2009 VL 119 IS 24 BP 3093 EP U84 DI 10.1161/CIRCULATIONAHA.108.834424 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 461PI UT WOS:000267279900009 PM 19506112 ER PT J AU Vincent, JL AF Vincent, Justin L. TI Learning and Memory: While You Rest, Your Brain Keeps Working SO CURRENT BIOLOGY LA English DT Editorial Material ID SLEEP; FLUCTUATIONS; ADAPTATION; SEQUENCES; CORTEX; REPLAY C1 [Vincent, Justin L.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Vincent, Justin L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Vincent, Justin L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Vincent, JL (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St,WJH 274, Cambridge, MA 02138 USA. EM vincent@nmr.mgh.harvard.edu RI Vincent, Justin/B-5033-2012 NR 20 TC 6 Z9 6 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 23 PY 2009 VL 19 IS 12 BP R484 EP R486 DI 10.1016/j.cub.2009.05.024 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 462GH UT WOS:000267338500013 PM 19549494 ER PT J AU Losina, E Walensky, RP Kessler, CL Emrani, PS Reichmann, WM Wright, EA Holt, HL Solomon, DH Yelin, E Paltiel, AD Katz, JN AF Losina, Elena Walensky, Rochelle P. Kessler, Courtenay L. Emrani, Parastu S. Reichmann, William M. Wright, Elizabeth A. Holt, Holly L. Solomon, Daniel H. Yelin, Edward Paltiel, A. David Katz, Jeffrey N. TI Cost-effectiveness of Total Knee Arthroplasty in the United States Patient Risk and Hospital Volume SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID TOTAL HIP; REPLACEMENT; OSTEOARTHRITIS; OUTCOMES; ARTHRITIS; HEALTH; SURGERY; UNCERTAINTY; ADULTS; MODEL AB Background: Total knee arthroplasty (TKA) relieves pain and improves quality of life for persons with advanced knee osteoarthritis. However, to our knowledge, the cost-effectiveness of TKA and the influences of hospital volume and patient risk on TKA cost-effectiveness have not been investigated in the United States. Methods: We developed a Markov, state-transition, computer simulation model and populated it with Medicare claims data and cost and outcomes data from national and multinational sources. We projected lifetime costs and quality-adjusted life expectancy (QALE) for different risk populations and varied TKA intervention and hospital volume. Cost-effectiveness of TKA was estimated across all patient risk and hospital volume permutations. Finally, we conducted sensitivity analyses to determine various parameters' influences on cost-effectiveness. Results: Overall, TKA increased QALE from 6.822 to 7.957 quality-adjusted life years (QALYs). Lifetime costs rose from $37 100 (no TKA) to $57 900 after TKA, resulting in an incremental cost-effectiveness ratio of $18 300 per QALY. For high-risk patients, TKA increased QALE from 5.713 to 6.594 QALY, yielding a cost-effectiveness ratio of $28 100 per QALY. At all risk levels, TKA was more costly and less effective in low-volume centers than in high-volume centers. Results were insensitive to variations of key input parameters within policy-relevant, clinically plausible ranges. The greatest variations were seen for the quality of life gain after TKA and the cost of TKA. Conclusions: Total knee arthroplasty appears to be cost-effective in the US Medicare-aged population, as currently practiced across all risk groups. Policy decisions should be made on the basis of available local options for TKA. However, when a high-volume hospital is available, TKAs performed in a high-volume hospital confer even greater value per dollar spent than TKAs performed in low-volume centers. C1 [Losina, Elena; Kessler, Courtenay L.; Emrani, Parastu S.; Reichmann, William M.; Wright, Elizabeth A.; Holt, Holly L.; Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Orthoped Surg, Orthoped & Arthrit Ctr Outcomes Res, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena; Wright, Elizabeth A.; Solomon, Daniel H.; Katz, Jeffrey N.] Brigham & Womens Hosp, Clin Sci Sect, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Losina, Elena; Reichmann, William M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Yelin, Edward] Univ Calif San Francisco, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA 94143 USA. [Paltiel, A. David] Yale Univ, Sch Med, New Haven, CT USA. [Katz, Jeffrey N.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Losina, E (reprint author), Brigham & Womens Hosp, Dept Orthoped Surg, Orthoped & Arthrit Ctr Outcomes Res, 75 Francis St,BC-4, Boston, MA 02115 USA. EM elosina@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR053112, P60 AR 47782, K24 AR 02123]; Arthritis Foundation Innovative FX This research was supported in part by National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01 AR053112, P60 AR 47782, and K24 AR 02123, and an Arthritis Foundation Innovative Research Grant. NR 41 TC 190 Z9 192 U1 4 U2 12 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 JUN 22 PY 2009 VL 169 IS 12 BP 1113 EP 1121 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 461BN UT WOS:000267239300005 PM 19546411 ER PT J AU Ratai, EM Pilkenton, SJ Greco, JB Lentz, MR Bombardier, JP Turk, KW He, JL Joo, CG Lee, V Westmoreland, S Halpern, E Lackner, AA Gonzalez, RG AF Ratai, Eva-Maria Pilkenton, Sarah J. Greco, Jane B. Lentz, Margaret R. Bombardier, Jeffrey P. Turk, Katherine W. He, Julian Joo, Chan-Gyu Lee, Vallent Westmoreland, Susan Halpern, Elkan Lackner, Andrew A. Gonzalez, R. Gilberto TI In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain SO BMC NEUROSCIENCE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; AIDS DEMENTIA COMPLEX; H-1 MR SPECTROSCOPY; HIV-INFECTION; N-ACETYLASPARTATE; NEURONAL INJURY; SEROPOSITIVE INDIVIDUALS; RHESUS MACAQUES; NMR-SPECTRA; MODEL AB Background: In vivo proton magnetic resonance spectroscopy ((1)H-MRS) studies of HIV-infected humans have demonstrated significant metabolic abnormalities that vary by brain region, but the causes are poorly understood. Metabolic changes in the frontal cortex, basal ganglia and white matter in 18 SIV-infected macaques were investigated using MRS during the first month of infection. Results: Changes in the N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), creatine (Cr) and glutamine/glutamate (Glx) resonances were quantified both in absolute terms and relative to the creatine resonance. Most abnormalities were observed at the time of peak viremia, 2 weeks post infection (wpi). At that time point, significant decreases in NAA and NAA/Cr, reflecting neuronal injury, were observed only in the frontal cortex. Cr was significantly elevated only in the white matter. Changes in Cho and Cho/Cr were similar across the brain regions, increasing at 2 wpi, and falling below baseline levels at 4 wpi. MI and MI/Cr levels were increased across all brain regions. Conclusion: These data best support the hypothesis that different brain regions have variable intrinsic vulnerabilities to neuronal injury caused by the AIDS virus. C1 [Ratai, Eva-Maria; Pilkenton, Sarah J.; Greco, Jane B.; Lentz, Margaret R.; Bombardier, Jeffrey P.; Turk, Katherine W.; He, Julian; Joo, Chan-Gyu; Lee, Vallent; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Neuroradiol Div, Dept Radiol, Charlestown, MA 02129 USA. [Ratai, Eva-Maria; Pilkenton, Sarah J.; Greco, Jane B.; Lentz, Margaret R.; Bombardier, Jeffrey P.; Turk, Katherine W.; He, Julian; Joo, Chan-Gyu; Lee, Vallent; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ratai, Eva-Maria; Pilkenton, Sarah J.; Greco, Jane B.; Lentz, Margaret R.; He, Julian; Joo, Chan-Gyu; Westmoreland, Susan; Halpern, Elkan; Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Westmoreland, Susan] New England Reg Primate Res Ctr, Southborough, MA 01772 USA. [Halpern, Elkan] Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, Charlestown, MA 02129 USA. [Lackner, Andrew A.] Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. RP Gonzalez, RG (reprint author), Massachusetts Gen Hosp, Neuroradiol Div, Dept Radiol, Charlestown, MA 02129 USA. EM ratai@nmr.mgh.harvard.edu; spilkenton@framingham.edu; jrb@alumni.caltech.edu; mlentz@nmr.mgh.harvard.edu; bombardi@nmr.mgh.harvard.edu; kwtster@gmail.com; hej@helix.mgh.harvard.edu; cjoo@nmr.mgh.harvard.edu; vallent@nmr.mgh.harvard.edu; susan_westmorelant@hms.harvard.edu; elk@mgh-ita.org; alackner@tpc.tulane.edu; rggonzalez@partners.org FU NIH, including National Center for Research Resources (NCRR) [RR13214, RR13213, NS34626, RR000150, RR00168, NS051129, NS30769, MH61192, R21NS059331]; National Institute of Allergy and Infectious Diseases [A1028691]; National Center for Research Resources grant [P41RR14075]; Mental Illness and Neuroscience Discovery (MIND) Institute FX We thank Drs. Angela Carville and Elisabeth Ludlage-Moeller for animal care at the NERPRC, Eric Broadbent and Ernest Neale for veterinary technical assistance, Elizabeth Curran and Mike O'Connell for pathology support, and Robert Fuller and John Kim for participating in MR experiments and analysis. This work was supported by grants from the NIH, including National Center for Research Resources (NCRR) RR13214, RR13213, NS34626 (to RGG), and RR000150 and RR00168 (to NERPRC), NS051129 (MRL), NS30769 and MH61192 (to AAL), R21NS059331 (to EMR), and National Institute of Allergy and Infectious Diseases A1028691 (to EMR). The MGH A. A. Martinos Center for Biomedical Imaging is also supported by P41RR14075 (National Center for Research Resources grant) and the Mental Illness and Neuroscience Discovery (MIND) Institute. NR 58 TC 23 Z9 23 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD JUN 22 PY 2009 VL 10 AR 63 DI 10.1186/1471-2202-10-63 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 470PI UT WOS:000267987700001 PM 19545432 ER PT J AU Yaqoob, Z Choi, W Oh, S Lue, N Park, Y Fang-Yen, C Dasari, RR Badizadegan, K Feld, MS AF Yaqoob, Zahid Choi, Wonshik Oh, Seungeun Lue, Niyom Park, Yongkeun Fang-Yen, Christopher Dasari, Ramachandra R. Badizadegan, Kamran Feld, Michael S. TI Improved phase sensitivity in spectral domain phase microscopy using line-field illumination and self phase-referencing SO OPTICS EXPRESS LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; DYNAMICS; INTERFEROMETRY AB We report a quantitative phase microscope based on spectral domain optical coherence tomography and line-field illumination. The line illumination allows self phase-referencing method to reject common-mode phase noise. The quantitative phase microscope also features a separate reference arm, permitting the use of high numerical aperture (NA > 1) microscope objectives for high resolution phase measurement at multiple points along the line of illumination. We demonstrate that the path-length sensitivity of the instrument can be as good as 41 pm / root Hz, which makes it suitable for nanometer scale study of cell motility. We present the detection of natural motions of cell surface and two-dimensional surface profiling of a HeLa cell. (C) 2009 Optical Society of America C1 [Yaqoob, Zahid; Choi, Wonshik; Oh, Seungeun; Lue, Niyom; Park, Yongkeun; Fang-Yen, Christopher; Dasari, Ramachandra R.; Badizadegan, Kamran; Feld, Michael S.] MIT, George R Harrison Spect Lab, Cambridge, MA 02139 USA. [Choi, Wonshik] Korea Univ, Dept Phys, Seoul 136701, South Korea. [Badizadegan, Kamran] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Badizadegan, Kamran] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Choi, W (reprint author), MIT, George R Harrison Spect Lab, Cambridge, MA 02139 USA. EM wonshik@mit.edu RI Park, YongKeun/B-9017-2009; OI Fang-Yen, Christopher/0000-0002-4568-3218 FU National Center for Research Resources of the National Institutes of Health [P41-RR02594-18]; National Science Foundation [DBI-0754339]; Hamamatsu Corporation FX This work was funded by the National Center for Research Resources of the National Institutes of Health ( P41-RR02594-18), the National Science Foundation ( DBI-0754339), and Hamamatsu Corporation. NR 21 TC 23 Z9 23 U1 1 U2 10 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUN 22 PY 2009 VL 17 IS 13 BP 10681 EP 10687 DI 10.1364/OE.17.010681 PG 7 WC Optics SC Optics GA 467RW UT WOS:000267761100025 PM 19550464 ER PT J AU Spalke, T Craft, D Bortfeld, T AF Spalke, Tobias Craft, David Bortfeld, Thomas TI Analyzing the main trade-offs in multiobjective radiation therapy treatment planning databases SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID RADIOTHERAPY; OPTIMIZATION AB Multiobjective radiotherapy planning aims to capture all clinically relevant trade-offs between the various planning goals. This is accomplished by calculating a representative set of Pareto optimal solutions and storing them in a database. The structure of these representative Pareto sets is still not fully investigated. We propose two methods for a systematic analysis of multiobjective databases: principal component analysis and the isomap method. Both methods are able to extract the key trade-offs from a database and provide information which can lead to a better understanding of the clinical case and intensity-modulated radiation therapy planning in general. C1 [Spalke, Tobias] DKFZ Heidelberg, Dept Med Phys Radiat Oncol, Heidelberg, Germany. [Craft, David; Bortfeld, Thomas] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Craft, David; Bortfeld, Thomas] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Spalke, T (reprint author), DKFZ Heidelberg, Dept Med Phys Radiat Oncol, Heidelberg, Germany. EM t.spalke@dkfz-heidelberg.de FU DAAD(GermanAcademic Exchange Service) [CA103904]; National Institute of Health of the United States of America. FX This work was supported by a scholarship of the DAAD(GermanAcademic Exchange Service) and by grant CA103904 from the National Institute of Health of the United States of America. NR 10 TC 13 Z9 13 U1 2 U2 2 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 JUN 21 PY 2009 VL 54 IS 12 BP 3741 EP 3754 DI 10.1088/0031-9155/54/12/009 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 453AM UT WOS:000266582300009 PM 19478382 ER PT J AU van den Bent, MJ Vogelbaum, MA Wen, PY Macdonald, DR Chang, SM AF van den Bent, Martin J. Vogelbaum, Michael A. Wen, Patrick Y. Macdonald, David R. Chang, Susan M. TI End Point Assessment in Gliomas: Novel Treatments Limit Usefulness of Classical Macdonald's Criteria SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RECURRENT MALIGNANT GLIOMA; PROGRESSION-FREE SURVIVAL; PHASE-III TRIAL; BRAIN-TUMOR; RADIATION-THERAPY; GLIOBLASTOMA-MULTIFORME; EUROPEAN ORGANIZATION; RESPONSE CRITERIA; CLINICAL-TRIALS; MR C1 [van den Bent, Martin J.] Erasmus Univ Hosp, Daniel den Hoed Canc Ctr, Neurooncol Unit, Rotterdam, Netherlands. [Vogelbaum, Michael A.] Cleveland Clin, Dept Neurosurg, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44106 USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Div Neurol, Boston, MA 02115 USA. [Macdonald, David R.] Univ Western Ontario, Dept Oncol, London Reg Canc Program, London, ON, Canada. [Macdonald, David R.] Univ Western Ontario, Div Med Oncol, London, ON, Canada. [Chang, Susan M.] Univ Calif San Francisco, Dept Neurol Surg, Div Neurooncol, San Francisco, CA 94143 USA. RP van den Bent, MJ (reprint author), Erasmus Univ Hosp, Daniel den Hoed Canc Ctr, Neurooncol Unit, Rotterdam, Netherlands. FU NCI NIH HHS [P01 CA118816] NR 38 TC 153 Z9 154 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 2905 EP 2908 DI 10.1200/JCO.2009.22.4998 PG 4 WC Oncology SC Oncology GA 459TP UT WOS:000267133300007 PM 19451418 ER PT J AU Bilimoria, KY Bentrem, DJ Hansen, NM Bethke, KP Rademaker, AW Ko, CY Winchester, DP Winchester, DJ AF Bilimoria, Karl Y. Bentrem, David J. Hansen, Nora M. Bethke, Kevin P. Rademaker, Alfred W. Ko, Clifford Y. Winchester, David P. Winchester, David J. TI Comparison of Sentinel Lymph Node Biopsy Alone and Completion Axillary Lymph Node Dissection for Node-Positive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 94th Annual Clinical Congress of the American-College-of-Surgeons/63rd Annual Sessions of the Owen H Wangensteen Forum on Fundamental Surgical Problems CY OCT 12-16, 2008 CL San Francisco, CA SP Amer Coll Surg ID FOLLOW-UP; CONTROLLED-TRIALS; TOTAL MASTECTOMY; ACOSOG Z0011; CARCINOMA; NOMOGRAM; IRRADIATION; WOMEN AB Purpose For women with breast cancer, the role of completion axillary lymph node dissection (ALND) after identification of nodal metastases by sentinel lymph node biopsy (SLNB) has been questioned. Our objectives were to assess national nodal evaluation practice patterns and to examine differences in recurrence and survival for SLNB alone versus SLNB with completion ALND. Patients and Methods From the National Cancer Data Base (1998 to 2005), women with clinically node-negative breast cancer who underwent SLNB and who had nodal metastases were identified. Practice patterns and outcomes were examined for patients who underwent SLNB alone versus SLNB with completion ALND (median follow-up, 63 months). Results Of 97,314 patients, 20.8% underwent SLNB alone, and 79.2% underwent SLNB with completion ALND. In 2004 to 2005, patients were significantly more likely to undergo SLNB alone if they were older, had smaller tumors, or were treated at non-National Cancer Institute-designated cancer centers. In patients with macroscopic nodal metastases (n = 20,075 during 1998 to 2000), there was a nonsignificant trend toward better outcomes for completion ALND (v SLNB alone) after analysis was adjusted for differences between the two groups: axillary recurrence (hazard ratio [HR], 0.58; 95% CI, 0.32 to 1.06) and overall survival (HR, 0.89; 95% CI, 0.76 to 1.04). In patients with microscopic nodal metastases (n = 2,203 during 1998 to 2000), there were no significant differences in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND. Conclusion Compared with SLNB alone, completion ALND does not appear to improve outcomes for breast cancer patients with microscopic nodal metastases; however, there was a nonsignificant trend toward better outcomes with completion ALND for those with macroscopic disease. J Clin Oncol 27: 2946-2953. (C) 2009 by American Society of Clinical Oncology C1 [Winchester, David P.] Northwestern Univ, Amer Coll Surg, Canc Programs, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NorthShore Univ HealthSyst, Dept Surg, Evanston, IL USA. Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Winchester, DP (reprint author), Northwestern Univ, Amer Coll Surg, Canc Programs, 633 N St Claire, Chicago, IL 60611 USA. EM dwinchester@facs.org NR 43 TC 177 Z9 183 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 2946 EP 2953 DI 10.1200/JCO.2008.19.5750 PG 8 WC Oncology SC Oncology GA 459TP UT WOS:000267133300013 PM 19364968 ER PT J AU Dowsett, M Procter, M McCaskill-Stevens, W de Azambuja, E Dafni, U Rueschoff, J Jordan, B Dolci, S Abramovitz, M Stoss, O Viale, G Gelber, RD Piccart-Gebhart, M Leyland-Jones, B AF Dowsett, Mitch Procter, Marion McCaskill-Stevens, Worta de Azambuja, Evandro Dafni, Urania Rueschoff, Josef Jordan, Bruce Dolci, Stella Abramovitz, Mark Stoss, Oliver Viale, Giuseppe Gelber, Richard D. Piccart-Gebhart, Martine Leyland-Jones, Brian TI Disease-Free Survival According to Degree of HER2 Amplification for Patients Treated With Adjuvant Chemotherapy With or Without 1 Year of Trastuzumab: The HERA Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 30th Annual San Antonio Breast Cancer Symposium CY DEC 13-16, 2007 CL San Antonio, TX SP San Antonio Canc Inst, Baylor Coll Med ID HER2-POSITIVE BREAST-CANCER; GENE; HER-2/NEU; ONCOGENE AB Purpose To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. Patients and Methods IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up. Results Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab. Conclusion There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+ FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy. J Clin Oncol 27: 2962-2969. (C) 2009 by American Society of Clinical Oncology C1 [Dowsett, Mitch] Royal Marsden Hosp, Dept Acad Biochem, London SW3 6JJ, England. Frontier Sci Scotland Ltd, Kincraig, Kingussie, Scotland. NCI, NIH, Bethesda, MD 20892 USA. Univ Libre Bruxelles, Inst Jules Bordet, Dept Med Oncol, Brussels, Belgium. Univ Libre Bruxelles, Inst Jules Bordet, Dept Med, Brussels, Belgium. Breast European Adjuvant Studies Team, Brussels, Belgium. Univ Athens, Sch Nursing, Dept Publ Hlth, Athens, Greece. TARGOS Mol Pathol GmbH, Kassel, Germany. F Hoffmann La Roche Ltd, Roche Profess Diagnost, Basel, Switzerland. VM Inst Res, Montreal, PQ, Canada. European Inst Oncol, Div Pathol & Lab Med, Milan, Italy. Univ Milan, Milan, Italy. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Emory Winship Canc Inst, Atlanta, GA USA. RP Dowsett, M (reprint author), Royal Marsden Hosp, Dept Acad Biochem, Fulham Rd, London SW3 6JJ, England. EM mitch.dowsett@icr.ac.uk NR 25 TC 106 Z9 111 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 2962 EP 2969 DI 10.1200/JCO.2008.19.7939 PG 8 WC Oncology SC Oncology GA 459TP UT WOS:000267133300015 PM 19364966 ER PT J AU Willett, CG Duda, DG di Tomaso, E Boucher, Y Ancukiewicz, M Sahani, DV Lahdenranta, J Chung, DC Fischman, AJ Lauwers, GY Shellito, P Czito, BG Wong, TZ Paulson, E Poleski, M Vujaskovic, Z Bentley, R Chen, HX Clark, JW Jain, RK AF Willett, Christopher G. Duda, Dan G. di Tomaso, Emmanuelle Boucher, Yves Ancukiewicz, Marek Sahani, Dushyant V. Lahdenranta, Johanna Chung, Daniel C. Fischman, Alan J. Lauwers, Gregory Y. Shellito, Paul Czito, Brian G. Wong, Terence Z. Paulson, Erik Poleski, Martin Vujaskovic, Zeljko Bentley, Rex Chen, Helen X. Clark, Jeffrey W. Jain, Rakesh K. TI Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VASCULAR ENDOTHELIAL GROWTH; TYROSINE KINASE INHIBITOR; METASTATIC COLORECTAL-CANCER; ANTIANGIOGENIC THERAPY; TUMOR VASCULATURE; FACTOR RECEPTOR; CHEMORADIOTHERAPY; CHEMOTHERAPY; CARCINOMA; MARKERS AB Purpose To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. Patients and Methods In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. Results Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. Conclusion Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen. J Clin Oncol 27: 3020-3026. (C) 2009 by American Society of Clinical Oncology C1 [Willett, Christopher G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Willett, CG (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, Box 3085, Durham, NC 27710 USA. EM christopher.willett@duke.edu FU National Institutes of Health [R21CA099237, P01CA80124, R01CA115767]; National Foundation for Cancer Research FX Supported by the Grants No. R21CA099237 (C. G. W.), P01CA80124, and R01CA115767 from the National Institutes of Health, and a grant from the National Foundation for Cancer Research (R. K. J.). NR 18 TC 274 Z9 284 U1 4 U2 18 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 3020 EP 3026 DI 10.1200/JCO.2008.21.1771 PG 7 WC Oncology SC Oncology GA 459TP UT WOS:000267133300023 PM 19470921 ER PT J AU Zhu, AX Sahani, DV Duda, DG di Tomaso, E Ancukiewicz, M Catalano, OA Sindhwani, V Blaszkowsky, LS Yoon, SS Lahdenranta, J Bhargava, P Meyerhardt, J Clark, JW Kwak, EL Hezel, AF Miksad, R Abrams, TA Enzinger, PC Fuchs, CS Ryan, DP Jain, RK AF Zhu, Andrew X. Sahani, Dushyant V. Duda, Dan G. di Tomaso, Emmanuelle Ancukiewicz, Marek Catalano, Onofrio A. Sindhwani, Vivek Blaszkowsky, Lawrence S. Yoon, Sam S. Lahdenranta, Johanna Bhargava, Pankaj Meyerhardt, Jeffrey Clark, Jeffrey W. Kwak, Eunice L. Hezel, Aram F. Miksad, Rebecca Abrams, Thomas A. Enzinger, Peter C. Fuchs, Charles S. Ryan, David P. Jain, Rakesh K. TI Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RECEPTOR TYROSINE KINASES; ADVANCED BREAST-CANCER; TUMOR ANGIOGENESIS; CLINICAL-TRIALS; MYELOID CELLS; THERAPY; EPIDEMIOLOGY; VASCULATURE; BEVACIZUMAB AB Purpose To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response. Patients and Methods We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment. Results Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1 alpha, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome. Conclusion Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC. J Clin Oncol 27: 3027-3035. (C) 2009 by American Society of Clinical Oncology C1 [Zhu, Andrew X.] Massachusetts Gen Hosp, Dept Radiol, Dept Radiat Oncol, Div Hematol Oncol,Div Surg Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. RP Zhu, AX (reprint author), Massachusetts Gen Hosp, Dept Radiol, Dept Radiat Oncol, Div Hematol Oncol,Div Surg Oncol, 55 Fruit St,LH-POB,Room 232, Boston, MA 02114 USA. EM azhu@partners.org OI Miksad, Rebecca/0000-0003-3194-5122 FU Pfizer; National Institutes of Health [P01CA80124, R01CA115767, M01-RR-01066]; Harvard Clinical and Translational Science Center FX Supported in part by Pfizer (A. X. Z.) and by National Institutes of Health Grants No. P01CA80124 and R01CA115767 (R. K. J.) and M01-RR-01066, Harvard Clinical and Translational Science Center. A. X. Z., NR 38 TC 292 Z9 301 U1 1 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 JUN 20 PY 2009 VL 27 IS 18 BP 3027 EP 3035 DI 10.1200/JCO.2008.20.9908 PG 9 WC Oncology SC Oncology GA 459TP UT WOS:000267133300024 PM 19470923 ER PT J AU Freedman, A Neelapu, SS Nichols, C Robertson, MJ Djulbegovic, B Winter, JN Bender, JF Gold, DP Ghalie, RG Stewart, ME Esquibel, V Hamlin, P AF Freedman, Arnold Neelapu, Sattva S. Nichols, Craig Robertson, Michael J. Djulbegovic, Benjamin Winter, Jane N. Bender, John F. Gold, Daniel P. Ghalie, Richard G. Stewart, Morgan E. Esquibel, Vanessa Hamlin, Paul TI Placebo-Controlled Phase III Trial of Patient-Specific Immunotherapy With Mitumprotimut-T and Granulocyte-Macrophage Colony-Stimulating Factor After Rituximab in Patients With Follicular Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-of-Hematology CY DEC 09-12, 2006 CL Orlando, FL SP Amer Soc Hematol ID NON-HODGKINS-LYMPHOMA; MONOCLONAL-ANTIBODY THERAPY; B-CELL LYMPHOMA; LOW-GRADE; VACCINATION; RESPONSES AB Purpose To evaluate patient-specific immunotherapy with mitumprotimut-T (idiotype keyhole limpet hemocyanin [Id-KLH]) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD20(+) follicular lymphoma. Patients and Methods Patients with treatment-naive or relapsed/refractory disease achieving a complete response (CR), partial response (PR), or stable disease (SD) with four weekly rituximab infusions were randomly assigned to mitumprotimut-T/GM-CSF or placebo/GM-CSF, with doses given monthly for six doses, every 2 months for six doses, and then every 3 months until disease progression (PD). Randomization was stratified by prior therapy (treatment-naive or relapsed/refractory) and response to rituximab (CR/PR or SD). The primary end point was time to progression (TTP) from randomization. Results A total of 349 patients were randomly assigned; median age was 54 years, 79% were treatment naive, and 86% had stage III/IV disease. Median TTP was 9.0 months for mitumprotimut-T/GMCSF and 12.6 months for placebo/GM-CSF (hazard ratio [HR] = 1.384; P = .019). TTP was comparable between the two arms in treatment-naive patients (HR = 1.196; P = .258) and shorter with mitumprotimut-T/GM-CSF in relapsed/refractory disease (HR = 2.265; P = .004). After adjusting for Follicular Lymphoma International Prognostic Index (FLIPI) scores, the difference in TTP between the two arms was no longer significant. Overall objective response rate, rate of response improvement, and duration of response were comparable between the two arms. Toxicity was similar in the two arms; 76% of adverse events were mild or moderate, and 94% of patients had injection site reactions. Conclusion TTP was shorter with mitumprotimut-T/GM-CSF compared with placebo/GM-CSF. This difference was possibly due to the imbalance in FLIPI scores. J Clin Oncol 27: 3036-3043. (C) 2009 by American Society of Clinical Oncology C1 [Freedman, Arnold] Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Earle A Chiles Res Inst, Providence Canc Ctr, Portland, OR USA. Indiana Univ, Med Ctr, Indianapolis, IN USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Favrille Inc, San Diego, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Freedman, A (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM arnold_freedman@dfci.harvard.edu RI Djulbegovic, Benjamin/I-3661-2012; OI Djulbegovic, Benjamin/0000-0003-0671-1447; Ghalie, Richard/0000-0001-6882-8179 NR 20 TC 78 Z9 79 U1 1 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 3036 EP 3043 DI 10.1200/JCO.2008.19.8903 PG 8 WC Oncology SC Oncology GA 459TP UT WOS:000267133300025 PM 19414675 ER PT J AU Herbst, RS Sun, Y Korfee, S Germonpre, P Saijo, N Zhou, C Wang, J Langmuir, P Kennedy, SJ Johnson, BE AF Herbst, R. S. Sun, Y. Korfee, S. Germonpre, P. Saijo, N. Zhou, C. Wang, J. Langmuir, P. Kennedy, S. J. Johnson, B. E. TI Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZODIAC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Canc Hosp, Beijing, Peoples R China. Univ Duisburg Essen, W German Tumor Ctr, Essen, Germany. Univ Antwerp Hosp, Edegem, Belgium. Natl Canc Ctr Hosp E, Chiba, Japan. Tongji Univ, Shanghai 200092, Peoples R China. Beijing Inst Canc Res, Beijing, Peoples R China. AstraZeneca, Wilmington, DE USA. AstraZeneca, Macclesfield, Cheshire, England. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 SU S PG 2 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000034 ER PT J AU Rini, BI Halabi, S Rosenberg, J Stadler, WM Vaena, DA Atkins, JN Picus, J Czaykowski, P Dutcher, J Small, EJ AF Rini, B. I. Halabi, S. Rosenberg, J. Stadler, W. M. Vaena, D. A. Atkins, J. N. Picus, J. Czaykowski, P. Dutcher, J. Small, E. J. TI First results of a phase III multicenter randomized controlled trial of intensity modulated (IMRT) versus conventional radiotherapy (RT) in head and neck cancer (PARSPORT: ISRCTN48243537; CRUK/03/005) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Cleveland Clin Taussig Canc Inst, Cleveland, OH USA. CALGB Stat Off, Durham, NC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Iowa, Iowa City, IA USA. SE Canc Control Consortium Inc, Winston Salem, NC USA. Washington Univ, St Louis, MO USA. Natl Canc Inst Canada, Kingston, ON, Canada. New York Med Coll, New York, NY USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 SU S PG 2 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000028 ER PT J AU Rini, BI Halabi, S Rosenberg, J Stadler, WM Vaena, DA Atkins, JN Picus, J Czaykowski, P Dutcher, J Small, EJ AF Rini, B. I. Halabi, S. Rosenberg, J. Stadler, W. M. Vaena, D. A. Atkins, J. N. Picus, J. Czaykowski, P. Dutcher, J. Small, E. J. TI Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for CALGB 90206 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Cleveland Clin Taussig Canc Inst, Cleveland, OH USA. CALGB Stat Off, Durham, NC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Iowa, Iowa City, IA USA. SE Canc Control Consortium Inc, Winston Salem, NC USA. Washington Univ, St Louis, MO USA. Natl Canc Inst Canada, Kingston, ON, Canada. New York Med Coll, New York, NY USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 SU S PG 1 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000027 ER PT J AU Tutt, A Robson, M Garber, JE Domchek, S Audeh, MW Weitzel, JN Friedlander, M Carmichael, J AF Tutt, A. Robson, M. Garber, J. E. Domchek, S. Audeh, M. W. Weitzel, J. N. Friedlander, M. Carmichael, J. TI Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Kings Coll London, Sch Med, Guys Hosp, Breakthrough Breast Canc Res Unit, London, England. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Penn, Philadelphia, PA 19104 USA. Cedars Sinai Outpatient Canc Ctr, Los Angeles, CA USA. City Hope Comprehens Canc Ctr, Duarte, CA USA. Prince Wales Canc Ctr, Sydney, NSW, Australia. AstraZeneca, Macclesfield, Cheshire, England. RI friedlander, michael/G-3490-2013 OI friedlander, michael/0000-0002-6488-0604 NR 0 TC 14 Z9 14 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 JUN 20 PY 2009 VL 27 IS 18 SU S PG 2 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000010 ER PT J AU Butt, AA McGinnis, K Rodriguez-Barradas, MC Crystal, S Simberkoff, M Goetz, MB Leaf, D Justice, AC AF Butt, Adeel A. McGinnis, Kathleen Rodriguez-Barradas, Maria C. Crystal, Stephen Simberkoff, Michael Goetz, Matthew Bidwell Leaf, David Justice, Amy C. CA Veterans Aging Cohort Study TI HIV infection and the risk of diabetes mellitus SO AIDS LA English DT Article DE antiretroviral therapy; diabetes; HCV; HIV; risk ID CHRONIC HEPATITIS-C; MULTICENTER AIDS COHORT; INSULIN-RESISTANCE; VIRUS-INFECTION; ANTIRETROVIRAL THERAPY; POST-HAART; VETERANS; PREVALENCE; HEALTH; HCV AB Background: The influence of HIV infection on the risk of diabetes is unclear. We determined the association and predictors of prevalent diabetes mellitus in HIV infected and uninfected veterans. Methods: We determined baseline prevalence and risk factors for diabetes between HIV infected and uninfected veterans in the Veterans Aging Cohort Study. Logistic regression was used to determine the odds of diabetes in HIV infected and uninfected persons. Results: We studied 3227 HIV-infected and 3240 HIV-uninfected individuals. HIV-infected individuals were younger, more likely to be black males, have HCV coinfection and a lower BMI. HIV-infected individuals had a lower prevalence of diabetes at baseline (14.9 vs. 21.4%, P < 0.0001). After adjustment for known risk factors, HIV-infected individuals had a lower risk of diabetes (odds ratio = 0.84, 95% confidence interval = 0.72-0.97). Increasing age, male sex, minority race, and BMI were associated with an increased risk. The odds ratio for diabetes associated with increasing age, minority race and BMI were greater among HIV-infected veterans. HCV coinfection and nucleoside and nonnucleoside reverse transcriptase inhibitor therapy were associated with a higher risk of diabetes in HIV-infected veterans. Conclusion: Although HIV infection itself is not associated with increased risk of diabetes, increasing age; HCV coinfection and BMI have a more profound effect upon the risk of diabetes among HIV-infected persons. Further, long-term ARV treatment also increases risk. Future studies will need to determine whether incidence of diabetes mellitus differs by HIV status. (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Butt, Adeel A.; McGinnis, Kathleen] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Crystal, Stephen] Rutgers State Univ, Ctr Pharmacotherapy Dr Crystal Chron Dis Manageme, New Brunswick, NJ 08903 USA. [Simberkoff, Michael] New York VA Med Ctr, New York, NY USA. [Goetz, Matthew Bidwell; Leaf, David] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Goetz, Matthew Bidwell; Leaf, David] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Justice, Amy C.] W Haven & Yale Univ, Sch Med & Publ Hlth, VA Connecticut Healthcare Syst, West Haven, CT USA. RP Butt, AA (reprint author), 3601 5th Ave,Suite 3A, Pittsburgh, PA 15213 USA. EM butta@dom.pitt.edu OI Goetz, Matthew/0000-0003-4542-992X FU National Institute on Alcohol Abuse and Alcoholism [U10 AA 13566]; VHA Public Health Strategic Health Core Group; National Institutes of Health /National Institute on Drug Abuse [DA01617501A1] FX Veterans Aging Cohort Study funded by: National Institute on Alcohol Abuse and Alcoholism (U10 AA 13566) and VHA Public Health Strategic Health Core Group. Dr Butt is supported by a Career Developmnt Award from the National Institutes of Health /National Institute on Drug Abuse (DA01617501A1). NR 29 TC 102 Z9 105 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2009 VL 23 IS 10 BP 1227 EP 1234 DI 10.1097/QAD.0b013e32832bd7af PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 461PH UT WOS:000267279800005 PM 19444074 ER PT J AU Cha-Molstad, H Saxena, G Chen, JQ Shalev, A AF Cha-Molstad, Hyunjoo Saxena, Geetu Chen, Junqin Shalev, Anath TI Glucose-stimulated Expression of Txnip Is Mediated by Carbohydrate Response Element-binding Protein, p300, and Histone H4 Acetylation in Pancreatic Beta Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THIOREDOXIN-INTERACTING PROTEIN; TRANSCRIPTION FACTOR; ORDERED RECRUITMENT; MICROARRAY ANALYSIS; GENE-TRANSCRIPTION; APOPTOSIS; MLX; CHREBP; MONDOA; COACTIVATOR AB Recently, we identified Txnip (thioredoxin-interacting protein) as a mediator of glucotoxic beta cell death and discovered that lack of Txnip protects against streptozotocin- and obesity-induced diabetes by preventing beta cell apoptosis and preserving endogenous beta cell mass. Txnip has therefore become an attractive target for diabetes therapy, but although we have found that txnip transcription is highly induced by glucose through a unique carbohydrate response element, the factors controlling this effect have remained unknown. Using transient transfection experiments, we now show that overexpression of the carbohydrate response element-binding protein (ChREBP) transactivates the txnip promoter, whereas ChREBP knockdown by small interfering RNA completely blunts glucose-induced txnip transcription. Moreover, chromatin immunoprecipitation demonstrated that glucose leads to a dose- and time-dependent recruitment of ChREBP to the txnip promoter in vivo in INS-1 beta cells as well as human islets. Furthermore, we found that the co-activator and histone acetyltransferase p300 co-immunoprecipitates with ChREBP and also binds to the txnip promoter in response to glucose. Interestingly, this is associated with specific acetylation of histone H4 and recruitment of RNA polymerase II as measured by chromatin immunoprecipitation. Thus, with this study we have identified ChREBP as the transcription factor that mediates glucose-induced txnip expression in human islets and INS-1 beta cells and have characterized the chromatin modification associated with glucose-induced txnip transcription. In addition, the results reveal for the first time that ChREBP interacts with p300. This may explain how ChREBP induces H4 acetylation and sheds new light on glucose-mediated regulation of chromatin structure and transcription. C1 [Cha-Molstad, Hyunjoo; Saxena, Geetu; Chen, Junqin; Shalev, Anath] Univ Wisconsin, Dept Med, Madison, WI 53792 USA. [Cha-Molstad, Hyunjoo; Saxena, Geetu; Chen, Junqin; Shalev, Anath] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Shalev, A (reprint author), Univ Wisconsin, Dept Med, H4-526 Clin Sci Ctr,600 Highland Ave, Madison, WI 53792 USA. EM as7@medicine.wisc.edu FU National Institutes of Health [R01DK-078752, R21HL-089205]; American Diabetes Association [7-07-CD-22]; Juvenile Diabetes Research Foundation [1-2007-790] FX This work was supported, in whole or in part, by National Institutes of Health, NIDDK, Grant R01DK-078752 and National Institutes of Health, NHLBI, Grant R21HL-089205. This work was also supported by American Diabetes Association Grant 7-07-CD-22 and Juvenile Diabetes Research Foundation Grant 1-2007-790. NR 45 TC 82 Z9 86 U1 1 U2 6 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 JUN 19 PY 2009 VL 284 IS 25 BP 16898 EP 16905 DI 10.1074/jbc.M109.010504 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 457VM UT WOS:000266962400026 PM 19411249 ER PT J AU Stone, RM AF Stone, Richard M. TI How I treat patients with myelodysplastic syndromes SO BLOOD LA English DT Review ID COLONY-STIMULATING FACTOR; BONE-MARROW-TRANSPLANTATION; LEUKEMIA GROUP-B; QUALITY-OF-LIFE; HEMATOPOIETIC-CELL TRANSPLANTATION; RANDOMIZED PHASE-III; SYNDROME MDS; REFRACTORY-ANEMIA; MYELOID-LEUKEMIA; LOW-RISK C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Stone, RM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM rstone@partners.org NR 72 TC 50 Z9 54 U1 0 U2 3 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 JUN 18 PY 2009 VL 113 IS 25 BP 6296 EP 6303 DI 10.1182/blood-2008-09-038935 PG 8 WC Hematology SC Hematology GA 459XV UT WOS:000267147400010 PM 19383969 ER PT J AU Niethammer, P Grabher, C Look, AT Mitchison, TJ AF Niethammer, Philipp Grabher, Clemens Look, A. Thomas Mitchison, Timothy J. TI A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish SO NATURE LA English DT Article ID TUMOR-SUPPRESSOR PTEN; ENDOTHELIAL-CELLS; NOX INHIBITOR; DUAL OXIDASES; INFLAMMATION; CHEMOTAXIS; MIGRATION; GROWTH; NEUTROPHILS; EXPRESSION AB Barrier structures (for example, epithelia around tissues and plasma membranes around cells) are required for internal homeostasis and protection from pathogens. Wound detection and healing represent a dormant morphogenetic program that can be rapidly executed to restore barrier integrity and tissue homeostasis. In animals, initial steps include recruitment of leukocytes to the site of injury across distances of hundreds of micrometres within minutes of wounding. The spatial signals that direct this immediate tissue response are unknown. Owing to their fast diffusion and versatile biological activities, reactive oxygen species, including hydrogen peroxide (H2O2), are interesting candidates for wound-to-leukocyte signalling. Here we probe the role of H2O2 during the early events of wound responses in zebrafish larvae expressing a genetically encoded H2O2 sensor(1). This reporter revealed a sustained rise in H2O2 concentration at the wound margin, starting similar to 3 min after wounding and peaking at similar to 20 min, which extended similar to 100-200 mu m into the tail-fin epithelium as a decreasing concentration gradient. Using pharmacological and genetic inhibition, we show that this gradient is created by dual oxidase (Duox), and that it is required for rapid recruitment of leukocytes to the wound. This is the first observation, to our knowledge, of a tissue-scale H2O2 pattern, and the first evidence that H2O2 signals to leukocytes in tissues, in addition to its known antiseptic role. C1 [Niethammer, Philipp; Mitchison, Timothy J.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Grabher, Clemens; Look, A. Thomas] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Look, A. Thomas] Harvard Univ, Sch Med, Dept Pediat,Childrens Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Niethammer, P (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. EM Philipp_Niethammer@hms.harvard.edu RI Grabher, Clemens/H-2064-2013 FU National Institutes of Health [GM023928] FX P. N. was supported by a Human Frontiers Science Program long-term fellowship. This work was supported by the National Institutes of Health grant GM023928. We would like to thank A. Huttenlocher and P. Crosier for providing us with the mpo::GFP and lysC::DsRED2 transgenic zebrafish lines, respectively. NR 33 TC 572 Z9 587 U1 28 U2 129 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 JUN 18 PY 2009 VL 459 IS 7249 BP 996 EP U123 DI 10.1038/nature08119 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458XS UT WOS:000267063500045 PM 19494811 ER PT J AU Kwak, EL Hong, TS Berger, DL Forcione, DG Uppot, RN Lauwers, GY AF Kwak, Eunice L. Hong, Theodore S. Berger, David L. Forcione, David G. Uppot, Raul N. Lauwers, Gregory Y. TI A Woman with Carcinoma of the Gastroesophageal Junction Adenocarcinoma of the gastroesophageal junction, pathological stage ypT2N1MX after preoperative chemotherapy, arising in Barrett's esophagus. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHASE-III TRIAL; ESOPHAGOGASTRIC JUNCTION; PREDICTS SURVIVAL; LYMPH-NODES; CANCER; CHEMORADIATION; RESECTION; SURGERY; CHEMORADIOTHERAPY; LAPAROSCOPY C1 [Kwak, Eunice L.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Forcione, David G.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Berger, David L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Uppot, Raul N.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kwak, Eunice L.; Forcione, David G.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Hong, Theodore S.] Harvard Univ, Sch Med, Dept Radiat Oncol, Cambridge, MA 02138 USA. [Berger, David L.] Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. [Uppot, Raul N.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Lauwers, Gregory Y.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Kwak, EL (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. NR 20 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 18 PY 2009 VL 360 IS 25 BP 2656 EP 2664 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 458WR UT WOS:000267060000012 PM 19535805 ER PT J AU Jain, RK AF Jain, Rakesh K. TI A New Target for Tumor Therapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ANTI-ANGIOGENIC THERAPY; NORMALIZATION; OXYGENATION C1 [Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. FU NCI NIH HHS [P01 CA080124] NR 5 TC 35 Z9 41 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 JUN 18 PY 2009 VL 360 IS 25 BP 2669 EP 2671 DI 10.1056/NEJMcibr0902054 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 458WR UT WOS:000267060000015 PM 19535806 ER PT J AU Santini, S Crowet, JM Thomas, A Paquot, M Vandenbol, M Thonart, P Wathelet, JP Blecker, C Lognay, G Brasseur, R Lins, L Charloteaux, B AF Santini, S. Crowet, J. M. Thomas, A. Paquot, M. Vandenbol, M. Thonart, P. Wathelet, J. P. Blecker, C. Lognay, G. Brasseur, R. Lins, L. Charloteaux, B. TI Study of Thermomyces lanuginosa Lipase in the Presence of Tributyrylglycerol and Water SO BIOPHYSICAL JOURNAL LA English DT Article ID RHIZOMUCOR-MIEHEI LIPASE; HUMICOLA-LANUGINOSA; PANCREATIC LIPASE; INTERFACIAL ACTIVATION; MOLECULAR-DYNAMICS; PROCOLIPASE COMPLEX; LIGAND COMPLEXES; MIXED MICELLES; CRYSTALLOGRAPHY; PATTERN AB The Thermomyces lanuginosa lipase has been extensively studied in industrial and biotechnological research because of its potential for triacylglycerol transformation. This protein is known to catalyze both hydrolysis at high water contents and transesterification in quasi-anhydrous conditions. Here, we investigated the Thermomyces lanuginosa lipase structure in solution in the presence of a tributyrin aggregate using 30 ns molecular-dynamics simulations. The water content of the active-site groove was modified between the runs to focus on the protein-water molecule interactions and their implications for protein structure and protein-lipid interactions. The simulations confirmed the high plasticity of the lid fragment and showed that lipid molecules also bind to a secondary pocket beside the lid. Together, these results strongly suggest that the lid plays a role in the anchoring of the protein to the aggregate. The simulations also revealed the existence of a polar channel that connects the active-site groove to the outside solvent. At the inner extremity of this channel, a tyrosine makes hydrogen bonds with residues interacting with the catalytic triad. This system could function as a pipe (polar channel) controlled by a valve (the tyrosine) that could regulate the water content of the active site. C1 [Santini, S.; Crowet, J. M.; Thomas, A.; Brasseur, R.; Lins, L.; Charloteaux, B.] Gembloux Agr Univ, Ctr Numer Mol Biophys, Gembloux, Belgium. [Paquot, M.] Gembloux Agr Univ, Lab Ind Biol Chem, Gembloux, Belgium. [Vandenbol, M.] Gembloux Agr Univ, Lab Anim & Microbial Biol, Gembloux, Belgium. [Thonart, P.] Gembloux Agr Univ, Lab Bioind, Gembloux, Belgium. [Wathelet, J. P.] Gembloux Agr Univ, Lab Gen & Organ Chem, Gembloux, Belgium. [Blecker, C.] Gembloux Agr Univ, Lab Food Technol, Gembloux, Belgium. [Lognay, G.] Gembloux Agr Univ, Analyt Chem Lab, Gembloux, Belgium. RP Charloteaux, B (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Syst Biol, 44 Binney St, Boston, MA 02115 USA. EM charloteaux.b@fsagx.ac.be OI Lins, Laurence/0000-0001-7772-6748 FU Gembloux Agricultural University (Belgium); Belgian Program on Interuniversity Attraction Poles [IAP. P6/19 PROFUSA]; Fonds National pour la Recherche Scientifique (Belgium) FX S.S. is supported by a grant front the Gembloux Agricultural University (Belgium), and J.M.C. and B.C. are supported by the Belgian Program on Interuniversity Attraction Poles initiated by the Federal Office for Scientific, Technical and Cultural Affairs (IAP. P6/19 PROFUSA). L.L. is a research associate and R.B. is a research director for the Fonds National pour la Recherche Scientifique (Belgium). AT. is a research director at the French Institute for Medical Research. NR 41 TC 14 Z9 14 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN 17 PY 2009 VL 96 IS 12 BP 4814 EP 4825 DI 10.1016/j.bpj.2009.03.040 PG 12 WC Biophysics SC Biophysics GA 460NO UT WOS:000267194600006 PM 19527641 ER PT J AU Zeman, RJ Bauman, WA Wen, XL Ouyang, N Etlinger, JD Cardozo, CR AF Zeman, Richard J. Bauman, William A. Wen, Xialing Ouyang, Nengtai Etlinger, Joseph D. Cardozo, Christopher R. TI Improved functional recovery with oxandrolone after spinal cord injury in rats SO NEUROREPORT LA English DT Article DE anabolic steroid; axonal sprouting; locomotor function; oxandrolone; spinal cord injury ID HISTOLOGICAL OUTCOMES; CONTUSION; LOCOMOTOR; AGONIST AB At present only the corticosteroid, methylprednisolone, is used for acute spinal cord injury to improve function. However, improvements are modest, and are associated with myopathy and immunosuppression so that alternative treatments are needed. Oxandrolone is an androgenic steroid with potential neuroprotective properties that is used to prevent muscle loss and is not immunosuppressive. Oxandrolone increased locomotor recovery concomitant with reduced loss of cord tissue in a standard weight drop model of spinal cord contusion injury indicating oxandrolone as a possible alternative to methylprednisolone. Oxandrolone also increased axonal sprouting within the ventral horns distal to the injury consistent with formation of relay circuits mediating locomotor recovery. NeuroReport 20:864-868 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Bauman, William A.; Cardozo, Christopher R.] James J Peters VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY 10468 USA. [Zeman, Richard J.; Wen, Xialing; Ouyang, Nengtai; Etlinger, Joseph D.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. [Bauman, William A.; Cardozo, Christopher R.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Bauman, William A.; Cardozo, Christopher R.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [Zeman, Richard J.; Etlinger, Joseph D.] MotoGen Inc, Mt Kisco, NY USA. RP Cardozo, CR (reprint author), James J Peters VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM chris.cardozo@mssm.edu FU Veterans Health Administration, Rehabilitation Research and Development Service [B4162C, B3347 K] FX This study was supported by Veterans Health Administration, Rehabilitation Research and Development Service (B4162C to WAB, B3347 K to CC). NR 19 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 17 PY 2009 VL 20 IS 9 BP 864 EP 868 DI 10.1097/WNR.0b013e32832c5cc2 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 457DU UT WOS:000266908300009 PM 19424096 ER PT J AU Lee, TH Ferris, TG AF Lee, Thomas H. Ferris, Timothy G. TI Pay for Performance A Work in Progress SO CIRCULATION LA English DT Editorial Material DE Editorials; hypertension; health policy and outcomes research ID QUALITY; CARE C1 [Lee, Thomas H.] Brigham & Womens Hosp, Partners Healthcare Syst, Boston, MA 02199 USA. [Ferris, Timothy G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Lee, TH (reprint author), Brigham & Womens Hosp, Partners Healthcare Syst, Prudential Tower,11th Floor,800 Boylston St, Boston, MA 02199 USA. EM thlee@partners.org NR 7 TC 1 Z9 1 U1 1 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 JUN 16 PY 2009 VL 119 IS 23 BP 2965 EP 2966 DI 10.1161/CIRCULATIONAHA.109.869958 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 458KH UT WOS:000267016900001 PM 19487591 ER PT J AU Petersen, LA Woodard, LD Henderson, LM Urech, TH Pietz, K AF Petersen, Laura A. Woodard, LeChauncy D. Henderson, Louise M. Urech, Tracy H. Pietz, Kenneth TI Will Hypertension Performance Measures Used for Pay-for-Performance Programs Penalize Those Who Care for Medically Complex Patients? SO CIRCULATION LA English DT Article; Proceedings Paper CT Annual Meeting of the Veterans-Affairs-Health-Services-Research-and-Development-Service CY FEB 21-23, 2007 CL Arlington, VA SP Vet Affairs Hlth Serv Res & Dev Serv DE comorbidity; hypertension; physician incentive plans; process assessment (health care); quality indicators, health care ID QUALITY-OF-CARE; DAILY DOSE FREQUENCY; HEALTH-CARE; MYOCARDIAL-INFARCTION; COMPETING DEMANDS; DEPRESSION CARE; BLOOD-PRESSURE; DIABETES CARE; MEDICATION; DISEASES AB Background-There is concern that performance measures, patient ratings of their care, and pay-for-performance programs may penalize healthcare providers of patients with multiple chronic coexisting conditions. We examined the impact of coexisting conditions on the quality of care for hypertension and patient perception of overall quality of their health care. Methods and Results-We classified 141 609 veterans with hypertension into 4 condition groups: those with hypertension-concordant ( diabetes mellitus, ischemic heart disease, dyslipidemia) and/or -discordant ( arthritis, depression, chronic obstructive pulmonary disease) conditions or neither. We measured blood pressure control at the index visit, overall good quality of care for hypertension, including a follow-up interval, and patient ratings of satisfaction with their care. Associations between condition type and number of coexisting conditions on receipt of overall good quality of care were assessed with logistic regression. The relationship between patient assessment and objective measures of quality was assessed. Of the cohort, 49.5% had concordant-only comorbidities, 8.7% had discordant-only comorbidities, 25.9% had both, and 16.0% had none. Odds of receiving overall good quality after adjustment for age were higher for those with concordant comorbidities ( odds ratio, 1.78; 95% confidence interval, 1.70 to 1.87), discordant comorbidities ( odds ratio, 1.32; 95% confidence interval, 1.23 to 1.41), or both ( odds ratio, 2.25; 95% confidence interval, 2.13 to 2.38) compared with neither. Findings did not change after adjustment for illness severity and/or number of primary care and specialty care visits. Patient assessment of quality did not vary by the presence of coexisting conditions and was not related to objective ratings of quality of care. Conclusions-Contrary to expectations, patients with greater complexity had higher odds of receiving high-quality care for hypertension. Subjective ratings of care did not vary with the presence or absence of comorbid conditions. Our findings should be reassuring to those who care for the most medically complex patients and are concerned that they will be penalized by performance measures or patient ratings of their care. ( Circulation. 2009; 119: 2978-2985.) C1 Houston VA Med Ctr, Hlth Serv Res & Dev, Houston Ctr Qual Care & Utilizat Studies, Ctr Excellence,Hlth Policy & Qual Program, Houston, TX 77030 USA. Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Petersen, LA (reprint author), Houston Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM laurap@bcm.edu FU NHLBI NIH HHS [R01 HL079173, R01 HL079173-01] NR 41 TC 31 Z9 31 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 16 PY 2009 VL 119 IS 23 BP 2978 EP 2985 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 458KH UT WOS:000267016900004 PM 19487595 ER PT J AU Ho, PM Bryson, CL Rumsfeld, JS AF Ho, P. Michael Bryson, Chris L. Rumsfeld, John S. TI Medication Adherence Its Importance in Cardiovascular Outcomes SO CIRCULATION LA English DT Article DE cardiovascular diseases; healthcare quality assessment; medication adherence; outcomes research ID ACUTE CORONARY SYNDROMES; ACUTE MYOCARDIAL-INFARCTION; EVIDENCE-BASED PHARMACOTHERAPY; RANDOMIZED CONTROLLED-TRIALS; CHRONIC HEART-FAILURE; LONG-TERM MORTALITY; DEPRESSIVE SYMPTOMS; BLOOD-PRESSURE; DRUG-THERAPY; ANTIHYPERTENSIVE MEDICATION AB Medication adherence usually refers to whether patients take their medications as prescribed (eg, twice daily), as well as whether they continue to take a prescribed medication. Medication nonadherence is a growing concern to clinicians, healthcare systems, and other stakeholders (eg, payers) because of mounting evidence that it is prevalent and associated with adverse outcomes and higher costs of care. To date, measurement of patient medication adherence and use of interventions to improve adherence are rare in routine clinical practice. The goals of the present report are to address (1) different methods of measuring adherence, (2) the prevalence of medication nonadherence, (3) the association between nonadherence and outcomes, (4) the reasons for nonadherence, and finally, (5) interventions to improve medication adherence. (Circulation. 2009; 119: 3028-3035.) C1 [Ho, P. Michael; Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. [Ho, P. Michael; Rumsfeld, John S.] Univ Colorado, Denver, CO 80202 USA. [Ho, P. Michael; Rumsfeld, John S.] Kaiser Permanente, Inst Hlth Res, Aurora, CO USA. [Bryson, Chris L.] Puget Sound VA Med Ctr, Seattle, WA USA. [Bryson, Chris L.] Univ Washington, Seattle, WA 98195 USA. RP Ho, PM (reprint author), 1055 Clermont St 111B, Denver, CO 80220 USA. EM michael.ho@va.gov FU Veterans Administration Health Service Research and Career Development FX Drs Ho and Bryson are supported by Veterans Administration Health Service Research and Career Development. NR 79 TC 471 Z9 489 U1 3 U2 24 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 16 PY 2009 VL 119 IS 23 BP 3028 EP 3035 DI 10.1161/CIRCULATIONAHA.108.768986 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 458KH UT WOS:000267016900010 PM 19528344 ER PT J AU Bilimoria, KY Bentrem, DJ Lillemoe, KD Talamonti, MS Ko, CY AF Bilimoria, Karl Y. Bentrem, David J. Lillemoe, Keith D. Talamonti, Mark S. Ko, Clifford Y. CA Amer Coll Surg Pancreatic Canc TI Assessment of Pancreatic Cancer Care in the United States Based on Formally Developed Quality Indicators SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NEW-YORK-STATE; HOSPITAL VOLUME; OF-CARE; SURGICAL MORTALITY; CARDIAC-SURGERY; UNINTENDED CONSEQUENCES; CARDIOTHORACIC SURGEONS; APPROPRIATENESS METHOD; COLORECTAL-CANCER; HEALTH-CARE AB Pancreatic cancer outcomes vary considerably among hospitals. Assessing pancreatic cancer care by using quality indicators could help reduce this variability. However, valid quality indicators are not currently available for pancreatic cancer management, and a composite assessment of the quality of pancreatic cancer care in the United States has not been done. Potential quality indicators were identified from the literature, consensus guidelines, and interviews with experts. A panel of 20 pancreatic cancer experts ranked potential quality indicators for validity based on the RAND/UCLA Appropriateness Methodology. The rankings were rated as valid (high or moderate validity) or not valid. Adherence with valid indicators at both the patient and the hospital levels and a composite measure of adherence at the hospital level were assessed using data from the National Cancer Data Base (2004-2005) for 49 065 patients treated at 1134 hospitals. Summary statistics were calculated for each individual candidate quality indicator to assess the median ranking and distribution. Of the 50 potential quality indicators identified, 43 were rated as valid (29 as high and 14 as moderate validity). Of the 43 valid indicators, 11 (25.6%) assessed structural factors, 19 (44.2%) assessed clinical processes of care, four (9.3%) assessed treatment appropriateness, four (9.3%) assessed efficiency, and five (11.6%) assessed outcomes. Patient-level adherence with individual indicators ranged from 49.6% to 97.2%, whereas hospital-level adherence with individual indicators ranged from 6.8% to 99.9%. Of the 10 component indicators (contributing 1 point each) that were used to develop the composite score, most hospitals were adherent with fewer than half of the indicators (median score = 4; interquartile range = 3-5). Based on the quality indicators developed in this study, there is considerable variability in the quality of pancreatic cancer care in the United States. Hospitals can use these indicators to evaluate the pancreatic cancer care they provide and to identify potential quality improvement opportunities. C1 [Bilimoria, Karl Y.; Ko, Clifford Y.] Amer Coll Surg, Canc Programs, Chicago, IL 60611 USA. [Bilimoria, Karl Y.; Bentrem, David J.; Talamonti, Mark S.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Lillemoe, Keith D.] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN USA. [Talamonti, Mark S.] NorthShore 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 Angeles Healthcare Syst, Los Angeles, CA USA. RP Bilimoria, KY (reprint author), Amer Coll Surg, Canc Programs, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM kbilimoria@facs.org FU American College of Surgeons, Clinical Scholars in Residence program; American Cancer Society, Illinois Division; National Cancer Institute [NCI-60058-NE] FX American College of Surgeons, Clinical Scholars in Residence program (to K.Y.B); American Cancer Society, Illinois Division (to D. J. B); National Cancer Institute (NCI-60058-NE to C.Y.K). NR 62 TC 49 Z9 51 U1 1 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 JUN 16 PY 2009 VL 101 IS 12 BP 848 EP 859 DI 10.1093/jnci/djp107 PG 12 WC Oncology SC Oncology GA 460XH UT WOS:000267225000007 PM 19509366 ER PT J AU Gore, JL Kwan, L Lee, SP Reiter, RE Litwin, MS AF Gore, John L. Kwan, Lorna Lee, Steve P. Reiter, Robert E. Litwin, Mark S. TI Survivorship Beyond Convalescence: 48-Month Quality-of-Life Outcomes After Treatment for Localized Prostate Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article; Proceedings Paper CT 103rd Annual Meeting of the American-Urological-Association CY MAY 17-22, 2008 CL Orlando, FL SP Amer Urol Assoc ID NEOADJUVANT HORMONAL-THERAPY; EXTERNAL-BEAM RADIOTHERAPY; RADICAL PROSTATECTOMY; CONFORMAL RADIOTHERAPY; BRACHYTHERAPY; RADIATION; BOTHER; CAPSURE; INDEX AB Decision making for treatment of localized prostate cancer is often guided by therapeutic side-effect profiles. We sought to assess health-related quality-of-life outcomes for patients 48 months after treatment for localized prostate cancer. Men treated for localized prostate cancer (N = 475) were evaluated before treatment and at 11 intervals during the 48 months after intervention. Changes in mean health-related quality-of-life scores and the probability of regaining baseline levels of health-related quality of life were compared between treatment groups. All statistical tests were two-sided. Urinary incontinence was more common after prostatectomy (n = 307) than after brachytherapy (n = 90) or external beam radiation therapy (n = 78) (both P < .001), whereas voiding and storage urinary symptoms were more prevalent after brachytherapy than after prostatectomy (both P <.001). Sexual dysfunction profoundly affected all three treatment groups, with a lower likelihood of regaining baseline function after prostatectomy than after external beam radiation therapy or brachytherapy (P <.001). Bowel dysfunction was more common after either form of radiation therapy than after prostatectomy. These results may guide decision making for treatment selection and clinical management of patients with health-related quality-of-life impairments after treatment for localized prostate cancer. C1 [Gore, John L.] Univ Calif Los Angeles, Robert Wood Johnson Clin Scholars Program, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res,Dept Med, Los Angeles, CA 90024 USA. [Gore, John L.] VA Greater Los Angeles Healthcare Syst, Div Gen Internal Med, Los Angeles, CA USA. [Kwan, Lorna; Reiter, Robert E.] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Gore, John L.; Reiter, Robert E.; Litwin, Mark S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90024 USA. [Lee, Steve P.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiat Oncol, Los Angeles, CA 90024 USA. RP Gore, JL (reprint author), Univ Calif Los Angeles, Robert Wood Johnson Clin Scholars Program, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res,Dept Med, 911 Broxton Ave,3rd Floor, Los Angeles, CA 90024 USA. EM jgore@mednet.ucla.edu OI Gore, John/0000-0002-2847-5062 NR 21 TC 76 Z9 81 U1 1 U2 3 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 JUN 16 PY 2009 VL 101 IS 12 BP 888 EP 892 DI 10.1093/jnci/djp114 PG 5 WC Oncology SC Oncology GA 460XH UT WOS:000267225000011 PM 19509365 ER PT J AU Makhani, N Gorman, MP Branson, HM Stazzone, L Banwell, BL Chitnis, T AF Makhani, N. Gorman, M. P. Branson, H. M. Stazzone, L. Banwell, B. L. Chitnis, T. TI Cyclophosphamide therapy in pediatric multiple sclerosis SO NEUROLOGY LA English DT Article ID INTENSIVE IMMUNOSUPPRESSION; PLASMA-EXCHANGE; INTERFERON-BETA; FOLLOW-UP; CHILDHOOD; ONSET; CANCER; SAFETY; TOLERABILITY; MITOXANTRONE AB Objective: To review our multicenter experience with cyclophosphamide in the treatment of children with multiple sclerosis (MS). Methods: Retrospective chart review of children with MS treated with cyclophosphamide. Demographic, clinical, treatment, and MRI parameters were collected. Results: We identified 17 children with MS treated with cyclophosphamide. All but one had worsening of Expanded Disability Status Scale scores or multiple relapses prior to treatment initiation. Children were treated with one of three regimens: 1) induction therapy alone; 2) induction therapy with pulse maintenance therapy; or 3) pulse maintenance therapy alone. Treatment resulted in a reduction in relapse rate and stabilization of disability scores assessed 1 year after treatment initiation in the majority of patients. Longer follow-up was available for most cases. Cyclophosphamide was well tolerated in most patients. However, side effects included vomiting, transient alopecia, osteoporosis, and amenorrhea. One patient developed bladder carcinoma that was successfully treated. Conclusions: Cyclophosphamide is an option for the treatment of children with aggressive multiple sclerosis refractory to first-line therapies. Recommendations regarding patient selection, treatment administration, and monitoring are discussed. Neurology (R) 2009;72:2076-2082 C1 [Makhani, N.; Branson, H. M.; Banwell, B. L.] Univ Toronto, Hosp Sick Children, Toronto, ON M5S 1A1, Canada. [Gorman, M. P.; Chitnis, T.] Massachusetts Gen Hosp Children, Partners Pediat Multiple Sclerosis Ctr, Boston, MA USA. [Gorman, M. P.] Childrens Hosp, Boston, MA 02115 USA. [Stazzone, L.; Chitnis, T.] Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. RP Chitnis, T (reprint author), Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, ACC-708,55 Fruit St, Boston, MA 02114 USA. EM tchitnis@partners.org FU Pediatric Multiple Sclerosis Centers of Excellence Grant from the National Multiple Sclerosis Society, USA ( T. C.); Multiple Sclerosis Scientific Research Foundation of Canada ( B. L. B.).; National Multiple Sclerosis Society (Central New England Chapter) Clinical Fellowship FX Supported by the Pediatric Multiple Sclerosis Centers of Excellence Grant from the National Multiple Sclerosis Society, USA ( T. C.), and by the Multiple Sclerosis Scientific Research Foundation of Canada ( B. L. B.). M. P. G. is supported by a National Multiple Sclerosis Society (Central New England Chapter) Clinical Fellowship. NR 38 TC 56 Z9 57 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 16 PY 2009 VL 72 IS 24 BP 2076 EP 2082 DI 10.1212/WNL.0b013e3181a8164c PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 458KC UT WOS:000267016300005 PM 19439723 ER PT J AU Sims, JR Gharai, LR Schaefer, PW Vangel, M Rosenthal, ES Lev, MH Schwamm, LH AF Sims, J. R. Gharai, L. Rezai Schaefer, P. W. Vangel, M. Rosenthal, E. S. Lev, M. H. Schwamm, L. H. TI ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes SO NEUROLOGY LA English DT Article ID CEREBRAL-ARTERY INFARCTION; AGGRESSIVE DECOMPRESSIVE SURGERY; TISSUE-PLASMINOGEN ACTIVATOR; HIGH-RESOLUTION MEASUREMENT; TRACER BOLUS PASSAGES; ACUTE ISCHEMIC-STROKE; LESION VOLUME; MRI; TRIAL; THROMBOLYSIS AB Background: Rapid and easy clinical assessments for volumes of infarction and perfusion mismatch are needed. We tested whether simple geometric models generated accurate estimates of these volumes. Methods: Acute diffusion-weighted image (DWI) and perfusion (mean transit time [MTT]) in 63 strokes and established infarct volumes in 50 subacute strokes were measured by computerized planimetry. Mismatch was defined as MTT/DWI >= 1.2. Observers, blinded to planimetric values, measured lesions in three perpendicular axes A, B, and C. Geometric estimates of sphere, ellipsoid, bicone, and cylinder were compared to planimetric volume by least-squares linear regression. Results: The ABC/2 formula (ellipsoid) was superior to other geometries for estimating volume of DWI (slope 1.16, 95% confidence interval [CI] 0.94 to 1.38; R(2) = 0.91, p = 0.001) and MTT (slope 1.11, 95% CI 0.99 to 1.23; R(2) = 0.89, p = 0.001). The intrarater and interrater reliability for ABC/2 was high for both DWI (0.992 and 0.965) and MTT (0.881 and 0.712). For subacute infarct, the ABC/2 formula also best estimated planimetric volume (slope 1.00, 95% CI 0.98 to 1.19; R(2) = 0.74, p = 0.001). In general, sphere and cylinder geometries overestimated all volumes and bicone underestimated all volumes. The positive predictive value for mismatch was 92% and negative predictive value was 33%. Conclusions: Of the models tested, ABC/2 is reproducible, is accurate, and provides the best simple geometric estimate of infarction and mean transit time volumes. ABC/2 has a high positive predictive value for identifying mismatch greater than 20% and might be a useful tool for rapid determination of acute stroke treatment. Neurology (R) 2009;72:2104-2110 C1 [Sims, J. R.; Schwamm, L. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Charlestown, MA 02129 USA. [Sims, J. R.; Gharai, L. Rezai; Schaefer, P. W.; Vangel, M.; Rosenthal, E. S.; Lev, M. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. RP Sims, JR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, CNY149 Rm 6403,13th St, Charlestown, MA 02129 USA. EM jsims@partners.org OI Schwamm, Lee/0000-0003-0592-9145; Rosenthal, Eric/0000-0003-3900-356X FU American Heart Association, Scientist Development [0535138N]; NIH [K08 NS049241] FX Supported by the American Heart Association, Scientist Development Grant 0535138N and NIH K08 NS049241. NR 34 TC 126 Z9 131 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 16 PY 2009 VL 72 IS 24 BP 2104 EP 2110 DI 10.1212/WNL.0b013e3181aa5329 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 458KC UT WOS:000267016300009 PM 19528517 ER PT J AU Lu, PH Edland, SD Teng, E Tingus, K Petersen, RC Cummings, JL AF Lu, P. H. Edland, S. D. Teng, E. Tingus, K. Petersen, R. C. Cummings, J. L. CA Alzheimer's Dis Cooperative Study TI Donepezil delays progression to AD in MCI subjects with depressive symptoms SO NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; NEUROPSYCHIATRIC SYMPTOMS; FOLLOW-UP; DEVELOPING DEMENTIA; CONVERSION; APATHY; GALANTAMINE; HYPOTHESIS; PREDICTION AB Objective: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. Methods: The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD. Results: Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score >= 10; n = 208) and nondepressed (BDI < 10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants. Conclusions: Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms. Neurology (R) 2009;72:2115-2121 C1 [Lu, P. H.; Teng, E.; Tingus, K.; Cummings, J. L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Cummings, J. L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Edland, S. D.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Teng, E.] Greater Los Angeles VA Healthcare Syst, Neurobehav Unit, Los Angeles, CA USA. [Petersen, R. C.] Mayo Clin, Coll Med, Dept Neurol, Rochester, MN USA. RP Lu, PH (reprint author), Mary S Easton Ctr Alzheimers Dis Res, 10911 Weyburn Ave,Suite 200, Los Angeles, CA 90095 USA. EM plu@mednet.ucla.edu OI Adler, Lawrence/0000-0002-6619-2493 FU National Institute on Aging [K23-AG028727, P50 AG-16570]; Alzheimer's Association [NIRG-07-60424]; Alzheimer's Disease Cooperative Study [U01 AG010483]; Alzheimer's Disease Research Center of California, Jim Easton, and the Sidell Kagan Foundation FX Supported by grants from the National Institute on Aging (K23-AG028727), Alzheimer's Association (NIRG-07-60424), the Alzheimer's Disease Cooperative Study (U01 AG010483), the Alzheimer's Disease Research Center (P50 AG-16570 from the National Institute on Aging), Alzheimer's Disease Research Center of California, Jim Easton, and the Sidell Kagan Foundation. NR 40 TC 60 Z9 70 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 16 PY 2009 VL 72 IS 24 BP 2115 EP 2121 DI 10.1212/WNL.0b013e3181aa52d3 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 458KC UT WOS:000267016300011 PM 19528519 ER PT J AU Hayden, D Lazar, P Schoenfeld, D AF Hayden, Douglas Lazar, Peter Schoenfeld, David CA Inflammation Host Response Injury TI Assessing Statistical Significance in Microarray Experiments Using the Distance Between Microarrays SO PLOS ONE LA English DT Article AB We propose permutation tests based on the pairwise distances between microarrays to compare location, variability, or equivalence of gene expression between two populations. For these tests the entire microarray or some pre-specified subset of genes is the unit of analysis. The pairwise distances only have to be computed once so the procedure is not computationally intensive despite the high dimensionality of the data. An R software package, permtest, implementing the method is freely available from the Comprehensive R Archive Network at http://cran.r-project.org. RP Hayden, D (reprint author), Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. EM dhayden@partners.org FU NIGMS NIH HHS [U54 GM-62119-02, U54 GM062119] NR 17 TC 6 Z9 6 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 JUN 16 PY 2009 VL 4 IS 6 AR e5838 DI 10.1371/journal.pone.0005838 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458NA UT WOS:000267029500001 PM 19529777 ER PT J AU Morris, ZS McClatchey, AI AF Morris, Zachary S. McClatchey, Andrea I. TI Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EGFR; kidney; Merlin; Nf2; renal cell carcinoma ID CELL CARCINOMA; TUMOR-SUPPRESSOR; TYROSINE PHOSPHORYLATION; EMBRYONIC LETHALITY; POLYCYSTIC KIDNEYS; TSC2 MUTATION; TUBULAR CELLS; FACTOR-ALPHA; ABX-EGF; MICE AB The epidermal growth factor receptor (EGFR) has frequently been implicated in hyperproliferative diseases of renal tubule epithelia. We have shown that the NF2 tumor suppressor Merlin inhibits EGFR internalization and signaling in a cell contact-dependent manner. Interestingly, despite the paucity of recurring mutations in human renal cell carcinoma (RCC), homozygous mutation of the NF2 gene is found in approximate to 2% of RCC patient samples in the Sanger COSMIC database. To examine the roles of Merlin and EGFR in kidney tumorigenesis, we generated mice with a targeted deletion of Nf2 in the proximal convoluted epithelium using a Villin-Cre transgene. All of these mice developed intratubular neoplasia by 3 months, which progressed to invasive carcinoma by 6-10 months. Kidneys from these mice demonstrated marked hyperproliferation and a concomitant increase in label-retaining putative progenitor cells. Early lumen-filling lesions in this model exhibited hyperactivation of EGFR signaling, altered solubility of adherens junctions components, and loss of epithelial polarity. Renal cortical epithelial cells derived from either early or late lesions were dependent on EGF for in vitro proliferation and were arrested by pharmacologic inhibition of EGFR or re-expression of Nf2. These cells formed malignant tumors upon s.c. injection into immunocompromised mice before in vitro passage. Treatment of Vil-Cre;Nf2(lox/lox) mice with the EGFR inhibitor erlotinib halted the proliferation of tumor cells. These studies give added credence to the role of EGFR signaling and perhaps Nf2 deficiency in RCC and describe a rare and valuable mouse model for exploring the molecular basis of this disease. C1 [McClatchey, Andrea I.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Charlestown, MA 02129 USA. RP McClatchey, AI (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. EM mcclatch@helix.mgh.harvard.edu OI Morris, Zachary/0000-0001-5558-3547 FU National Institutes of Health (NIH)/National Cancer Institute [CA113733]; NIH/National Institute of General Medical Sciences [T32 GM07306]; Department of Defense [W81XWH-05-1-0189] FX We thank Marco Giovannini and Sylvie Robine for Nf2lox/lox and Villin-Cre mice, respectively; Othon Iliopoulos, Jordan Kreidberg, and Marcello Curto for advice and discussion; Rod Bronson, Sabina Signoretti, and Chin-Lee Wu for pathology consultation; and Andrew Gladden and Brett Morris for assistance with FACS and immunohistochemistry, respectively. This work was supported by National Institutes of Health (NIH)/National Cancer Institute Grant CA113733 (to A.I.M.); NIH/National Institute of General Medical Sciences Grant T32 GM07306 (to Z.S.M.); and Department of Defense Grant W81XWH-05-1-0189 (to A.I.M.). NR 57 TC 30 Z9 30 U1 0 U2 0 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 JUN 16 PY 2009 VL 106 IS 24 BP 9767 EP 9772 DI 10.1073/pnas.0902031106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458TD UT WOS:000267045500041 PM 19487675 ER PT J AU Freston, JW Hisada, M Peura, DA Haber, MM Kovacs, TO Atkinson, S Hunt, B AF Freston, J. W. Hisada, M. Peura, D. A. Haber, M. M. Kovacs, T. O. Atkinson, S. Hunt, B. TI The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; PROTON PUMP INHIBITORS; CLOSTRIDIUM-DIFFICILE DIARRHEA; ESOMEPRAZOLE 20 MG; DOSE LANSOPRAZOLE; COLORECTAL-CANCER; GASTRIC-MUCOSA; DOUBLE-BLIND; RISK; THERAPY AB The clinical safety of long-term lansoprazole therapy for the maintenance of healed erosive oesophagitis has not been extensively studied in clinical trials. To assess the long-term clinical safety of dose-titrated lansoprazole as maintenance therapy for up to 82 months in subjects with healed erosive oesophagitis. Clinical safety was assessed by monitoring adverse events (AEs), laboratory data including serum gastrin levels, and endoscopy. Mean duration (+/- s.d.) of lansoprazole treatment during the titrated open-label period was 56 +/- 24 months (range < 1-82 months). Overall, 189 of 195 (97%) subjects experienced a total of 2825 treatment-emergent AEs. Most AEs occurred during the first year of treatment, were mild-to-moderate in severity and resolved while on treatment. Of 155 serious AEs (in 74 subjects), only two (colitis and rectal haemorrhage in one subject) were considered treatment-related. Sixty-nine of 195 subjects (35%) experienced 187 treatment-related AEs, with diarrhoea (10%), headache (8%) and abdominal pain (6%) being the most common. Gastrin levels >= 400 pg/mL were seen in 9% of subjects; hypergastrinemia was not associated with gastro-intestinal AEs or nodules/polyps. Lansoprazole maintenance therapy for up to 6 years is safe and well tolerated in subjects with healed erosive oesophagitis. C1 [Hisada, M.; Atkinson, S.; Hunt, B.] Takeda Global Res & Dev Ctr Inc, Deerfield, IL 60015 USA. [Freston, J. W.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Peura, D. A.] Univ Virginia Hlth Syst, Div Gastroenterol & Hepatol, Charlottesville, VA USA. [Haber, M. M.] Drexel Univ, Dept Pathol, Coll Med, Philadelphia, PA 19104 USA. [Kovacs, T. O.] VA Greater LA Healthcare Syst, CURE Clin, Los Angeles, CA USA. RP Hisada, M (reprint author), Takeda Global Res & Dev Ctr Inc, 1 Takeda Pkwy, Deerfield, IL 60015 USA. EM michie.hisada@tgrd.com FU Takeda Global Research & Development Center, Inc [M94-140]; Gillian Gummer of Rx Communications (UK); Takeda Pharmaceuticals North America, Inc FX This study (M94-140) was funded by Takeda Global Research & Development Center, Inc. Writing support was provided by Gillian Gummer of Rx Communications (UK) and funded by Takeda Pharmaceuticals North America, Inc. The authors would like to thank the M94-140 investigators for participating in the study. NR 46 TC 15 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUN 15 PY 2009 VL 29 IS 12 BP 1249 EP 1260 DI 10.1111/j.1365-2036.2009.03998.x PG 12 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 448MT UT WOS:000266267400004 PM 19416133 ER PT J AU Preis, SR Hwang, SJ Fox, CS Massaro, JM Levy, D Hoffmann, U O'Donnell, CJ AF Preis, Sarah Rosner Hwang, Shih-Jen Fox, Caroline S. Massaro, Joseph M. Levy, Daniel Hoffmann, Udo O'Donnell, Christopher J. TI Eligibility of Individuals With Subclinical Coronary Artery Calcium and Intermediate Coronary Heart Disease Risk for Reclassification (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ELECTRON-BEAM TOMOGRAPHY; C-REACTIVE PROTEIN; COMPUTED-TOMOGRAPHY; EVENTS; PREDICTION; COHORT; ADULTS; AGE; REPRODUCIBILITY; QUANTIFICATION AB Coronary artery calcium (CAC) predicts risk for coronary heart disease (CRD) events and perhaps CAC testing may further stratify risk in individuals at intermediate CHD risk. We sought to determine the percentage of participants at intermediate CHD risk who could potentially be reclassified as having a high CHD risk based on the presence of a high CAC score and the prevalence, treatment, and control of CHD risk factors in this group. Framingham Heart Study Offspring and Third Generation cohort participants underwent multidetector computed tomography (n = 3,529, mean age 51 years, 48% women). High CAC was defined as >= 90th age- and gender-specific percentiles based on a healthy reference group or by an absolute modified Agatston score of 100 HU. Prevalence of CHD risk factors (hypertension, hypercholesterolemia, high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, smoking, and obesity), their treatment, and control was compared between nondiabetic participants with and without high CAC. Of the 595 participants at intermediate CHD risk, 22% had CAC 90th percentile and 39% had CAC 100 and could be eligible for reclassification as having a high CHD risk based on the presence of a high CAC score. There were no statistically significant differences in prevalence, treatment, and control of risk factors between those with and without high CAC. In conclusion, prevalence of CHD risk factors did not differ between intermediate-risk participants with and without high CAC. Approximately 25% of intermediate-risk individuals have high CAC scores and may be eligible for reclassification into a higher-risk category. (C) 2009 Published by Elsevier Inc. (Am J Cardiol 2009;103:1710-1715) C1 [Preis, Sarah Rosner; Hwang, Shih-Jen; Fox, Caroline S.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,MGH Cardiac MR PET CT Prog, Boston, MA 02115 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Div Cardiol, Massachusetts Gen Hosp,Dept Med, Boston, MA 02115 USA. RP O'Donnell, CJ (reprint author), NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA. EM codonnell@nih.gov OI Preis, Sarah/0000-0002-9360-4166; Massaro, Joseph/0000-0002-2682-4812 FU Intramural NIH HHS [ZIA HL006002-04, Z99 HL999999]; NHLBI NIH HHS [N01-HC-25195, N01HC25195, N01 HC025195] NR 28 TC 18 Z9 19 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2009 VL 103 IS 12 BP 1710 EP 1715 DI 10.1016/j.amjcard.2009.02.020 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 463CS UT WOS:000267407000014 PM 19539080 ER PT J AU Thompson, LR Boudreau, R Hannon, MJ Newman, AB Chu, CR Jansen, M Nevitt, MC Kwoh, CK AF Thompson, Laura R. Boudreau, Robert Hannon, Michael J. Newman, Anne B. Chu, Constance R. Jansen, Mary Nevitt, Michael C. Kwoh, C. Kent CA Osteoarthritis Initiative Inves TI The Knee Pain Map: Reliability of a Method to Identify Knee Pain Location and Pattern SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID BONE-MARROW; OSTEOARTHRITIS; ASSOCIATION AB Objective. To describe the location and pattern of knee pain in patients with chronic, frequent knee pain using the Knee Pain Map, and to evaluate the inter- and intrarater reliability of the map. Methods. A cohort of 799 participants from the University of Pittsburgh Osteoarthritis Initiative Clinical Center who had knee pain in the last 12 months were studied. Trained interviewers assessed and recorded participant-reported knee pain patterns into 8 local areas, 4 regional areas, or as diffuse. Inter- and intrarater reliability were assessed using Fleiss' kappa. Results. Participants most often reported localized (69%) followed by regional (14%) or diffuse (10%) knee pain. In those with localized pain, the most commonly reported locations were the medial (56%) and lateral (43%) joint lines. In those with regional pain, the most commonly reported regions were the patella (44%) and medial region (38%). There was. excellent interrater reliability for the identification of localized and regional pain patterns (kappa = 0.7-0.9 and 0.7-0.8, respectively). The interrater reliability for specific locations was also excellent (kappa = 0.7-1.0) when the number of participants with pain in a location was >4. For regional pain, the kappa for specific regions varied from 0.7-1.0. Conclusion. The majority of participants could identify the location of their knee pain, and trained interviewers could reliably record those locations. The variation in locations suggests that there are multiple sources of pain in knee OA. Additional studies are needed to determine whether specific knee pain patterns correlate with discrete pathologic findings on radiographs or magnetic resonance images. C1 [Thompson, Laura R.; Boudreau, Robert; Hannon, Michael J.; Newman, Anne B.; Chu, Constance R.; Jansen, Mary; Kwoh, C. Kent] Univ Pittsburgh, Pittsburgh, PA USA. [Nevitt, Michael C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. RP Kwoh, CK (reprint author), S702 BSTWR,200 Lothrop St, Pittsburgh, PA 15261 USA. EM kwoh@pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Boudreau, Robert/0000-0003-0162-5187 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR-12262]; National Institute of Aging Ruth L. Kirschstein National Research Service Award Institutional Research [AG-021885]; University of Pittsburgh School of Medicine Clinical Scientist FX Supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant AR-12262), the National Institute of Aging Ruth L. Kirschstein National Research Service Award Institutional Research Training (grant AG-021885), and the University of Pittsburgh School of Medicine Clinical Scientist Training Program. NR 12 TC 25 Z9 26 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD JUN 15 PY 2009 VL 61 IS 6 BP 725 EP 731 DI 10.1002/art.24543 PG 7 WC Rheumatology SC Rheumatology GA 459PI UT WOS:000267115300003 PM 19479703 ER PT J AU La Fountaine, MF Heffernan, KS Gossett, JD Bauman, WA De Meersman, RE AF La Fountaine, Michael F. Heffernan, Kevin S. Gossett, James D. Bauman, William A. De Meersman, Ronald E. TI Transient suppression of heart rate complexity in concussed athletes SO AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL LA English DT Review DE Mild traumatic brain injury; Concussion; Autonomic nervous system; Approximate entropy; Heart rate complexity ID TRAUMATIC BRAIN-INJURY; RATE-VARIABILITY; APPROXIMATE ENTROPY; DYNAMICS AB Heart rate variability (HRV) and complexity (HRC) were calculated at rest and during an isometric hand grip test (IHGT) within 48-hours (48 h) and two weeks (Week Two) of a concussion in athletes (CG) and control subjects. No differences were present at rest or in HRV during IGHT. HRC was significantly lower in the CG compared to controls at 48 h during IHGT. In CG at Week Two during IHGT, HRC was significantly greater than 48 h observations and not significantly different than controls. The findings suggest that HRC may have utility in detecting efferent cardiac autonomic anomalies within two weeks of concussion. Published by Elsevier B.V. C1 [La Fountaine, Michael F.; Bauman, William A.] James J Peter VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY 10468 USA. [De Meersman, Ronald E.] Columbia Univ, Teachers Coll, Dept Biobehav Sci, New York, NY 10027 USA. [Heffernan, Kevin S.] Tufts Med Ctr, Dept Med, Div Cardiol & Mol Cardiol, Res Inst, Boston, MA USA. [Bauman, William A.] Mt Sinai Sch Med, Dept Med & Rehabil Med, New York, NY USA. [Gossett, James D.] Columbia Univ, Dept Sports Med, New York, NY USA. RP La Fountaine, MF (reprint author), James J Peter VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Room 1E-02,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM Michael.LaFountaine@va.gov FU Department of Veterans Affairs Rehabilitation Research and Development Center of Excellence for the Medical Consequences of Spinal Cord Injury [B4162C]; VIDDA Foundation FX The authors would like to thank the athletes, coaches and administrators of the Columbia University Athletics Department for their cooperation during this study. Also, special recognition is warranted for the Columbia University sports medicine staff for their professionalism and enthusiasm. The study was conducted in cooperation with the Department of Veterans Affairs Rehabilitation Research and Development Center of Excellence for the Medical Consequences of Spinal Cord Injury (# B4162C) and the VIDDA Foundation. NR 19 TC 10 Z9 10 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1566-0702 J9 AUTON NEUROSCI-BASIC JI Auton. Neurosci-Basic Clin. PD JUN 15 PY 2009 VL 148 IS 1-2 BP 101 EP 103 DI 10.1016/j.autneu.2009.03.001 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 455DW UT WOS:000266738600015 PM 19303821 ER PT J AU Norton, D McBain, R Holt, DJ Ongur, D Chen, Y AF Norton, Daniel McBain, Ryan Holt, Daphne J. Ongur, Dost Chen, Yue TI Association of Impaired Facial Affect Recognition with Basic Facial and Visual Processing Deficits in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cognitive; emotion recognition; face recognition; neuroscience; perception; schizophrenic ID EMOTION RECOGNITION; PERCEPTION; FACE; AMYGDALA; DISCRIMINATION; ACTIVATION AB Background: Impaired emotion recognition has been reported in schizophrenia, yet the nature of this impairment is not completely understood. Recognition of facial emotion depends on processing affective and nonaffective facial signals, as well as basic visual attributes. We examined whether and how poor facial emotion recognition in schizophrenia is related to basic visual processing and nonaffective face recognition. Methods: Schizophrenia patients (n = 32) and healthy control subjects (n = 29) performed emotion discrimination, identity discrimination, and visual contrast detection tasks, where the emotionality, distinctiveness of identity, or visual contrast was systematically manipulated. Subjects determined which of two presentations in a trial contained the target: the emotional face for emotion discrimination, a specific individual for identity discrimination, and a sinusoidal grating for contrast detection. Results: Patients had significantly higher thresholds (worse performance) than control subjects for discriminating both fearful and happy faces. Furthermore, patients' poor performance in fear discrimination was predicted by performance in visual detection and face identity discrimination. Conclusions: Schizophrenia patients require greater emotional signal strength to discriminate fearful or happy face images from neutral ones. Deficient emotion recognition in schizophrenia does not appear to be determined solely by affective processing but is also linked to the processing of basic visual and facial information. C1 [Holt, Daphne J.; Ongur, Dost; Chen, Yue] Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. [Holt, Daphne J.] Massachusetts Gen Hosp, Charlestown, MA USA. [Norton, Daniel; McBain, Ryan; Ongur, Dost; Chen, Yue] McLean Hosp, Belmont, MA 02178 USA. RP Chen, Y (reprint author), Harvard Univ, Sch Med, Dept Psychiat, 115 Mill St,Room G06,Ctr Bldg, Belmont, MA 02478 USA. EM ychen@mclean.harvard.edu FU National Institutes of Health (NIH); Harvard University FX This work was supported in part by grants from the National Institutes of Health (NIH) and Harvard University. NR 20 TC 44 Z9 44 U1 2 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 JUN 15 PY 2009 VL 65 IS 12 BP 1094 EP 1098 DI 10.1016/j.biopsych.2009.01.026 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 455IW UT WOS:000266753300014 PM 19268917 ER PT J AU Jackson, NA Barrueco, J Soufi-Mahjoubi, R Marshall, J Mitchell, E Zhang, XX Meyerhardt, J AF Jackson, Nadine A. Barrueco, Jose Soufi-Mahjoubi, Raoudha Marshall, John Mitchell, Edith Zhang, Xiaoxi Meyerhardt, Jeffrey TI Comparing Safety and Efficacy of First-line Irinotecan/Fluoropyrimidine Combinations in Elderly Versus Nonelderly Patients With Metastatic Colorectal Cancer Findings From the Bolus, Infusional, or Capecitabine With Camptostar-Celecoxib Study SO CANCER LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 01-05, 2007 CL Chicago, IL SP Amer Soc Clin Oncol DE colorectal cancer; fluoropyrimidine; irinotecan; elderly ID PHASE-II TRIAL; CLINICAL-TRIALS; UNDERREPRESENTED POPULATIONS; OLDER PATIENTS; IRINOTECAN CPT-11; RANDOMIZED-TRIAL; FOLFIRI REGIMEN; CHEMOTHERAPY; OXALIPLATIN; LEUCOVORIN AB BACKGROUND: Irinotecan-based chemotherapy regimens are I option for treatment of metastatic colorectal cancer (mCRC). The authors report the safety and efficacy of such regimens in elderly patients using a large phase III trial (bolus, infusional, or capecitabine with camptostar-celecoxib [BICC-C]) cohort. METHODS: In period 1, 430 previously untreated patients with mCRC were randomized in a 3-by-2 design to receive irinotecan plus infusional 5-fluorouracil, and leucovorin (FOLFIRI), irinotecan plus bolus 5-fluorouracil/leucovorin (mIFL), and irinotecan plus oral capecitabine (CapeIRI). In period 2, an additional 117 patients were randomized to receive FOLFIRI or mIFL and bevacizumab. In both periods patients were also randomized to a double-blind treatment with celecoxib or placebo. A secondary analysis was conducted examining the safety and efficacy of these regimens in elderly (age >70 years) versus nonelderly (age <= 70 years) patients. RESULTS: In period 1, 19.5% of patients were elderly, compared with 24.8% in period 2. Rates of grade 3 and higher toxicity did not differ significantly between age groups in either period by treatment arm, with the exception of asthenia in the FOLFIRI and CapeIRI arms (P=.05 and P=.03, respectively) and dehydration in the CapeIRI arm in period I (P=.02). Overall progression-free survival for FOLFIRI in both periods was not statistically different by age. Objective responses and overall survival did not differ by patient age within treatment arms and periods. CONCLUSIONS: Irinotecan/fluoropyrimidine combinations are well tolerated in the elderly population, with similar efficacy to that found in nonelderly patients in first-line mCRC. Cancer 2009;115:2617-29. (C) 2009 American Cancer Society. C1 [Jackson, Nadine A.; Meyerhardt, Jeffrey] Dana Farber Canc Inst, Dept Gastrointestinal Oncol, Boston, MA 02115 USA. [Barrueco, Jose; Soufi-Mahjoubi, Raoudha; Zhang, Xiaoxi] Pfizer Global Pharmaceut, New York, NY USA. [Marshall, John] Georgetown Univ, Dept Med Oncol, Lombardi Canc Ctr, Washington, DC USA. [Mitchell, Edith] Thomas Jefferson Univ, Jefferson Med Coll, Dept Med Oncol, Philadelphia, PA 19107 USA. RP Meyerhardt, J (reprint author), 44 Binney St, Boston, MA 02115 USA. EM jmeyerhardt@partners.org NR 50 TC 28 Z9 28 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2009 VL 115 IS 12 BP 2617 EP 2629 DI 10.1002/cncr.24305 PG 13 WC Oncology SC Oncology GA 455UD UT WOS:000266790900008 PM 19382200 ER PT J AU Hassett, MJ O'Malley, AJ Keating, NL AF Hassett, Michael J. O'Malley, A. James Keating, Nancy L. TI Factors Influencing Changes in Employment Among Women With Newly Diagnosed Breast Cancer SO CANCER LA English DT Article DE breast cancer; employment; disability; outcomes; risk factors ID QUALITY-OF-LIFE; COMORBIDITY INDEX; CLAIMS DATA; LONG-TERM; SURVIVORS; WORK; CHEMOTHERAPY; HEALTH; COHORT; RETURN AB BACKGROUND: Although studies have demonstrated that women are less likely to work after they are diagnosed with breast cancer, the influence of cancer treatments on employment is less clear. The authors of this report assessed whether chemotherapy or radiation therapy was associated with a disruption in employment during the year after a breast cancer diagnosis. METHODS: Using a database of health insurance claims that covered 5.6 million US residents, 3233 women aged <= 63 years were identified who were working full time or part time when they were diagnosed with breast cancer between 1998 and 2002. All changes in employment during the year after a breast cancer diagnosis were identified. Using a Cox proportional hazards model that incorporated time-varying treatment variables, the authors evaluated the impact of chemotherapy and radiation therapy on the likelihood of experiencing an employment disruption. RESULTS: Although most women (93%) continued to work, chemotherapy recipients were more likely than nonrecipients to go on long-term disability, stop working, or retire (hazards ratio, 1.8; P<.01). Women aged :54 years were more likely to experience a change in employment than women aged <= 44 years (P<.01). Radiation therapy did not influence employment (P=.22). CONCLUSIONS: in this population of employed, insured women, chemotherapy had a negative impact on employment. This finding may aid treatment decision making and could foster the development of interventions that support a patient's ability to continue working after treatment. It also reinforces the need to assess the impact of treatments, especially new treatments, on patient-centered outcomes such as employment. Cancer 2009;115:2775-82. (C) 2009 American Cancer Society. C1 [Hassett, Michael J.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [O'Malley, A. James; Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02115 USA. RP Hassett, MJ (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, 44 Binney St, Boston, MA 02115 USA. EM mhassett@partners.org FU Agency for Healthcare Research and Quality [PO1-HS10803]; National Cancer Institute [R01 CA104118]; American Society of Clinical Oncology Career Development Award [R25 CA092203] FX Dr. Hassett received salary Support from Grant R25 CA092203 and an American Society of Clinical Oncology Career Development Award. NR 32 TC 30 Z9 30 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2009 VL 115 IS 12 BP 2775 EP 2782 DI 10.1002/cncr.24301 PG 8 WC Oncology SC Oncology GA 455UD UT WOS:000266790900023 PM 19365847 ER PT J AU Zhang, J Sattler, M Tonon, G Grabher, C Lababidi, S Zimmerhackl, A Raab, MS Vallet, S Zhou, YM Cartron, MA Hideshima, T Tai, YT Chauhan, D Anderson, KC Podar, K AF Zhang, Jing Sattler, Martin Tonon, Giovanni Grabher, Clemens Lababidi, Samir Zimmerhackl, Alexander Raab, Marc S. Vallet, Sonia Zhou, Yiming Cartron, Marie-Astrid Hideshima, Teru Tai, Yu-Tzu Chauhan, Dharminder Anderson, Kenneth C. Podar, Klaus TI Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1 alpha-Dependent Pathway in Multiple Myeloma SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; IN-VIVO; TUMOR PROGRESSION; KINASE INHIBITOR; TRANSGENIC ZEBRAFISH; FACTOR 1-ALPHA; MYC; HYPOXIA; CANCER; CELLS AB Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1 alpha (Hif-1 alpha) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1 alpha and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1 alpha-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1 alpha as a novel molecular target in MM and add another facet to anti-MM drug activity. [Cancer Res 2009;69(12):5082-90] C1 [Podar, Klaus] Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Tonon, Giovanni] Dana Farber Canc Inst, Ctr Appl Canc Sci, Boston, MA 02115 USA. [Grabher, Clemens] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Vallet, Sonia] Harvard Univ, Sch Med, Boston, MA USA. [Vallet, Sonia] Massachusetts Gen Hosp, Ctr Multiple Myeloma, Boston, MA 02114 USA. [Lababidi, Samir] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. [Zhou, Yiming; Cartron, Marie-Astrid] Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. [Tonon, Giovanni] Ist Sci San Raffaele, I-20132 Milan, Italy. [Podar, Klaus] Univ Heidelberg, Natl Ctr Tumor Dis NCT, Heidelberg, Germany. RP Podar, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, LeBow Inst Myeloma Therapeut, 44 Binney St, Boston, MA 02115 USA. EM klaus_podar@dfci.harvard.edu RI Grabher, Clemens/H-2064-2013 FU Multiple Myeloma Research Foundation Senior Research Grant Award; Dunkin' Donuts Rising Star Award; NIH [1P50 CA 1 00707, RO-1 CA 50947, PO-1 78378, CA134660-01]; LeBow Family Fund to Cure Myeloma FX Multiple Myeloma Research Foundation Senior Research Grant Award and Dunkin' Donuts Rising Star Award (K. Podar); NIH grants 1P50 CA 1 00707, RO-1 CA 50947, and PO-1 78378 and LeBow Family Fund to Cure Myeloma (K.C. Anderson); and NIH grant CA134660-01 (M. Sattler) NR 49 TC 43 Z9 46 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2009 VL 69 IS 12 BP 5082 EP 5090 DI 10.1158/0008-5472.CAN-08-4603 PG 9 WC Oncology SC Oncology GA 464LM UT WOS:000267506400022 PM 19509231 ER PT J AU Raina, D Ahmad, R Joshi, MD Yin, L Wu, ZK Kawano, T Vasir, B Avigan, D Kharbanda, S Kufe, D AF Raina, Deepak Ahmad, Rehan Joshi, Maya Datt Yin, Li Wu, Zekui Kawano, Takeshi Vasir, Baldev Avigan, David Kharbanda, Surender Kufe, Donald TI Direct Targeting of the Mucin 1 Oncoprotein Blocks Survival and Tumorigenicity of Human Breast Carcinoma Cells SO CANCER RESEARCH LA English DT Article ID BETA-CATENIN; C-SRC; APOPTOTIC RESPONSE; OXIDATIVE STRESS; DNA-DAMAGE; 2 PROTEINS; IN-VITRO; ANTIGEN; CANCER; GENE AB The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed by similar to 90% of human breast cancers. However, there are no effective agents that directly inhibit MUC1 and induce death of breast cancer cells. We have synthesized a MUC1 inhibitor (called GO-201) that binds to the MUC1 cytoplasmic domain and blocks the formation of MUC1 oligomers in cells. GO-201, and not an altered version, attenuates targeting of MUC1 to the nucleus of human breast cancer cells, disrupts redox balance, and activates the DNA damage response. GO-201 also arrests growth and induces necrotic death. By contrast, the MUC1 inhibitor has no effect on cells null for MUC1 expression or nonmalignant mammary epithelial cells. Administration of GO-201 to nude mice bearing human breast tumor xenografts was associated with loss of tumorigenicity and extensive necrosis, which results in prolonged regression of tumor growth. These findings show that targeting the MUC1 oncoprotein is effective in inducing death of human breast cancer cells in vitro and in tumor models. [Cancer Res 2009;69(12):5133-41] C1 [Raina, Deepak; Ahmad, Rehan; Joshi, Maya Datt; Yin, Li; Wu, Zekui; Kawano, Takeshi; Vasir, Baldev; Kharbanda, Surender; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Avigan, David] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Dana 830, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute [CA97098, CA42802] FX National Cancer Institute grants CA97098 and CA42802. NR 39 TC 78 Z9 79 U1 1 U2 9 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 JUN 15 PY 2009 VL 69 IS 12 BP 5133 EP 5141 DI 10.1158/0008-5472.CAN-09-0854 PG 9 WC Oncology SC Oncology GA 464LM UT WOS:000267506400028 PM 19491255 ER PT J AU Zhao, XS Graves, C Ames, SJ Fisher, DE Spanjaard, RA AF Zhao, Xiansi Graves, Carole Ames, Sarah J. Fisher, David E. Spanjaard, Remco A. TI Mechanism of Regulation and Suppression of Melanoma Invasiveness by Novel Retinoic Acid Receptor-gamma Target Gene Carbohydrate Sulfotransferase 10 SO CANCER RESEARCH LA English DT Article ID DEPENDENT SIGNALING PATHWAY; CELL-ADHESION MOLECULE; RAR-ALPHA; TRANSCRIPTIONAL ACTIVATION; NEUROBLASTOMA-CELLS; RNA ACTIVATOR; MUTANT MICE; F9 CELLS; BETA 2; EXPRESSION AB Retinoic acid (RA) induces growth arrest and differentiation of S91 murine melanoma cells and serves as a valuable model for this disease. RA acts through activation of RA receptors (RAR), which are members of the nuclear receptor superfamily of ligand-inducible transcription factors. Interestingly, differentiation is mediated by RAR gamma, but not by RAR alpha or RAR beta, suggesting that RAR gamma possesses unique and uncharacterized molecular properties. To address this question, DNA microarrays in combination with RAR isoform-specific agonists were employed to identify novel RAR gamma target genes that may play a role in this process. Here, we identified and validated carbohydrate sulfotransferase 10 (CHST10) as a novel RAR gamma target gene in S91 cells. The RAR gamma-inducible CHST10 promoter was obtained, and two atypical, independently functioning RA response elements were identified in a 425 bp region. Surprisingly, this fragment is bound by RAR gamma, but not by RAR alpha or RAR beta, thus providing a mechanism for the observed RAR gamma-specific regulation. CHST10 is a sulfotransferase that forms HNK-1 glycan on neural cell adhesion proteins and glycolipids, and HNK-1 is thought to modulate cell adhesion and possibly metastasis. We show that CHST10 is also regulated by RAR gamma in a significant subset of human melanoma cells, and three-dimensional cell culture migration assays suggest that CHST10 functions as a suppressor of invasiveness, but not proliferation, in these cells. Induction of CHST10 by RAR gamma-activating retinoids may present a novel therapeutic strategy to inhibit invasiveness in a subset of melanoma patients. [Cancer Res 2009;69(12):5218-25] C1 [Graves, Carole; Ames, Sarah J.; Spanjaard, Remco A.] Boston Univ, Sch Med, Dept Otolaryngol, Canc Res Ctr, Boston, MA 02118 USA. [Graves, Carole; Ames, Sarah J.; Spanjaard, Remco A.] Boston Univ, Sch Med, Dept Biochem, Canc Res Ctr, Boston, MA 02118 USA. [Zhao, Xiansi; Fisher, David E.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. RP Spanjaard, RA (reprint author), Boston Univ, Sch Med, Dept Otolaryngol, Canc Res Ctr, 72 E Concord St,R-903, Boston, MA 02118 USA. EM rspan@bu.edu FU Marshall and Missy Carter Family Foundation; Elsa U. Pardee Foundation FX Marshall and Missy Carter Family Foundation and Elsa U. Pardee Foundation (R.A. Spanjaard). NR 50 TC 15 Z9 15 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2009 VL 69 IS 12 BP 5218 EP 5225 DI 10.1158/0008-5472.CAN-09-0705 PG 8 WC Oncology SC Oncology GA 464LM UT WOS:000267506400038 PM 19470764 ER PT J AU Dakhova, O Ozen, M Creighton, CJ Li, RL Ayala, G Rowley, D Ittmann, M AF Dakhova, Olga Ozen, Mustafa Creighton, Chad J. Li, Rile Ayala, Gustavo Rowley, David Ittmann, Michael TI Global Gene Expression Analysis of Reactive Stroma in Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; EXTRACELLULAR-MATRIX; STEM-CELLS; PERINEURAL INVASION; BREAST-CANCER; IN-VITRO; PROGRESSION; CARCINOMA; TGF-BETA-1; LUNG AB Purpose: Marked reactive stroma formation, designated as grade 3 reactive stroma, is associated with poor outcome in clinically localized prostate cancer. To understand the biological processes and signaling mechanisms underlying the formation of such reactive stroma, we carried out microarray gene expression analysis of laser-captured reactive stroma and matched normal stroma. Experimental Design: Seventeen cases of reactive stroma grade 3 cancer were used to laser-capture tumor and normal stroma. Expression analysis was carried out using Agilent 44K arrays. Up-regulation of selected genes was confirmed by quantitative reverse transcription-PCR. Expression data was analyzed to identify significantly up- and down-regulated genes, and gene ontology analysis was used to define pathways altered in reactive stroma. Results: A total of 544 unique genes were significantly higher in the reactive stroma and 606 unique genes were lower. Gene ontology analysis revealed significant alterations in a number of novel processes in prostate cancer reactive stroma, including neurogenesis, axonogenesis, and the DNA damage/repair pathways, as well as evidence of increases in stem cells in prostate cancer reactive stroma. Conclusions: Formation of reactive stroma in prostate cancer is a dynamic process characterized by significant alterations in growth factor and signal transduction pathways and formation of new structures, including nerves and axons. C1 [Dakhova, Olga; Ozen, Mustafa; Li, Rile; Ayala, Gustavo; Ittmann, Michael] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Rowley, David] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Dakhova, Olga; Ozen, Mustafa; Ittmann, Michael] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. RP Ittmann, M (reprint author), Baylor Coll Med, Dept Pathol, 1 Baylor Plaza, Houston, TX 77030 USA. EM mittmann@bcm.tmc.edu FU National Cancer Institute [1U54CA126568]; P30 Cancer Center [P30 CA125123]; Baylor Prostate Cancer SPORE [P50CA058204]; Department of Veterans Affairs Merit Review; Diana Helis Henry Medical Research Foundation FX Grant support: National Cancer Institute to the Tumor Microenvironment Network (1U54CA126568; D. Rowley), the P30 Cancer Center support grant (P30 CA125123), the Baylor Prostate Cancer SPORE (P50CA058204), the Department of Veterans Affairs Merit Review program (M. Ittmann), the Diana Helis Henry Medical Research Foundation (M. Ittmann, G. Ayala, D. Rowley), and by the use of the facilities of the Michael E. DeBakey Veterans Affairs Medical Center. NR 54 TC 75 Z9 78 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2009 VL 15 IS 12 BP 3979 EP 3989 DI 10.1158/1078-0432.CCR-08-1899 PG 11 WC Oncology SC Oncology GA 459DP UT WOS:000267080800012 PM 19509179 ER PT J AU Ikeda, H Hideshima, T Fulciniti, M Lutz, RJ Yasui, H Okawa, Y Kiziltepe, T Vallet, S Pozzi, S Santo, L Perrone, G Tai, YT Cirstea, D Raje, NS Uherek, C Dalken, B Aigner, S Osterroth, F Munshi, N Richardson, P Anderson, KC AF Ikeda, Hiroshi Hideshima, Teru Fulciniti, Mariateresa Lutz, Robert J. Yasui, Hiroshi Okawa, Yutaka Kiziltepe, Tanyel Vallet, Sonia Pozzi, Samantha Santo, Loredana Perrone, Giulia Tai, Yu-Tzu Cirstea, Diana Raje, Noopur S. Uherek, Christoph Daelken, Benjamin Aigner, Silke Osterroth, Frank Munshi, Nikhil Richardson, Paul Anderson, Kenneth C. TI The Monoclonal Antibody nBT062 Conjugated to Cytotoxic Maytansinoids Has Selective Cytotoxicity Against CD138-Positive Multiple Myeloma Cells In vitro and In vivo SO CLINICAL CANCER RESEARCH LA English DT Article ID DRUG-RESISTANCE; BONE-MARROW; GEMTUZUMAB OZOGAMICIN; ANTITUMOR-ACTIVITY; CANCER-CELLS; GROWTH; SYNDECAN-1; APOPTOSIS; THERAPY; DIFFERENTIATION AB Purpose: We investigated the antitumor effect of murine/human chimeric CD138-specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid derivatives against multiple myeloma (MM) cells in vitro and in vivo. Experimental Design: We examined the growth inhibitory effect of BT062-SPDB-DM4, BT062-SMCC-DM1, and BT062-SPP-DM1 against MM cell lines and primary tumor cells from MM patients. We also examined in vivo activity of these agents in murine MM cell xenograft model of human and severe combined immunodeficient (SCID) mice bearing implant bone chips injected with human MM cells (SCID-hu model). Results: Anti-CD138 immunoconjugates significantly inhibited growth of MM cell lines and primary tumor cells from MM patients without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G(2)-M cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase. Nonconjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that specific binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells. The coculture of MM cells with bone marrow stromal cells protects against dexamethasone-induced death but had no effect on the cytotoxicity of immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo and prolonged host survival in both the xenograft mouse models of human MM and SCID-hu mouse model. Conclusion: These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM. C1 [Ikeda, Hiroshi; Hideshima, Teru; Fulciniti, Mariateresa; Yasui, Hiroshi; Okawa, Yutaka; Kiziltepe, Tanyel; Vallet, Sonia; Pozzi, Samantha; Santo, Loredana; Perrone, Giulia; Tai, Yu-Tzu; Cirstea, Diana; Raje, Noopur S.; Munshi, Nikhil; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, Dept Med Oncol, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut,Med Sch, Boston, MA 02115 USA. [Ikeda, Hiroshi; Hideshima, Teru; Fulciniti, Mariateresa; Yasui, Hiroshi; Okawa, Yutaka; Kiziltepe, Tanyel; Vallet, Sonia; Pozzi, Samantha; Santo, Loredana; Perrone, Giulia; Tai, Yu-Tzu; Cirstea, Diana; Raje, Noopur S.; Munshi, Nikhil; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Dana Farber Canc Inst,Med Sch, Boston, MA 02115 USA. [Ikeda, Hiroshi; Yasui, Hiroshi] Sapporo Med Univ, Dept Internal Med 1, Sapporo, Hokkaido, Japan. [Lutz, Robert J.] ImmunoGen Inc, Waltham, MA USA. [Uherek, Christoph; Daelken, Benjamin; Aigner, Silke; Osterroth, Frank] Biotest AG, Dreieich, Germany. RP Anderson, KC (reprint author), Harvard Univ, Dept Med Oncol, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut,Med Sch, Mayer 557,44 Binney St, Boston, MA 02115 USA. EM Kenneth_Anderson@dfci.harvard.edu RI Pozzi, Samantha/A-7617-2012 OI Pozzi, Samantha/0000-0001-7917-1774 FU NIH [CA50947, CA78373, CA10070]; Biotest Fellowship; LeBow Family Fund FX Grant support: NIH grants CA50947, CA78373, and CA10070; a Biotest Fellowship; and The LeBow Family Fund to Cure Myeloma. NR 36 TC 107 Z9 112 U1 1 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2009 VL 15 IS 12 BP 4028 EP 4037 DI 10.1158/1078-0432.CCR-08-2867 PG 10 WC Oncology SC Oncology GA 459DP UT WOS:000267080800017 PM 19509164 ER PT J AU Betts, RF Nucci, M Talwar, D Gareca, M Queiroz-Telles, F Bedimo, RJ Herbrecht, R Ruiz-Palacios, G Young, JAH Baddley, JW Strohmaier, KM Tucker, KA Taylor, AF Kartsonis, NA AF Betts, Robert F. Nucci, Marcio Talwar, Deepak Gareca, Marcelo Queiroz-Telles, Flavio Bedimo, Roger J. Herbrecht, Raoul Ruiz-Palacios, Guillermo Young, Jo-Anne H. Baddley, John W. Strohmaier, Kim M. Tucker, Kimberly A. Taylor, Arlene F. Kartsonis, Nicholas A. CA Caspofungin High-Dose Study Grp TI A Multicenter, Double-Blind Trial of a High-Dose Caspofungin Treatment Regimen versus a Standard Caspofungin Treatment Regimen for Adult Patients with Invasive Candidiasis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HIGH DRUG CONCENTRATIONS; AMPHOTERICIN-B; FUNGAL-INFECTIONS; RISK-FACTORS; CANDIDEMIA; FLUCONAZOLE; EPIDEMIOLOGY; CANDIDAEMIA; MICAFUNGIN; MORTALITY AB Background. The standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen. Methods. Patients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptom resolution and microbiological clearance at the end of caspofungin therapy. Results. A total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, -4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, -5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups. Conclusions. Both caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day. C1 [Betts, Robert F.] Univ Rochester, Rochester, NY USA. [Gareca, Marcelo] Lehigh Valley Hosp, Allentown, PA USA. [Strohmaier, Kim M.; Tucker, Kimberly A.; Taylor, Arlene F.; Kartsonis, Nicholas A.] Merck Res Labs, West Point, PA USA. [Young, Jo-Anne H.] Univ Minnesota, Minneapolis, MN USA. [Bedimo, Roger J.] Vet Affairs N Texas Hlth Care Syst, Dallas, TX USA. [Baddley, John W.] Univ Alabama, Birmingham, AL USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Nucci, Marcio] Univ Fed Rio de Janeiro, Univ Hosp, Rio De Janeiro, Brazil. [Queiroz-Telles, Flavio] Univ Fed Parana, Hosp Clin, BR-80060000 Curitiba, Parana, Brazil. [Talwar, Deepak] Metro Hosp, Noida, India. [Herbrecht, Raoul] Univ Hosp, Strasbourg, France. [Ruiz-Palacios, Guillermo] Natl Inst Med Sci & Nutr, Mexico City, DF, Mexico. RP Kartsonis, NA (reprint author), Merck Res Labs, POB 1000,UG3D-56, N Wales, PA 19454 USA. EM nicholas_kartsonis@merck.com RI Nucci, Marcio/G-4515-2012; Herbrecht, Raoul/D-3471-2013; Young, Jo-Anne/G-2617-2013; OI Nucci, Marcio/0000-0003-4867-0014; Young, Jo-Anne/0000-0003-4182-341X; Streinu-Cercel, Adrian/0000-0001-6382-5067; Herbrecht, Raoul/0000-0002-9381-4876 FU Merck Co FX Merck & Co. NR 20 TC 100 Z9 106 U1 1 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2009 VL 48 IS 12 BP 1676 EP 1684 DI 10.1086/598933 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 450YY UT WOS:000266439100009 PM 19419331 ER PT J AU Horn, DL Neofytos, D Anaissie, EJ Fishman, JA Steinbach, WJ Olyaei, AJ Marr, KA Pfaller, MA Chang, CH Webster, KM AF Horn, David L. Neofytos, Dionissios Anaissie, Elias J. Fishman, Jay A. Steinbach, William J. Olyaei, Ali J. Marr, Kieren A. Pfaller, Michael A. Chang, Chi-Hsing Webster, Karen M. TI Epidemiology and Outcomes of Candidemia in 2019 Patients: Data from the Prospective Antifungal Therapy Alliance Registry SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT 25, 2008 CL Washington, DC SP Infect Dis Soc Amer ID INTENSIVE-CARE-UNIT; HOSPITAL-ACQUIRED CANDIDEMIA; INVASIVE FUNGAL-INFECTIONS; BLOOD-STREAM INFECTIONS; CRITICALLY-ILL PATIENTS; ATTRIBUTABLE MORTALITY; RISK-FACTORS; HEMATOLOGIC MALIGNANCIES; NOSOCOMIAL CANDIDEMIA; CANCER-PATIENTS AB Background. Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. Methods. Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. Results. The incidence of candidemia caused by non-Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P < .001) and were less likely to be neutropenic (5.1%; P < .001) and to receive corticosteroids (33.5%; P < .001) or other immuno-suppressive drugs (7.9%; P = .002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P < .001), hematologic malignancy (52.9%; P < .001) or stem cell transplantation (17.7%; P < .001), neutropenia (45.1%; P < .001), and corticosteroid treatment (60.8%; P < .001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P < .001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered. Conclusions. The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen. C1 [Horn, David L.; Neofytos, Dionissios] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Neofytos, Dionissios; Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Anaissie, Elias J.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Fishman, Jay A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Steinbach, William J.] Duke Univ, Med Ctr, Durham, NC USA. [Olyaei, Ali J.] Oregon Hlth & Sci Univ, Portland, OR USA. [Pfaller, Michael A.] Univ Iowa Hlth Care, Iowa City, IA USA. [Chang, Chi-Hsing] Info Spectrum, Markham, ON, Canada. [Webster, Karen M.] EBM Consulting, Mississauga, ON, Canada. RP Horn, DL (reprint author), Thomas Jefferson Univ, Div Infect Dis, Ste 210,211 S 9th St, Philadelphia, PA 19107 USA. EM david.horn@jefferson.edu NR 45 TC 390 Z9 418 U1 1 U2 25 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2009 VL 48 IS 12 BP 1695 EP 1703 DI 10.1086/599039 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 450YY UT WOS:000266439100011 PM 19441981 ER PT J AU Nagy, N Mwizerwa, O Yaniv, K Carmel, L Pieretti-Vanmarcke, R Weinstein, BM Goldstein, AM AF Nagy, Nandor Mwizerwa, Olive Yaniv, Karina Carmel, Liran Pieretti-Vanmarcke, Rafael Weinstein, Brant M. Goldstein, Allan M. TI Endothelial cells promote migration and proliferation of enteric neural crest cells via beta 1 integrin signaling SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Enteric nervous system; Endothelial cells; Blood vessels; Hirschsprung's disease; Integrins; Avian; Zebrafish ID EXTRACELLULAR-MATRIX; MONOCLONAL-ANTIBODY; NERVOUS-SYSTEM; TRANSGENIC ZEBRAFISH; AGANGLIONIC BOWEL; AVIAN EMBRYO; LAMININ; FIBRONECTIN; RECEPTOR; NEURONS AB Enteric neural crest-derived cells (ENCCs) migrate along the intestine to form a highly organized network of ganglia that comprises the enteric nervous system (ENS). The signals driving the migration and patterning of these cells are largely unknown. Examining the spatiotemporal development of the intestinal neurovasculature in avian embryos, we find endothelial cells (ECs) present in the gut prior to the arrival of migrating ENCCs. These ECs are patterned in concentric rings that are predictive of the positioning of later arriving crest-derived cells, leading us to hypothesize that blood vessels may serve as a substrate to guide ENCC migration. Immunohistochemistry at multiple stages during ENS development reveals that ENCCs are positioned adjacent to vessels as they colonize the gut. A similar close anatomic relationship between vessels and enteric neurons was observed in zebrafish larvae. When EC development is inhibited in Cultured avian intestine, ENCC migration is arrested and distal aganglionosis results, suggesting that ENCCs require the presence of vessels to colonize the gut. Neural tube and avian midgut were explanted onto a variety of substrates, including components of the extracellular matrix and various cell types, such as fibroblasts, smooth muscle cells, and endothelial cells. We find that crest-derived cells from both the neural tube and the midgut migrate avidly onto Cultured endothelial cells. This EC-induced migration is inhibited by the presence of CSAT antibody, which blocks binding to beta 1 integrins expressed on the surface of crest-derived cells. These results demonstrate that ECs provide a Substrate for the migration of ENCCs via an interaction between beta 1 integrins on the ENCC surface and extracellular matrix proteins expressed by the intestinal vasculature. These interactions may play an important role in guiding migration and patterning in the developing ENS. (C) 2009 Elsevier Inc. All rights reserved. C1 [Nagy, Nandor; Mwizerwa, Olive; Pieretti-Vanmarcke, Rafael; Goldstein, Allan M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA 02115 USA. [Nagy, Nandor] Semmelweis Univ, Fac Med, Dept Human Morphol & Dev Biol, H-1094 Budapest, Hungary. [Yaniv, Karina; Weinstein, Brant M.] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Carmel, Liran] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Goldstein, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA 02115 USA. EM agoldstein@partners.org FU NIH [K08HD46655]; Hungarian Scientific Research Fund [K-69061]; Semmelweis University; NICHD; EMBO fellowship FX We thank Drucilla Roberts and Joanne Chan for helpful discussions, Csaba Bodor for Huvec cells, and Ajay Chitnis for the HuC:GFP transgenic zebrafish line. Several antibodies in Table 1 were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by University of Iowa, Dept. of Biological Sciences, Iowa City, IA 52242. AMG is supported by NIH K08HD46655, NN by a grant from the Hungarian Scientific Research Fund (K-69061) and a Young Investigator Award from Semmelweis University, BMW by the intramural program of the NICHD, and KY by an EMBO fellowship. NR 54 TC 38 Z9 41 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 15 PY 2009 VL 330 IS 2 BP 263 EP 272 DI 10.1016/j.ydbio.2009.03.025 PG 10 WC Developmental Biology SC Developmental Biology GA 452XN UT WOS:000266574600005 PM 19345201 ER PT J AU Tan, MH Smith, AJ Pawlyk, B Xu, XY Liu, XQ Bainbridge, JB Basche, M McIntosh, J Tran, HV Nathwani, A Li, TS Ali, RR AF Tan, Mei Hong Smith, Alexander J. Pawlyk, Basil Xu, Xiaoyun Liu, Xiaoqing Bainbridge, James B. Basche, Mark McIntosh, Jenny Tran, Hoai Viet Nathwani, Amit Li, Tiansen Ali, Robin R. TI Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors SO HUMAN MOLECULAR GENETICS LA English DT Article ID RCS RAT MODEL; RETINAL DEGENERATION; PHOTORECEPTOR DEGENERATION; CGMP PHOSPHODIESTERASE; CHILDHOOD BLINDNESS; REPLACEMENT THERAPY; RESTORES VISION; CANINE MODEL; PROTEIN; MICE AB Defects in the photoreceptor-specific gene encoding aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) are clinically heterogeneous and present as Leber Congenital Amaurosis, the severest form of early-onset retinal dystrophy and milder forms of retinal dystrophies such as juvenile retinitis pigmentosa and dominant cone-rod dystrophy. [Perrault, I., Rozet, J.M., Gerber, S., Ghazi, I., Leowski, C., Ducroq, D., Souied, E., Dufier, J.L., Munnich, A. and Kaplan, J. (1999) Leber congenital amaurosis. Mol. Genet. Metab., 68, 200-208.] Although not yet fully elucidated, AIPL1 is likely to function as a specialized chaperone for rod phosphodiesterase (PDE). We evaluate whether AAV-mediated gene replacement therapy is able to improve photoreceptor function and survival in retinal degeneration associated with AIPL1 defects. We used two mouse models of AIPL1 deficiency simulating three different rates of photoreceptor degeneration. The Aipl1 hypomorphic (h/h) mouse has reduced Aipl1 levels and a relatively slow degeneration. Under light acceleration, the rate of degeneration in the Aipl1 h/h mouse is increased by 2-3-fold. The Aipl1-/- mouse has no functional Aipl1 and has a very rapid retinal degeneration. To treat the different rates of degeneration, two pseudotypes of recombinant adeno-associated virus (AAV) exhibiting different transduction kinetics are used for gene transfer. We demonstrate restoration of cellular function and preservation of photoreceptor cells and retinal function in Aipl1 h/h mice following gene replacement therapy using an AAV2/2 vector and in the light accelerated Aipl1 h/h model and Aipl1-/- mice using an AAV2/8 vector. We have thus established the potential of gene replacement therapy in varying rates of degeneration that reflect the clinical spectrum of disease. This is the first gene replacement study to report long-term rescue of a photoreceptor-specific defect and to demonstrate effective rescue of a rapid photoreceptor degeneration. C1 [Pawlyk, Basil; Xu, Xiaoyun; Liu, Xiaoqing; Li, Tiansen] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. [Tan, Mei Hong; Smith, Alexander J.; Bainbridge, James B.; Basche, Mark; Tran, Hoai Viet; Ali, Robin R.] UCL, Inst Ophthalmol, NIHR Biomed Res Ctr, London, England. [McIntosh, Jenny; Nathwani, Amit] UCL, Canc Res Inst, London, England. RP Ali, RR (reprint author), 11-43 Bath St, London, England. EM tli@meei.harvard.edu; r.ali@ucl.ac.uk RI Smith, Alexander/A-5142-2009; OI Bainbridge, James/0000-0003-1318-8201 FU Fonds National Suisse de la Recherche Scientifique; Roche Research Foundation; Holcim Stiftung zur Forderung der wissenschaftlichen Fortbildung; European Union (AAVEYE),; UK Department of Health; National Institute of Health Research BMRC for Ophthalmology; NIH [EY10581]; Foundation Fighting Blindness FX H. V. T. is supported by Fonds National Suisse de la Recherche Scientifique, Roche Research Foundation and Holcim Stiftung zur Forderung der wissenschaftlichen Fortbildung. This work was also supported by grants from the European Union (AAVEYE), the UK Department of Health, National Institute of Health Research BMRC for Ophthalmology, NIH Grant EY10581 and Foundation Fighting Blindness. NR 40 TC 81 Z9 85 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2009 VL 18 IS 12 BP 2099 EP 2114 DI 10.1093/hmg/ddp133 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 449SD UT WOS:000266349400001 PM 19299492 ER PT J AU Lee, DS Burd, H Liu, JX Almaas, E Wiest, O Barabasi, AL Oltvai, ZN Kapatral, V AF Lee, Deok-Sun Burd, Henry Liu, Jiangxia Almaas, Eivind Wiest, Olaf Barabasi, Albert-Laszlo Oltvai, Zoltan N. Kapatral, Vinayak TI Comparative Genome-Scale Metabolic Reconstruction and Flux Balance Analysis of Multiple Staphylococcus aureus Genomes Identify Novel Antimicrobial Drug Targets SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI; SEQUENCE; NETWORK; GENES; IDENTIFICATION; INFECTIONS; EVOLUTION; DISCOVERY; DRAFT AB Mortality due to multidrug-resistant Staphylococcus aureus infection is predicted to surpass that of human immunodeficiency virus/AIDS in the United States. Despite the various treatment options for S. aureus infections, it remains a major hospital- and community-acquired opportunistic pathogen. With the emergence of multidrug-resistant S. aureus strains, there is an urgent need for the discovery of new antimicrobial drug targets in the organism. To this end, we reconstructed the metabolic networks of multidrug-resistant S. aureus strains using genome annotation, functional-pathway analysis, and comparative genomic approaches, followed by flux balance analysis-based in silico single and double gene deletion experiments. We identified 70 single enzymes and 54 pairs of enzymes whose corresponding metabolic reactions are predicted to be unconditionally essential for growth. Of these, 44 single enzymes and 10 enzyme pairs proved to be common to all 13 S. aureus strains, including many that had not been previously identified as being essential for growth by gene deletion experiments in S. aureus. We thus conclude that metabolic reconstruction and in silico analyses of multiple strains of the same bacterial species provide a novel approach for potential antibiotic target identification. C1 [Burd, Henry; Kapatral, Vinayak] Integrated Genom Inc, Chicago, IL 60612 USA. [Lee, Deok-Sun; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02215 USA. [Lee, Deok-Sun; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02215 USA. [Lee, Deok-Sun; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Biol, Boston, MA 02215 USA. [Lee, Deok-Sun; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Comp Sci, Boston, MA 02215 USA. [Lee, Deok-Sun; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Lee, Deok-Sun] Inha Univ, Dept Nat Med Sci, Inchon 402751, South Korea. [Liu, Jiangxia; Oltvai, Zoltan N.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA. [Almaas, Eivind] Lawrence Livermore Natl Lab, Biosci & Biotechnol Div, Livermore, CA 94551 USA. [Wiest, Olaf] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. RP Kapatral, V (reprint author), Integrated Genom Inc, 2201 W Campbell Pk Dr, Chicago, IL 60612 USA. EM vinayak@integratedgenomics.com RI Lee, Deok-Sun/D-1335-2011; OI Almaas, Eivind/0000-0002-9125-326X FU NIH [5U01AI070499-02] FX Support for this work was provided by NIH grant 5U01AI070499-02. NR 30 TC 82 Z9 86 U1 0 U2 22 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUN 15 PY 2009 VL 191 IS 12 BP 4015 EP 4024 DI 10.1128/JB.01743-08 PG 10 WC Microbiology SC Microbiology GA 451ET UT WOS:000266454200025 PM 19376871 ER PT J AU Mikhak, Z Farsidjani, A Luster, AD AF Mikhak, Zamaneh Farsidjani, Alireza Luster, Andrew D. TI Endotoxin Augmented Antigen-Induced Th1 Cell Trafficking Amplifies Airway Neutrophilic Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-GAMMA-RECEPTOR; INHERITED INTERLEUKIN-12 DEFICIENCY; BACILLE CALMETTE-GUERIN; MYCOBACTERIAL INFECTION; TARGETED DISRUPTION; SALMONELLA-ENTERITIDIS; MICE; RESPONSES; GENE; CHEMOKINE AB CD4(+) Th1 cells play a critical role in orchestrating host defense against pathogens and in the pathogenesis of many immune-mediated diseases. The control of Th1 cell trafficking into sites of infection and inflammation is an important determinant of Till cell function. We have previously shown that trafficking of adoptively transferred Ag-specific Th1 cells into the lung following airway Ag challenge depends on CXCR3 expression on Th1 cells and STAT1-inducible CXCR3 ligands in the lung. In this study, we show that LPS alters the mechanisms of Th1 cell recruitment. After a single intranasal dose of LPS, trafficking of adoptively transferred Ag-specific Th1 cell into the lung in response to airway Ag challenges was no longer dependent on CXCR3 and its ligands and instead was mediated through additional G alpha i-coupled chemoattractant receptor pathways, including CCR5. In addition, LPS markedly increased the magnitude of Ag-specific Th1 cell homing into the airways following airway Ag challenges. The increased trafficking of Ag-activated Th1 cells, in turn, dramatically amplified LPS-induced airway neutrophilic infiltration by maintaining high levels of the neutrophil active chemokines, KC and MIP-2, through an IFN-gamma dependent mechanism. Therefore, LPS increases Ag-specific Th1 cell trafficking into the airways and Ag-specific Th1 cells amplify the airway neutrophilic inflammatory response initiated by LPS. This reciprocal interaction between LPS and Ag-activated Th1 cells represents a collaborative connection between the innate and adaptive arms of the immune system. The Journal of Immunology, 2009, 182: 7946-7956. C1 [Mikhak, Zamaneh; Farsidjani, Alireza; Luster, Andrew D.] Harvard Univ, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp,Med Sch, Boston, MA 02129 USA. RP Luster, AD (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, 149 13th St,Suite 8301, Charlestown, MA 02129 USA. EM aluster@mgh.harvard.edu FU National Institute of Health [R37-AI40618, K08AI67519] FX This work was supported by the National Institute of Health (R37-AI40618 to A.D.L. and K08AI67519 to Z.M.). NR 44 TC 12 Z9 12 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2009 VL 182 IS 12 BP 7946 EP 7956 DI 10.4049/jimmunol.0803522 PG 11 WC Immunology SC Immunology GA 456HD UT WOS:000266833900066 PM 19494319 ER PT J AU Wolters, PJ Wray, C Sutherland, RE Kim, SS Koff, J Mao, Y Frank, JA AF Wolters, Paul J. Wray, Charlie Sutherland, Rachel E. Kim, Sophia S. Koff, Jon Mao, Ying Frank, James A. TI Neutrophil-Derived IL-6 Limits Alveolar Barrier Disruption in Experimental Ventilator-Induced Lung Injury SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; INTERLEUKIN-6-DEFICIENT MICE; INFLAMMATION; EXPRESSION; PROTECTION; MECHANISM; RESPONSES; BLOCKADE; IMMUNE AB IL-6 is a biological marker of ventilator-associated lung injury that may contribute to alveolar barrier dysfunction in acute respiratory distress syndrome. To determine whether IL-6 affects alveolar barrier disruption in a model of ventilator-induced lung injury, we examined alveolar barrier albumin flux in wild-type (WT) mice given an IL-6-blocking Ab (IL6AB) and mice deficient in IL-6 (LL6KO). Albumin flux was significantly higher in mice given IL6AB compared with mice given a control Ab. Unexpectedly, albumin flux was similar in WT and IL6KO mice. To examine the mechanisms for these findings, lung neutrophil accumulation (myeloperoxidase activity) was compared, revealing a correlation between lung neutrophil accumulation and albumin flux. IL6AB mice had significantly more lung neutrophils than WT and IL6KO mice, which were similar. Therefore, to determine whether the cellular source of IL-6 influences neutrophil accumulation and alveolar barrier function, chimeric mice were compared. WT/KO chimeras (WT mice with IL6KO hematopoietic cells) showed significantly greater albumin flux and neutrophil accumulation with mechanical ventilation than WT/WT mice. Neutrophil depletion decreased albumin flux in WT and WT/KO mice. IL6KO neutrophils were more adherent in an in vitro assay compared with WT neutrophils. IL-6 from a hematopoietic cell source limits alveolar barrier disruption potentially by reducing neutrophil contact with the endothelium. Modulation of IL-6 signaling in a cell type-specific fashion may be a therapeutic target for patients with acute lung injury. The Journal of Immunology, 2009, 182: 8056-8062. C1 [Frank, James A.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Wolters, Paul J.; Sutherland, Rachel E.; Kim, Sophia S.; Koff, Jon; Frank, James A.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94121 USA. [Wray, Charlie; Mao, Ying; Frank, James A.] Vet Hlth Res Inst, No Calif Inst Res & Educ, San Francisco, CA 94121 USA. [Frank, James A.] San Francisco Vet Adm Med Ctr, San Francisco, CA 94121 USA. RP Frank, JA (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco Vet Affairs Med Ctr, 4150 Clement St,Box 111D, San Francisco, CA 94121 USA. EM james.frank@ucsf.edu RI Wolters, Paul/A-7181-2009 FU National Institutes of Health and National Heart, Lung and Blood Institute [HL088440, HL075026] FX This work was supported by funding from the National Institutes of Health and National Heart, Lung and Blood Institute Grants HL088440 (to J.A.F.) and HL075026 (to P.J.W.). NR 23 TC 34 Z9 36 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2009 VL 182 IS 12 BP 8056 EP 8062 PG 7 WC Immunology SC Immunology GA 456HD UT WOS:000266833900078 PM 19494331 ER PT J AU Camargo, JF Kulkarni, H Agan, BK Gaitan, AA Beachy, LA Srinivas, S He, WJ Anderson, S Marconi, VC Dolan, MJ Ahuja, SK AF Camargo, Jose F. Kulkarni, Hemant Agan, Brian K. Gaitan, Alvaro A. Beachy, Lisa A. Srinivas, Sowmya He, Weijing Anderson, Stephanie Marconi, Vincent C. Dolan, Matthew J. Ahuja, Sunil K. TI Responsiveness of T Cells to Interleukin-7 Is Associated with Higher CD4(+) T Cell Counts in HIV-1-Positive Individuals with Highly Active Antiretroviral Therapy-Induced Viral Load Suppression SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SURFACE CCR5 DENSITY; IL-7 RECEPTOR-ALPHA; DISEASE PROGRESSION; SINGLE-CELL; IN-VIVO; HOMEOSTATIC PROLIFERATION; HIV-1-INFECTED PATIENTS; LYMPHOID HOMEOSTASIS; INFECTED PATIENTS AB Background. Despite suppression of the human immunodeficiency virus type 1 (HIV-1) load by highly active antiretroviral therapy (HAART), recovery of CD4(+) T cell counts can be impaired. We investigated whether this impairment may be associated with hyporesponsiveness of T cells to gamma-chain (gamma c) cytokines known to influence T cell homeostasis. Methods. The responsiveness of T cells to interleukin (IL)-2, IL-7, and IL-15 was determined by assessing cytokine-induced phosphorylation of the signal transducer and activator of transcription 5 (STAT5) in peripheral T cells obtained from 118 HIV-positive subjects and 13 HIV-negative subjects. Results. The responsiveness of T cells to interleukin (IL)-7 but not to IL-2 or IL-15 was lower among HIV-positive subjects than among HIV-negative subjects. Among subjects with viral load suppression, the degree of IL-7 responsiveness (1) correlated with naive CD4(+) T cell counts and was a better immune correlate of the prevailing CD4(+) T cell count than were levels of human leukocyte antigen-DR1 or programmed death-1, which are predictors of T cell homeostasis during HIV infection; and (2) was greater in subjects with complete (i.e., attainment of >= 500 CD4(+) T cells/mm(3) >= 5 years after initiation of HAART) versus incomplete immunologic responses. The correlation between plasma levels of IL-7 and CD4(+) T cell counts during HAART was maximal in subjects with increased IL-7 responsiveness. Conclusions. Responsiveness of T cells to IL-7 is associated with higher CD4(+) T cell counts during HAART and thus may be a determinant of the extent of immune reconstitution. C1 [Camargo, Jose F.; Kulkarni, Hemant; Gaitan, Alvaro A.; Beachy, Lisa A.; Srinivas, Sowmya; He, Weijing; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol, San Antonio, TX 78229 USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Immunol, San Antonio, TX 78229 USA. [Camargo, Jose F.; Kulkarni, Hemant; Gaitan, Alvaro A.; Beachy, Lisa A.; Srinivas, Sowmya; He, Weijing; Ahuja, Sunil K.] S Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV Infect 1, San Antonio, TX 78229 USA. [Anderson, Stephanie; Marconi, Vincent C.; Dolan, Matthew J.] Wilford Hall USAF Med Ctr, Infect Dis Serv, Lackland AFB, TX 78236 USA. [Anderson, Stephanie; Dolan, Matthew J.] Wilford Hall USAF Med Ctr, Henry M Jackson Fdn, Lackland AFB, TX 78236 USA. [Anderson, Stephanie; Marconi, Vincent C.; Dolan, Matthew J.] San Antonio Mil Med Ctr, Ft Sam Houston, TX USA. [Anderson, Stephanie; Marconi, Vincent C.; Dolan, Matthew J.] San Antonio Mil Med Ctr, Lackland AFB, TX USA. [Agan, Brian K.; Anderson, Stephanie; Marconi, Vincent C.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. RP Ahuja, SK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr,Rm 5-009R, San Antonio, TX 78229 USA. EM mdolan@hjf.org; ahujas@uthscsa.edu RI Marconi, Vincent/N-3210-2014; OI Marconi, Vincent/0000-0001-8409-4689; Agan, Brian/0000-0002-5114-1669 FU Veterans Administration Center on AIDS and HIV Infection, South Texas Veterans Health Care System; National Institutes of Health (NIH) [R37046326, HU0001-05-2-0011]; Elizabeth Glaser Scientist Award; Burroughs Wellcome Clinical Scientist Award in Translational Research; Uniformed Services University of the Health Sciences (USUHS) FX Veterans Administration Center on AIDS and HIV Infection, South Texas Veterans Health Care System; National Institutes of Health (NIH; MERIT award R37046326 to S. K. A.). S. K. A. is a recipient of the Elizabeth Glaser Scientist Award and the Burroughs Wellcome Clinical Scientist Award in Translational Research. Support for the Wilford Hall Medical Center cohort was provided by the Infectious Disease Clinical Research Program (IDCRP) of the Uniformed Services University of the Health Sciences (USUHS). The IDCRP is a Department of Defense triservice program executed through the USUHS and the Henry M. Jackson Foundation for the Advancement of Military Medicine, in collaboration with the Department of Health and Human Services/ NIH/National Institute of Allergy and Infectious Diseases/Division of Clinical Research through Interagency Agreement HU0001-05-2-0011. NR 43 TC 36 Z9 37 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2009 VL 199 IS 12 BP 1872 EP 1882 DI 10.1086/598858 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 448BM UT WOS:000266236500021 PM 19432535 ER PT J AU Raval, MV Bilimoria, KY Stewart, AK Bentrem, DJ Ko, CY AF Raval, Mehul V. Bilimoria, Karl Y. Stewart, Andrew K. Bentrem, David J. Ko, Clifford Y. TI Using the NCDB for Cancer Care Improvement: An Introduction to Available Quality Assessment Tools SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Review DE quality of health care; Health Care Quality Assessment; National Cancer Database ID UNITED-STATES; DATA-BASE AB Improving the quality of cancer care requires high-quality data, mechanisms to feed back information to hospitals, systems to act on the data, and participation of providers. The purpose of this review is to describe how the National Cancer Database (NCDB) can be utilized to improve the quality of cancer care in the United States through a variety of benchmarking reports and data feedback mechanisms available to hospitals approved by the Commission on Cancer (CoC). J. Surg. Oncol. 2009;99:485-490. (C) 2009 Wiley-Liss, Inc. C1 [Raval, Mehul V.; Bilimoria, Karl Y.; Stewart, Andrew K.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Canc Programs, Chicago, IL 60611 USA. [Raval, Mehul V.; Bilimoria, Karl Y.; Bentrem, David J.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 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 Ko, CY (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, Canc Programs, 636 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM CKo@mednet.ucla.edu OI Raval, Mehul/0000-0002-1527-2661 NR 16 TC 56 Z9 56 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD JUN 15 PY 2009 VL 99 IS 8 BP 488 EP 490 DI 10.1002/jso.21173 PG 3 WC Oncology; Surgery SC Oncology; Surgery GA 455DS UT WOS:000266738200008 PM 19466738 ER PT J AU Robertson, SA Koleva, RI Argetsinger, LS Carter-Su, C Marto, JA Feener, EP Myers, MG AF Robertson, Scott A. Koleva, Rositsa I. Argetsinger, Lawrence S. Carter-Su, Christin Marto, Jarrod A. Feener, Edward P. Myers, Martin G., Jr. TI Regulation of Jak2 Function by Phosphorylation of Tyr(317) and Tyr(637) during Cytokine Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TYROSINE KINASE TYK2; GROWTH-HORMONE RECEPTOR; LEPTIN RECEPTOR; FERM DOMAIN; PSEUDOKINASE DOMAIN; CATALYTIC ACTIVITY; ACTIVATION; AUTOPHOSPHORYLATION; PATHWAYS; SITE AB Jak2, the cognate tyrosine kinase for numerous cytokine receptors, undergoes multisite phosphorylation during cytokine stimulation. To understand the role of phosphorylation in Jak2 regulation, we used mass spectrometry to identify numerous Jak2 phosphorylation sites and characterize their significance for Jak2 function. Two sites outside of the tyrosine kinase domain, Tyr(317) in the FERM domain and Tyr(637) in the JH2 domain, exhibited strong regulation of Jak2 activity. Mutation of Tyr(317) promotes increased Jak2 activity, and the phosphorylation of Tyr(317) during cytokine signaling requires prior activation loop phosphorylation, which is consistent with a role for Tyr(317) in the feedback inhibition of Jak2 kinase activity after receptor stimulation. Comparison to several previously identified regulatory phosphorylation sites on Jak2 revealed a dominant role for Tyr(317) in the attenuation of Jak2 signaling. In contrast, mutation of Tyr(637) decreased Jak2 signaling and activity and partially suppressed the activating JH2 V617F mutation, suggesting a role for Tyr(637) phosphorylation in the release of JH2 domain-mediated suppression of Jak2 kinase activity during cytokine stimulation. The phosphorylation of Tyr(317) and Tyr(637) act in concert with other regulatory events to maintain appropriate control of Jak2 activity and cytokine signaling. C1 [Robertson, Scott A.; Myers, Martin G., Jr.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Robertson, Scott A.; Argetsinger, Lawrence S.; Carter-Su, Christin; Myers, Martin G., Jr.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Koleva, Rositsa I.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Feener, Edward P.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. RP Myers, MG (reprint author), Univ Michigan, Sch Med, Div Metab Endocrinol & Diabet, Dept Med, 5560 MSRB 2,MSP5678,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM mgmyers@umich.edu FU NIH [DK57631, D57768, DK20572, P30 CA46592]; Dana Farber Cancer Institute FX This study was supported by NIH DK57631 and NIH D57768 (to M. G. M.), NIH DK34171 (to C. C.-S.), predoctoral fellowships from the American Diabetes Association and the American Heart Association (to S. A. R.), and support from the Dana Farber Cancer Institute (to J. A. M.). Support for peptide synthesis and DNA sequencing was provided by the Biomedical Research Core facilities at the University of Michigan, which are supported in part by the Michigan Diabetes Research and Training Center (NIH P60 DK20572) and the University of Michigan Comprehensive Cancer Center (NIH P30 CA46592). NR 39 TC 18 Z9 18 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN 15 PY 2009 VL 29 IS 12 BP 3367 EP 3378 DI 10.1128/MCB.00278-09 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 450XW UT WOS:000266436300012 PM 19364823 ER PT J AU Lupien, M Eeckhoute, J Meyer, CA Krum, SA Rhodes, DR Liu, XS Brown, M AF Lupien, Mathieu Eeckhoute, Jerome Meyer, Clifford A. Krum, Susan A. Rhodes, Daniel R. Liu, X. Shirley Brown, Myles TI Coactivator Function Defines the Active Estrogen Receptor Alpha Cistrome SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GENE-EXPRESSION PATTERNS; HUMAN BREAST-CANCER; EMBRYONIC STEM-CELLS; RNA-POLYMERASE; HUMAN GENOME; CHROMATIN SIGNATURES; HISTOLOGIC GRADE; BINDING-SITES; CHIP-CHIP; TRANSCRIPTION AB Proper activation of transcriptional networks in complex organisms is central to the response to stimuli. We demonstrate that the selective activation of a subset of the estrogen receptor alpha (ER alpha) cistrome in MCF7 breast cancer cells provides specificity to the estradiol (E2) response. ER alpha-specific enhancers that are subject to E2-induced coactivator-associated arginine methyltransferase 1 (CARM1) action are critical to E2-stimulated gene expression. This is true for both FoxA1-dependent and independent enhancers. In contrast, a subset of E2-suppressed genes are controlled by FoxA1-independent ER alpha binding sites. Nonetheless, these are sites of E2-induced CARM1 activity. In addition, the MCF7 RNA polymerase II cistrome reveals preferential occupancy of E2-regulated promoters prior to stimulation. Interestingly, E2-suppressed genes tend to lie in otherwise silent genomic regions. Together, our results suggest that the transcriptional response to E2 in breast cancer cells is dependent on the interplay between polymerase II pre-occupied promoters and the subset of the ER alpha cistrome associated with coactivation. C1 [Lupien, Mathieu; Eeckhoute, Jerome; Krum, Susan A.; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Div Mol & Cellular Oncol, Boston, MA 02115 USA. [Lupien, Mathieu; Eeckhoute, Jerome; Krum, Susan A.; Brown, Myles] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Lupien, Mathieu; Eeckhoute, Jerome; Krum, Susan A.; Brown, Myles] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Meyer, Clifford A.; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Meyer, Clifford A.; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Rhodes, Daniel R.] Compendia Biosci Inc, Ann Arbor, MI 48104 USA. RP Brown, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Div Mol & Cellular Oncol, 44 Binney St, Boston, MA 02115 USA. EM myles_brown@dfci.harvard.edu RI krum, susan/D-7282-2013; OI Brown, Myles/0000-0002-8213-1658; Eeckhoute, Jerome/0000-0002-7222-9264 FU NIDDK [R01DK074967]; NCI [P01 CA8011105]; DF/HCC Breast Cancer SPORE; DFCI Women's Cancers Program; DFCI Women's Cancers Program [W81XWH-08-1-0214] FX This study was supported by grants from the NIDDK (R01DK074967 to M. B.), the NCI (P01 CA8011105) and a DF/HCC Breast Cancer SPORE Grant (to M. B.), the DFCI Women's Cancers Program, and the U. S. Department of Defense Breast Cancer Research Program Awards (W81XWH-08-1-0214 to M. L.). NR 70 TC 44 Z9 46 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN 15 PY 2009 VL 29 IS 12 BP 3413 EP 3423 DI 10.1128/MCB.00020-09 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 450XW UT WOS:000266436300016 PM 19364822 ER PT J AU Ehrlich, S Burghardt, R Schneider, N Broecker-Preuss, M Weiss, D Merle, JV Craciun, EM Pfeiffer, E Mann, K Lehmkuhl, U Hebebrand, J AF Ehrlich, Stefan Burghardt, Roland Schneider, Nora Broecker-Preuss, Martina Weiss, Deike Merle, Julia V. Craciun, Eugenia Maria Pfeiffer, Ernst Mann, Klaus Lehmkuhl, Ulrike Hebebrand, Johannes TI The role of leptin and cortisol in hyperactivity in patients with acute and weight-recovered anorexia nervosa SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Anorexia nervosa; Cortisol; Hyperactivity; Leptin ID CORTICOTROPIN-RELEASING-FACTOR; PITUITARY-ADRENAL AXIS; PHYSICAL-ACTIVITY; BEHAVIORAL ACTIVATION; RATS; EXERCISE; ADOLESCENTS; OBESE; RESTLESSNESS; DISORDERS AB Introduction: In food-restricted rats, leptin as well as corticotropin releasing factor attenuate semistarvation-induced hyperactivity (SIH). Results from studies in patients with anorexia nervosa (AN) showed an association between excessive physical activity (PA) and leptin. One recent report suggests a role for cortisol in PA. In this study, we assessed the relationships between PA and both, cortisol and leptin levels at the same time in patients with acute anorexia nervosa (acAN) in comparison to recovered patients (recAN). Methods: Plasma leptin, plasma cortisol, body mass index (BMI), and expert-ratings of qualities of PA were assessed in 36 acAN patients, 27 recAN patients and 44 healthy control woman (HCW). Regression analyses were used to predict PA using BMI, leptin and cortisol levels as predictor variables. Results: Leptin levels but not cortisol significantly contributed to the prediction of PA in acAN. In recAN PA was not elevated and not related to endocrine parameters but correlated positively with core eating disorder symptoms. Conclusions: Our work lends support to the proposed inverse association between peripheral leptin levels and excessive physical activity in AN. This relationship is specific to the state of semistarvation. The role of additional mediators remains to be clarified. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ehrlich, Stefan; Burghardt, Roland; Schneider, Nora; Weiss, Deike; Merle, Julia V.; Pfeiffer, Ernst; Lehmkuhl, Ulrike] Charite Univ Med Berlin, Dept Child & Adolescent Psychiat Psychosomat & Ps, CVK, D-13353 Berlin, Germany. [Ehrlich, Stefan] Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, CCM, D-10117 Berlin, Germany. [Broecker-Preuss, Martina; Mann, Klaus] Univ Duisburg Essen, Dept Endocrinol, Div Clin Chem & Lab Med, D-45147 Essen, Germany. [Craciun, Eugenia Maria] Charite Univ Med Berlin, Dept Psychosomat Med, CCM, D-10117 Berlin, Germany. [Hebebrand, Johannes] Univ Duisburg Essen, Dept Child & Adolescent Psychiat & Psychotherapy, D-45147 Essen, Germany. RP Ehrlich, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dr R Gollubs Lab, Dept Psychiat,Athinoula A Martinos Ctr Biomed Ima, Bldg 149,13th St,Room 2311, Charlestown, MA 02129 USA. EM stefan@nmr.mgh.harvard.edu OI Ehrlich, Stefan/0000-0003-2132-4445 NR 39 TC 10 Z9 10 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUN 15 PY 2009 VL 33 IS 4 BP 658 EP 662 DI 10.1016/j.pnpbp.2009.03.007 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 455MC UT WOS:000266763400012 PM 19296912 ER PT J AU Medarova, Z Vallabhajosyula, P Tena, A Evgenov, N Pantazopoulos, P Tchipashvili, V Weir, G Sachs, D Moore, A AF Medarova, Zdravka Vallabhajosyula, Prashanth Tena, Aseda Evgenov, Natalia Pantazopoulos, Pamela Tchipashvili, Vaja Weir, Gordon Sachs, David Moore, Anna TI In Vivo Imaging of Autologous Islet Grafts in the Liver and Under the Kidney Capsule in Non-Human Primates SO TRANSPLANTATION LA English DT Article DE Islet; Islet labeling; Feridex; Islet transplant; MRI; Non-human primate ID TRANSPLANTED PANCREATIC-ISLETS; POSITRON-EMISSION-TOMOGRAPHY; SURFACE-BASED ANALYSIS; EDMONTON PROTOCOL; MRI; CELLS; ENGRAFTMENT; REJECTION; TRACKING; SURVIVAL AB Objective. As islet transplantation begins to show promise as a clinical method, there is a critical need for reliable, noninvasive techniques to monitor islet graft survival. Previous work in our laboratory has shown that human islets labeled with a superparamagnetic iron oxide contrast agent and transplanted into mice could be detected by magnetic resonance imaging (MRI). The potential translation of these findings to the clinical situation requires validation of our methodology in a non-human primate model, which we have now carried out in baboons (Papio hamadryas) and reported here. Research Design and Methods. For islet labeling, we adapted the Food and Drug Administration-approved superparamagnetic iron oxide contrast agent, Feridex, which is used clinically for liver imaging. After partial pancreatectomy, Feridex-labeled islets were prepared and autotransplanted underneath the renal capsule and into the liver. Longitudinal in vivo MRI at days 1, 3, 8, 16, 23, and 30 after transplantation was performed to track the islet grafts. Results. The renal subcapsular islet graft was easily detectable on T2*-weighted MR images as a pocket of signal loss disrupting the contour of the kidney at the transplantation site. Islets transplanted in the liver appeared as distinct signal voids dispersed throughout the liver parenchyma. A semiautomated computational analysis of our MRI data established the feasibility of monitoring both the renal and intrahepatic grafts during the studied posttransplantation period. Conclusion. This study establishes a method for the noninvasive, longitudinal detection of pancreatic islets transplanted into non-human primates using a low-field clinical MRI system. C1 [Medarova, Zdravka; Evgenov, Natalia; Pantazopoulos, Pamela; Moore, Anna] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol,Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02129 USA. [Vallabhajosyula, Prashanth; Tena, Aseda; Sachs, David] Harvard Univ, Sch Med, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Boston, MA 02129 USA. [Tchipashvili, Vaja; Weir, Gordon] Harvard Univ, Sch Med, Sect Islet Transplantat & Cell Biol, Joslin Diabet Ctr, Boston, MA 02129 USA. RP Moore, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol,Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Room 2301,Bldg 149,13th St, Boston, MA 02129 USA. EM amoore@helix.mgh.harvard.edu FU NIH [1RO1 DK078615, 5P30 DK 36836] FX This study was supported in part by NIH 1RO1 DK078615 (A.M.). Also supported by NIH 5P30 DK 36836. NR 31 TC 28 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 15 PY 2009 VL 87 IS 11 BP 1659 EP 1666 DI 10.1097/TP.0b013e3181a5cbc0 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 456YG UT WOS:000266889900009 PM 19502957 ER PT J AU Shah, AA Sainani, NI Ramesh, AK Shah, ZK Deshpande, V Hahn, PF Sahani, DV AF Shah, Anjuli A. Sainani, Nisha I. Ramesh, Avinash Kambadakone Shah, Zarine K. Deshpande, Vikram Hahn, Peter F. Sahani, Dushyant V. TI Predictive value of multi-detector computed tomography for accurate diagnosis of serous cystadenoma: Radiologic-pathologic correlation SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Pancreas; Serous cystadenoma; Multi-detector computed tomography; Central scar; Lobulations; Microcystic ID CYSTIC NEOPLASMS; MUCINOUS CYSTADENOMA; PANCREAS; CT; MANAGEMENT; ADENOMA; RECOMMENDATIONS; DISCRIMINATION; FEATURES; LESIONS AB AIM: To identify multi-detector computed tomography (MDCT) features most predictive of serous cystadenomas (SCAs), correlating with histopathology, and to study the impact of cyst size and MDCT technique on reader performance. METHODS: The MDCT scans of 164 patients with surgically verified pancreatic cystic lesions were reviewed by two readers to study the predictive value of various morphological features for establishing a diagnosis of SCAs. Accuracy in lesion characterization and reader confidence were correlated with lesion size (<= 3 cm or >= 3 cm) and scanning protocols (dedicated vs routine). RESULTS: 28/164 cysts (mean size, 39 mm; range, 8-92 mm) were diagnosed as SCA on pathology. The MDCT features predictive of diagnosis of SCA were microcystic appearance (22/28, 78.6%), surface lobulations (25/28, 89.3%) and central scar (9/28, 32.4%). Stepwise logistic regression analysis showed that only microcystic appearance was significant for CT diagnosis of SCA (P = 0.0001). The sensitivity, specificity and PPV of central scar and of combined microcystic appearance and lobulations were 32.4%/100%/100% and 68%/100%/100%, respectively. The reader confidence was higher for lesions > 3 cm (P = 0.02) and for MDCT scans performed using thin collimation (1.25-2.5 mm) compared to routine 5 mm collimation exams (P > 0.05). CONCLUSION: Central scar on MDCT is diagnostic of SCA but is seen in only one third of SCAs. Microcystic morphology is the most significant CT feature in diagnosis of SCA. A combination of microcystic appearance and surface lobulations offers accuracy comparable to central scar with higher sensitivity. (C) 2009 The WIG Press and Baishideng. All rights reserved. C1 [Shah, Anjuli A.; Sainani, Nisha I.; Ramesh, Avinash Kambadakone; Shah, Zarine K.; Hahn, Peter F.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Dept Radiol, Boston, MA 02114 USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org RI Shah, Zarine/E-4064-2011 OI Shah, Zarine/0000-0002-0354-9678 NR 21 TC 9 Z9 13 U1 0 U2 1 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUN 14 PY 2009 VL 15 IS 22 BP 2739 EP 2747 DI 10.3748/wjg.15.2739 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 460DU UT WOS:000267169100008 PM 19522024 ER PT J AU Woolf, CJ AF Woolf, Clifford J. TI Mu and Delta Opioid Receptors Diverge SO CELL LA English DT Editorial Material ID ANALGESIA; MORPHINE; TOLERANCE; MICE AB Contrary to current models, Scherrer et al. (2009) provide evidence that mu and delta opioid receptors are not expressed by the same pain-sensing neurons. In mice, agonists for these receptors produce analgesia restricted to either noxious heat or mechanical stimuli, implying that the receptors act on distinct fibers to mediate completely different types of pain relief. C1 [Woolf, Clifford J.] Massachusetts Gen Hosp, Neural Plast Res Grp, Dept Anesthesia & Crit Care, Boston, MA 02129 USA. [Woolf, Clifford J.] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Neural Plast Res Grp, Dept Anesthesia & Crit Care, Boston, MA 02129 USA. EM cwoolf@partners.org NR 9 TC 9 Z9 12 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUN 12 PY 2009 VL 137 IS 6 BP 987 EP 988 DI 10.1016/j.cell.2009.05.033 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 457GL UT WOS:000266916400007 PM 19524498 ER PT J AU Kim, JH Ellwood, PE Asher, MI AF Kim, June-Ho Ellwood, Philippa E. Asher, M. Innes TI Diet and asthma: looking back, moving forward SO RESPIRATORY RESEARCH LA English DT Review ID GENE-ENVIRONMENT INTERACTIONS; THRIFTY PHENOTYPE HYPOTHESIS; CHILDHOOD ASTHMA; VITAMIN-D; MEDITERRANEAN DIET; BRONCHIAL HYPERRESPONSIVENESS; ALLERGIC RHINOCONJUNCTIVITIS; INTESTINAL MICROBIOTA; HYGIENE HYPOTHESIS; ANTIOXIDANT INTAKE AB Asthma is an increasing global health burden, especially in the western world. Public health interventions are sought to lessen its prevalence or severity, and diet and nutrition have been identified as potential factors. With rapid changes in diet being one of the hallmarks of westernization, nutrition may play a key role in affecting the complex genetics and developmental pathophysiology of asthma. The present review investigates hypotheses about hygiene, antioxidants, lipids and other nutrients, food types and dietary patterns, breastfeeding, probiotics and intestinal microbiota, vitamin D, maternal diet, and genetics. Early hypotheses analyzed population level trends and focused on major dietary factors such as antioxidants and lipids. More recently, larger dietary patterns beyond individual nutrients have been investigated such as obesity, fast foods, and the Mediterranean diet. Despite some promising hypotheses and findings, there has been no conclusive evidence about the role of specific nutrients, food types, or dietary patterns past early childhood on asthma prevalence. However, diet has been linked to the development of the fetus and child. Breastfeeding provides immunological protection when the infant's immune system is immature and a modest protective effect against wheeze in early childhood. Moreover, maternal diet may be a significant factor in the development of the fetal airway and immune system. As asthma is a complex disease of gene-environment interactions, maternal diet may play an epigenetic role in sensitizing fetal airways to respond abnormally to environmental insults. Recent hypotheses show promise in a biological approach in which the effects of dietary factors on individual physiology and immunology are analyzed before expansion into larger population studies. Thus, collaboration is required by various groups in studying this enigma from epidemiologists to geneticists to immunologists. It is now apparent that this multidisciplinary approach is required to move forward and understand the complexity of the interaction of dietary factors and asthma. C1 [Kim, June-Ho] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Ellwood, Philippa E.; Asher, M. Innes] Univ Auckland, Dept Paediat Child & Youth Hlth, Auckland 1, New Zealand. RP Kim, JH (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM juneho.kim@post.harvard.edu; p.ellwood@auckland.ac.nz; mi.asher@auckland.ac.nz RI Ellwood, Philippa/G-7555-2015; Asher, Innes/O-2604-2016 OI Ellwood, Philippa/0000-0002-1994-4023; Asher, Innes/0000-0003-1768-3832 NR 94 TC 43 Z9 50 U1 4 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD JUN 12 PY 2009 VL 10 AR 49 DI 10.1186/1465-9921-10-49 PG 7 WC Respiratory System SC Respiratory System GA 475TB UT WOS:000268382800001 PM 19519921 ER PT J AU Corsello, SM Roti, G Ross, KN Chow, KT Galinsky, I DeAngelo, DJ Stone, RM Kung, AL Golub, TR Stegmaier, K AF Corsello, Steven M. Roti, Giovanni Ross, Kenneth N. Chow, Kwan T. Galinsky, Ilene DeAngelo, Daniel J. Stone, Richard M. Kung, Andrew L. Golub, Todd R. Stegmaier, Kimberly TI Identification of AML1-ETO modulators by chemical genomics SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; HIGH-DOSE METHYLPREDNISOLONE; ACUTE MYELOBLASTIC-LEUKEMIA; ACUTE MONOCYTIC LEUKEMIA; FUSION PROTEIN; GRANULOCYTIC DIFFERENTIATION; TRANSCRIPTION FACTOR; EXPRESSION PROFILES; PROSTATE-CANCER; SELF-RENEWAL AB Somatic rearrangements of transcription factors are common abnormalities in the acute leukemias. With rare exception, however, the resultant protein products have remained largely intractable as pharmacologic targets. One example is AML1-ETO, the most common translocation reported in acute myeloid leukemia (AML). To identify AML1-ETO modulators, we screened a small molecule library using a chemical genomic approach. Gene expression signatures were used as surrogates for the expression versus loss of the translocation in AML1-ETO-expressing cells. The top classes of compounds that scored in this screen were corticosteroids and dihydrofolate reductase (DHFR) inhibitors. In addition to modulating the AML1-ETO signature, both classes induced evidence of differentiation, dramatically inhibited cell viability, and ultimately induced apoptosis via on-target activity. Furthermore, AML1-ETO-expressing cell lines were exquisitely sensitive to the effects of corticosteroids on cellular viability compared with nonexpressers. The corticosteroids diminished AML1-ETO protein in AML cells in a proteasome-and glucocorticoid receptor-dependent manner. Moreover, these molecule classes demonstrated synergy in combination with standard AML chemotherapy agents and activity in an orthotopic model of AML1-ETO-positive AML. This work suggests a role for DHFR inhibitors and corticosteroids in treating patients with AML1-ETO-positive disease. (Blood. 2009; 113: 6193-6205) C1 [Corsello, Steven M.; Roti, Giovanni; Chow, Kwan T.; Kung, Andrew L.; Golub, Todd R.; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Corsello, Steven M.; Roti, Giovanni; Chow, Kwan T.; Kung, Andrew L.; Golub, Todd R.; Stegmaier, Kimberly] Harvard Univ, Sch Med, Childrens Hosp Boston, Cambridge, MA 02138 USA. [Ross, Kenneth N.; Golub, Todd R.; Stegmaier, Kimberly] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Ross, Kenneth N.; Golub, Todd R.; Stegmaier, Kimberly] MIT, Cambridge, MA 02139 USA. [Galinsky, Ilene; DeAngelo, Daniel J.; Stone, Richard M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Dana 322A,44 Binney St, Boston, MA 02115 USA. EM kimberly_stegmaier@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU American Society of Hematology (Washington, DC); Sidney Kimmel Foundation for Cancer Research (Baltimore, MD); National Cancer Institute (Bethesda, MD); Howard Hughes Medical Institute FX This work was funded by the American Society of Hematology (Washington, DC; K. S.), Sidney Kimmel Foundation for Cancer Research (Baltimore, MD; K. S.), the National Cancer Institute (Bethesda, MD; K. S.), and the Howard Hughes Medical Institute (K. S., T. R. G., and S. M. C.). NR 43 TC 22 Z9 29 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 11 PY 2009 VL 113 IS 24 BP 6193 EP 6205 DI 10.1182/blood-2008-07-166090 PG 13 WC Hematology SC Hematology GA 459XS UT WOS:000267147100024 PM 19377049 ER PT J AU Goel, VK Ibrahim, N Jiang, G Singhal, M Fee, S Flotte, T Westmoreland, S Haluska, FS Hinds, PW Haluska, FG AF Goel, V. K. Ibrahim, N. Jiang, G. Singhal, M. Fee, S. Flotte, T. Westmoreland, S. Haluska, F. S. Hinds, P. W. Haluska, F. G. TI Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice SO ONCOGENE LA English DT Article DE BRAF; p53; CDKN2A; AKT; melanoma; senescence ID MALIGNANT-MELANOMA; BRAF MUTATIONS; TUMOR SUPPRESSION; IN-VIVO; P53; SENESCENCE; MDM2; ACTIVATION; PATHWAYS; INK4A AB BRAF, a cellular oncogene and effector of RAS-mediated signaling, is activated by mutation in similar to 60% of melanomas. Most of these mutations consist of a V600E substitution resulting in constitutive kinase activation. Mutant BRAF thus represents an important therapeutic target in melanoma. In an effort to produce a pre-clinical model of mutant BRAF function in melanoma, we have generated a mouse expressing BRAF V600E targeted to melanocytes. We show that in these transgenic mice, widespread benign melanocytic hyperplasia with histological features of nevi occurs, with biochemical evidence of senescence. Melanocytic hyperplasia progresses to overt melanoma with an incidence dependent on BRAF expression levels. Melanomas show CDKN2A loss, and genetic disruption of the CDKN2A locus greatly enhances melanoma formation, consistent with collaboration between BRAF activation and CDKN2A loss suggested from studies of human melanoma. The development of melanoma also involves activation of the Mapk and Akt signaling pathways and loss of senescence, findings that faithfully recapitulate those seen in human melanomas. This murine model of mutant BRAF-induced melanoma formation thus provides an important tool for identifying further genetic alterations that cooperates with BRAF and that may be useful in enhancing susceptibility to BRAF-targeted therapeutics in melanoma. Oncogene (2009) 28, 2289-2298; doi: 10.1038/onc.2009.95; published online 27 April 2009 C1 [Goel, V. K.; Ibrahim, N.; Jiang, G.; Singhal, M.; Hinds, P. W.; Haluska, F. G.] Tufts Univ New England Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. [Fee, S.; Flotte, T.; Haluska, F. S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Westmoreland, S.] Harvard Univ, Sch Med, New England Primate Res Ctr, Boston, MA USA. RP Goel, VK (reprint author), Tufts Univ New England Med Ctr, Mol Oncol Res Inst, 750 Washington St, Boston, MA 02111 USA. EM vkumargoel@gmail.com; frank.haluska@ARIAD.com FU NIH [CA095798] FX This work was supported by NIH grant CA095798 to FGH. We thank Mohammad Miri for technical assistance, Dr Louis Montoliu for the tyrosinase promoter, Dr Lynda Chin for the mouse strains, and Dr Philip Tsichlis, Dr Amit Deshpande and Dr Trevor Pemberton for useful discussions. NR 36 TC 69 Z9 70 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 11 PY 2009 VL 28 IS 23 BP 2289 EP 2298 DI 10.1038/onc.2009.95 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 456XM UT WOS:000266886300005 PM 19398955 ER PT J AU Sabbisetti, V Di Napoli, A Seeley, A Amato, AM O'Regan, E Ghebremichael, M Loda, M Signoretti, S AF Sabbisetti, Venkata Di Napoli, Arianna Seeley, Apryle Amato, Angela M. O'Regan, Esther Ghebremichael, Musie Loda, Massimo Signoretti, Sabina TI p63 Promotes Cell Survival through Fatty Acid Synthase SO PLOS ONE LA English DT Article AB There is increasing evidence that p63, and specifically Delta Np63, plays a central role in both development and tumorigenesis by promoting epithelial cell survival. However, few studies have addressed the molecular mechanisms through which such important function is exerted. Fatty acid synthase (FASN), a key enzyme that synthesizes long-chain fatty acids and is involved in both embryogenesis and cancer, has been recently proposed as a direct target of p53 family members, including p63 and p73. Here we show that knockdown of either total or Delta N-specific p63 isoforms in squamous cell carcinoma (SCC9) or immortalized prostate epithelial (iPrEC) cells caused a decrease in cell viability by inducing apoptosis without affecting the cell cycle. p63 silencing significantly reduced both the expression and the activity of FASN. Importantly, stable overexpression of either FASN or myristoylated AKT (myr-AKT) was able to partially rescue cells from cell death induced by p63 silencing. FASN induced AKT phosphorylation and a significant reduction in cell viability was observed when FASN-overexpressing SCC9 cells were treated with an AKT inhibitor after p63 knockdown, indicating that AKT plays a major role in FASN-mediated survival. Activated AKT did not cause any alteration in the FASN protein levels but induced its activity, suggesting that the rescue from apoptosis documented in the p63-silenced cells expressing myr-AKT cells may be partially mediated by FASN. Finally, we demonstrated that p63 and FASN expression are positively associated in clinical squamous cell carcinoma samples as well as in the developing prostate. Taken together, our findings demonstrate that FASN is a functionally relevant target of p63 and is required for mediating its pro-survival effects. RP Sabbisetti, V (reprint author), Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp,Dana Farber Canc Inst, Boston, MA 02115 USA. EM ssignoretti@partners.org FU NCI NIH HHS [R01 CA131945]; NIDDK NIH HHS [R21 DK72152, R21 DK072152] NR 65 TC 15 Z9 16 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2009 VL 4 IS 6 AR e5877 DI 10.1371/journal.pone.0005877 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 456TJ UT WOS:000266873100010 PM 19517019 ER PT J AU Koreth, J Schlenk, R Kopecky, KJ Honda, S Sierra, J Djulbegovic, BJ Wadleigh, M DeAngelo, DJ Stone, RM Sakamaki, H Appelbaum, FR Dohner, H Antin, JH Soiffer, RJ Cutler, C AF Koreth, John Schlenk, Richard Kopecky, Kenneth J. Honda, Sumihisa Sierra, Jorge Djulbegovic, Benjamin J. Wadleigh, Martha DeAngelo, Daniel J. Stone, Richard M. Sakamaki, Hisashi Appelbaum, Frederick R. Doehner, Hartmut Antin, Joseph H. Soiffer, Robert J. Cutler, Corey TI Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission Systematic Review and Meta-analysis of Prospective Clinical Trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; FRENCH AML INTERGROUP; HIGH-DOSE CYTARABINE; POSTREMISSION THERAPY; CONSOLIDATION THERAPY; COMORBIDITY INDEX; COOPERATIVE-GROUP; ADULT PATIENTS; ONCOLOGY-GROUP AB Context The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (SCT) for poor-risk but not for good-risk AML. Allogeneic SCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML. Objective To quantify relapse-free survival (RFS) and overall survival benefit of allogeneic SCT for AML in CR1 overall and also for good-, intermediate-, and poor-risk AML. Methods Systematic review and meta-analysis of prospective trials evaluating allogeneic SCT vs nonallogeneic SCT therapies for AML in CR1. The search used the combined search terms allogeneic; acut* and leukem*/leukaem*/leucem*/leucaem*/aml; myelo* or nonlympho* in the PubMed, Embase, and Cochrane Registry of Controlled Trials databases in March 2009. The search identified 1712 articles. Study Selection Prospective trials assigning adult patients with AML in CR1 to undergo allogeneic SCT vs nonallogeneic SCT treatment(s) based on donor availability and trials reporting RFS and/or overall survival outcomes on an intention-to-treat, donor vs no-donor basis were identified. Data Extraction Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were determined. Data Synthesis Overall, 24 trials and 6007 patients were analyzed (5951 patients in RFS analyses and 5606 patients in overall survival analyses); 3638 patients were analyzed by cytogenetic risk (547, 2499, and 592 with good-, intermediate-, and poor-risk AML, respectively). Interstudy heterogeneity was not significant. Fixed-effects meta-analysis was performed. Compared with nonallogeneic SCT, the HR of relapse or death with allogeneic SCT for AML in CR1 was 0.80 (95% CI, 0.74-0.86). Significant RFS benefit of allogeneic SCT was documented for poor- risk (HR, 0.69; 95% CI, 0.57-0.84) and intermediate- risk AML (HR, 0.76; 95% CI, 0.68-0.85) but not for good- risk AML (HR, 1.06; 95% CI, 0.80-1.42). The HR of death with allogeneic SCT for AML in CR1 was 0.90 ( 95% CI, 0.82-0.97). Significant overall survival benefit with allogeneic SCT was documented for poor- risk (HR, 0.73; 95% CI, 0.59-0.90) and intermediate- risk AML (HR, 0.83; 95% CI, 0.74-0.93) but not for good- risk AML (HR, 1.07; 95% CI, 0.83-1.38). Conclusion Compared with nonallogeneic SCT therapies, allogeneic SCT has significant RFS and overall survival benefit for intermediate- and poor- risk AML but not for good- risk AML in first complete remission. JAMA. 2009;301(22):2349-2361 www.jama.com C1 [Koreth, John; Wadleigh, Martha; DeAngelo, Daniel J.; Stone, Richard M.; Antin, Joseph H.; Soiffer, Robert J.; Cutler, Corey] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Schlenk, Richard; Doehner, Hartmut] Univ Hosp Ulm, Ulm, Germany. [Kopecky, Kenneth J.; Appelbaum, Frederick R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Honda, Sumihisa] Nagasaki Univ, Inst Trop Med, Nagasaki 852, Japan. [Sierra, Jorge] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Djulbegovic, Benjamin J.] Univ S Florida, Ctr Evidence Based Med & Hlth Outcomes, Tampa, FL USA. [Djulbegovic, Benjamin J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Sakamaki, Hisashi] Tokyo Metropolitan Komagome Hosp, Tokyo, Japan. RP Koreth, J (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, 44 Binney St, Boston, MA 02115 USA. EM john_koreth@dfci.harvard.edu RI Djulbegovic, Benjamin/I-3661-2012; Lopez, Dulce/A-7700-2013 OI Djulbegovic, Benjamin/0000-0003-0671-1447; FU Stem Cell Cyclists of the Pan-Massachusetts Challenge FX Dr Sakamaki reported serving as a member of the advisory boards of Bristol-Myers Squibb Co and Wyeth Inc. Dr Cutler reported receiving partial funding from the Stem Cell Cyclists of the Pan-Massachusetts Challenge. No other authors reported financial disclosures. NR 45 TC 346 Z9 363 U1 0 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 10 PY 2009 VL 301 IS 22 BP 2349 EP 2361 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 455OT UT WOS:000266773400028 PM 19509382 ER PT J AU Thanassoulis, G O'Donnell, CJ AF Thanassoulis, George O'Donnell, Christopher J. TI Mendelian Randomization Nature's Randomized Trial in the Post-Genome Era SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CORONARY-HEART-DISEASE; APOLIPOPROTEIN(A) GENE; PLASMA LIPOPROTEIN(A); ARTERY-DISEASE; POLYMORPHISM; ASSOCIATION; PREVENTION; VARIANTS; RISK; MEN C1 [Thanassoulis, George; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Thanassoulis, George] Boston Univ, Sch Med, Boston, MA 02118 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM codonnell@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 17 TC 32 Z9 32 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 10 PY 2009 VL 301 IS 22 BP 2386 EP 2388 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 455OT UT WOS:000266773400034 PM 19509388 ER PT J AU Hoe, HS Lee, KJ Carney, RSE Lee, J Markova, A Lee, JY Howell, BW Hyman, BT Pak, DTS Bu, GJ Rebeck, GW AF Hoe, Hyang-Sook Lee, Kea Joo Carney, Rosalind S. E. Lee, Jiyeon Markova, Alexandra Lee, Ji-Yun Howell, Brian W. Hyman, Bradley T. Pak, Daniel T. S. Bu, Guojun Rebeck, G. William TI Interaction of Reelin with Amyloid Precursor Protein Promotes Neurite Outgrowth SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ALZHEIMERS-DISEASE; HIPPOCAMPAL-NEURONS; F-SPONDIN; SYNAPTIC PLASTICITY; TAU PHOSPHORYLATION; ACTIN CYTOSKELETON; SIGNALING PATHWAY; RNA INTERFERENCE; RECEPTOR APOER2; TRANSGENIC MICE AB The processing of amyloid precursor protein (APP) to A beta is an important event in the pathogenesis of Alzheimer's disease, but the physiological function of APP is not well understood. Our previous work has shown that APP processing and A beta production are regulated by the extracellular matrix protein Reelin. In the present study, we examined whether Reelin interacts with APP, and the functional consequences of that interaction in vitro. Using coimmunoprecipitation, we found that Reelin interacted with APP through the central domain of Reelin (repeats 3-6) and the E1 extracellular domain of APP. Reelin increased cell surface levels of APP and decreased endocytosis of APP in hippocampal neurons in vitro. In vivo, Reelin levels were increased in brains of APP knock-out mice and decreased in APP-overexpressing mice. RNA interference knockdown of APP decreased neurite outgrowth in vitro and prevented Reelin from increasing neurite outgrowth. Knock-out of APP or Reelin decreased dendritic arborization in cortical neurons in vivo, and APP overexpression increased dendritic arborization. APP and Reelin have previously been shown to promote neurite outgrowth through interactions with integrins. We confirmed that APP interacted with alpha 3 beta 1 integrin, and alpha 3 beta 1 integrin altered APP trafficking and processing. Addition of an alpha 3 beta 1 integrin antibody prevented APP and Reelin-induced neurite outgrowth. These findings demonstrate that Reelin interacts with APP, potentially having important effects on neurite development. C1 [Hoe, Hyang-Sook; Rebeck, G. William] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. [Lee, Kea Joo; Lee, Ji-Yun; Pak, Daniel T. S.] Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20057 USA. [Carney, Rosalind S. E.] Childrens Natl Med Ctr, Ctr Res Neurosci, Washington, DC 20010 USA. [Lee, Jiyeon; Bu, Guojun] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Markova, Alexandra; Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Disorders, Charlestown, MA 02129 USA. [Howell, Brian W.] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Rebeck, GW (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, 3970 Reservoir Rd NW, Washington, DC 20057 USA. EM gwr2@georgetown.edu RI Lee, Ji-Yun/F-8127-2013; OI Howell, Brian/0000-0002-0204-0773 FU National Institutes of Health [AG014473, R01 AG027924, R37 AG012406, AG032330]; Alzheimer's Research Fund FX This work was supported by National Institutes of Health Grants AG014473 ( G. W. R.), R01 AG027924 ( G. B.), R37 AG012406 ( B. T. H.), and AG032330 (H.-S.H.), and the Alzheimer's Research Fund in memory of Bill and Marie Drach. We thank Drs. Andre Goffinet and Tom Curren for providing Reelin constructs and Drs. Mary Ann Stepp and Susette Mueller for integrin antibodies. We thank Drs. Sam Gandy and Paul Mathews for APP antibodies, and Drs. Yasuji Matsuoka and Baoji Xu for helpful suggestions. We also thank Ulrike Muller for the APP/APLP1 DKO tissue. NR 55 TC 110 Z9 111 U1 0 U2 8 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 JUN 10 PY 2009 VL 29 IS 23 BP 7459 EP 7473 DI 10.1523/JNEUROSCI.4872-08.2009 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 459SV UT WOS:000267130800010 PM 19515914 ER PT J AU Korngold, EC Januzzi, JL Gantzer, ML Moorthy, MV Cook, NR Albert, CM AF Korngold, Ethan C. Januzzi, James L., Jr. Gantzer, Mary Lou Moorthy, M. V. Cook, Nancy R. Albert, Christine M. TI Amino-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity C-Reactive Protein as Predictors of Sudden Cardiac Death Among Women SO CIRCULATION LA English DT Article DE death, sudden; epidemiology; natriuretic peptides; risk factors; women ID CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; CORONARY DEATH; UNITED-STATES; RISK; HEART; ARRHYTHMIAS; POPULATION; OUTCOMES; FAILURE AB Background-Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been found to predict risk of sudden cardiac death (SCD) in patients with known cardiac disease, and C-reactive protein levels have been found to predict risk among apparently healthy men. However, there are no data on SCD risk prediction for either of these markers in a population of women unselected on the basis of cardiovascular disease. Methods and Results-In a prospective, nested, case-control analysis within the 121 700-participant Nurses' Health Study, 99 cases of definite or probable SCD were identified and matched to 294 controls. In multivariable models that adjusted for coronary heart disease risk factors, glomerular filtration rate, and other biomarkers, the trend across quartiles approached significance for NT-proBNP (rate ratio=2.37 for comparison of the highest and lowest quartile; P for trend=0.05) but not for high-sensitivity C-reactive protein (P for trend=0.60). When examined continuously, both NT-proBNP and high-sensitivity C-reactive protein were significantly associated with SCD risk in age-and fasting-adjusted models (P for linear trend=0.04 and 0.03). Adjustment for coronary heart disease risk factors and other biomarkers strengthened the relationship with NT-proBNP and SCD (relative risk for 1-SD increment=1.49; 95% confidence interval, 1.09 to 2.05; P=0.01) but eliminated the relationship with high-sensitivity C-reactive protein (P=0.34). Women with NT-proBNP levels above the prespecified cut point of 389 pg/mL were at a markedly increased risk of SCD in both models (rate ratio=5.68; 95% confidence interval, 1.78 to 18.2; P=0.003). Conclusions-In this population of women, baseline levels of NT-proBNP were associated with subsequent risk of SCD. If this association is confirmed in larger prospectively studied populations, these findings might provide another useful marker contributing to efforts to screen and prevent SCD among women. (Circulation. 2009; 119: 2868-2876.) C1 [Moorthy, M. V.; Albert, Christine M.] Brigham & Womens Hosp, Ctr Arrhythmia Prevent, Div Prevent Med, Boston, MA 02215 USA. [Albert, Christine M.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02215 USA. [Korngold, Ethan C.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02114 USA. [Gantzer, Mary Lou] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gantzer, Mary Lou] Siemens Healthcare Diagnost Inc, Newark, DE USA. RP Albert, CM (reprint author), Brigham & Womens Hosp, Ctr Arrhythmia Prevent, Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. EM calbert@partners.org FU Siemens Healthcare Diagnostics; National Institutes of Health [CA-87969, HL-34594, HL-03783] FX The study was supported by a research grant from Siemens Healthcare Diagnostics to Dr Albert. The Nurses' Health Study is supported by grants CA-87969, HL-34594, and HL-03783 from the National Institutes of Health. The study sponsor did not influence the study design, analysis, interpretation, and presentation of data. NR 30 TC 31 Z9 31 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 JUN 9 PY 2009 VL 119 IS 22 BP 2868 EP 2876 DI 10.1161/CIRCULATIONAHA.108.832576 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 455QM UT WOS:000266777900003 PM 19470888 ER PT J AU Galie, N Brundage, BH Ghofrani, HA Oudiz, RJ Simonneau, G Safdar, Z Shapiro, S White, RJ Chan, M Beardsworth, A Frumkin, L Barst, RJ AF Galie, Nazzareno Brundage, Bruce H. Ghofrani, Hossein A. Oudiz, Ronald J. Simonneau, Gerald Safdar, Zeenat Shapiro, Shelley White, R. James Chan, Melanie Beardsworth, Anthony Frumkin, Lyn Barst, Robyn J. CA Pulm Arterial Hypertension & Resp TI Tadalafil Therapy for Pulmonary Arterial Hypertension SO CIRCULATION LA English DT Article DE hypertension, pulmonary; phosphodiesterase inhibitors; tadalafil ID DOUBLE-BLIND; NITRIC-OXIDE; INHALED ILOPROST; CONTROLLED-TRIAL; SILDENAFIL; BOSENTAN; EFFICACY; PROSTACYCLIN; SITAXSENTAN; AMBRISENTAN AB Background-Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway. Methods and Results-In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing. Conclusions-In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening. (Circulation. 2009; 119: 2894-2903.) C1 [Galie, Nazzareno] Univ Bologna, Inst Cardiol, I-40138 Bologna, Italy. [Brundage, Bruce H.] Heart Inst Cascades, Bend, OR USA. [Ghofrani, Hossein A.] Univ Giessen, Univ Hosp, Giessen, Germany. [Oudiz, Ronald J.] Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Torrance, CA USA. [Simonneau, Gerald] Antoine Beclere Univ Hosp, Clamart, France. [Safdar, Zeenat] Baylor Coll Med, Div Pulm & Crit Care Med, Houston, TX 77030 USA. [Shapiro, Shelley] Univ Calif Los Angeles, David Geffen Sch Med, Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90095 USA. [White, R. James] Univ Rochester, Div Pulm & Crit Care Med, Rochester, NY USA. [Chan, Melanie] Eli Lilly & Co, Toronto, ON, Canada. [Frumkin, Lyn] ICOS Corp, Bothell, WA USA. [Barst, Robyn J.] Schneider Childrens Hosp N Shore Long Isl Jewish, New Hyde Pk, NY USA. RP Galie, N (reprint author), Univ Bologna, Inst Cardiol, Via Massarenti 9, I-40138 Bologna, Italy. EM nazzareno.galie@unibo.it RI Reynaud-Gaubert, Martine/P-6958-2016; OI Galie, Nazzareno/0000-0003-4271-8670 FU Eli Lilly and Company FX The study was funded by Eli Lilly and Company. NR 42 TC 418 Z9 450 U1 2 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 9 PY 2009 VL 119 IS 22 BP 2894 EP U65 DI 10.1161/CIRCULATIONAHA.108.839274 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 455QM UT WOS:000266777900006 PM 19470885 ER PT J AU Clardy, J Fischbach, MA Currie, CR AF Clardy, Jon Fischbach, Michael A. Currie, Cameron R. TI The natural history of antibiotics SO CURRENT BIOLOGY LA English DT Editorial Material ID FUNGUS-GROWING ANTS; BACTERIA; MOLECULES C1 [Clardy, Jon] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Fischbach, Michael A.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Currie, Cameron R.] Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 USA. RP Clardy, J (reprint author), Harvard Univ, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM jon_clardy@hms.harvard.edu FU NCI NIH HHS [R01 CA024487, R01 CA024487-30]; NIGMS NIH HHS [R01 GM086258] NR 10 TC 39 Z9 40 U1 4 U2 48 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 9 PY 2009 VL 19 IS 11 BP R437 EP R441 DI 10.1016/j.cub.2009.04.001 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 456YX UT WOS:000266891900009 PM 19515346 ER PT J AU Yaffe, K Fiocco, AJ Lindquist, K Vittinghoff, E Simonsick, EM Newman, AB Satterfield, S Rosano, C Rubin, SM Ayonayon, HN Harris, TB AF Yaffe, K. Fiocco, A. J. Lindquist, K. Vittinghoff, E. Simonsick, E. M. Newman, A. B. Satterfield, S. Rosano, C. Rubin, S. M. Ayonayon, H. N. Harris, T. B. CA Hlth ABC Study TI Predictors of maintaining cognitive function in older adults The Health ABC Study SO NEUROLOGY LA English DT Article ID ATTENTIONAL CONTROL; ALZHEIMERS-DISEASE; GLUCOSE-TOLERANCE; LIFE-STYLE; WOMEN; PLASTICITY; EXERCISE; DECLINE; BRAIN; AGE AB Background: Although several risk factors for cognitive decline have been identified, much less is known about factors that predict maintenance of cognitive function in advanced age. Methods: We studied 2,509 well-functioning black and white elders enrolled in a prospective study. Cognitive function was measured using the Modified Mini-Mental State Examination at baseline and years 3, 5, and 8. Random effects models were used to classify participants as cognitive maintainers (cognitive change slope >= 0), minor decliners (slope <0 and >1 SD below mean), or major decliners (slope <= 1 SD below mean). Logistic regression was used to identify domain-specific factors associated with being a maintainer vs a minor decliner. Results: Over 8 years, 30% of the participants maintained cognitive function, 53% showed minor decline, and 16% had major cognitive decline. In the multivariate model, baseline variables significantly associated with being a maintainer vs a minor decliner were age (odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.55-0.77 per 5 years), white race (OR = 1.72, 95% CI 1.30-2.28), high school education level or greater (OR = 2.75, 95% CI 1.78-4.26), ninth grade literacy level or greater (OR = 4.85, 95% CI 3.00-7.87), weekly moderate/vigorous exercise (OR = 1.31, 95% CI 1.06-1.62), and not smoking (OR = 1.84, 95% CI 1.14-2.97). Variables associated with major cognitive decline compared to minor cognitive decline are reported. Conclusion: Elders who maintain cognitive function have a unique profile that differentiates them from those with minor decline. Importantly, some of these factors are modifiable and thus may be implemented in prevention programs to promote successful cognitive aging. Further, factors associated with maintenance may differ from factors associated with major cognitive decline, which may impact prevention vs treatment strategies. Neurology (R) 2009; 72: 2029-2035 C1 [Yaffe, K.; Fiocco, A. J.] Univ San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94117 USA. [Yaffe, K.; Vittinghoff, E.; Rubin, S. M.; Ayonayon, H. N.] Univ San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94117 USA. [Yaffe, K.] Univ San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94117 USA. [Lindquist, K.] Univ San Francisco, Sch Med, Dept Med, San Francisco, CA 94117 USA. [Yaffe, K.] San Francisco VA Med Ctr, San Francisco, CA USA. [Simonsick, E. M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Baltimore, MD 21224 USA. [Newman, A. B.; Rosano, C.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Satterfield, S.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Fiocco, AJ (reprint author), Univ San Francisco, Sch Med, Dept Psychiat, 4150 Clement St, San Francisco, CA 94117 USA. EM jazzfiocco@hotmail.com RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU Intramural NIH HHS; NIA NIH HHS [AG 031155, AG021918, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 36 TC 112 Z9 118 U1 0 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 9 PY 2009 VL 72 IS 23 BP 2029 EP 2035 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 455QI UT WOS:000266777500012 PM 19506226 ER PT J AU Zhang, Q Zhou, YF Zhang, CZ Zhang, XH Lu, CF Springer, TA AF Zhang, Qing Zhou, Yan-Feng Zhang, Cheng-Zhong Zhang, Xiaohui Lu, Chafen Springer, Timothy A. TI Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID VONWILLEBRAND-FACTOR; DISEASE MUTATIONS; IIA; ISOMERIZATION; ACTIVATION; SYSTEM AB The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-angstrom crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the alpha 4 helix, and a cis-proline. The central beta 4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the beta 4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal alpha 6-helix. The alpha 6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure. C1 [Springer, Timothy A.] Harvard Univ, Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Childrens Hosp Boston, Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM springer@idi.harvard.edu RI Zhou, Yanfeng/B-3792-2012 FU National Institutes of Health [HL48675] FX We thank Drs. J. Evan Sadler and Wendy Thomas for reviewing the manuscript. This work was supported by National Institutes of Health Grant HL48675. NR 31 TC 90 Z9 92 U1 1 U2 7 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 JUN 9 PY 2009 VL 106 IS 23 BP 9226 EP 9231 DI 10.1073/pnas.0903679106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 456CN UT WOS:000266817500024 PM 19470641 ER PT J AU Guerau-De-Arellano, M Martinic, M Benoist, C Mathis, D AF Guerau-de-Arellano, Mireia Martinic, Marianne Benoist, Christophe Mathis, Diane TI Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MEMORY T-CELLS; CUTTING EDGE; MICE; PROLIFERATION; DISEASE; LYMPHOPENIA; SPECIFICITY; REPERTOIRE; INDUCTION; SELECTION AB There has long been conceptual and experimental support for, but also challenges to, the notion that the initial period of the immune system's development is particularly important for the establishment of tolerance to self. The display of self-antigens by thymic epithelial cells is key to inducing tolerance in the T lymphocyte compartment, a process enhanced by the Aire transcription factor. Using a doxycycline-regulated transgene to target Aire expression to the thymic epithelium, complementing the Aire knockout in a temporally controlled manner, we find that Aire is essential in the perinatal period to prevent the multiorgan autoimmunity that is typical of Aire deficiency. Surprisingly, Aire could be shut down soon thereafter and remain off for long periods, with few deleterious consequences. The lymphopenic state present in neonates was a factor in this dichotomy because inducing lymphopenia during Aire turnoff in adults recreated the disease, which, conversely, could be ameliorated by supplementing neonates with adult lymphocytes. In short, Aire expression during the perinatal period is both necessary and sufficient to induce long-lasting tolerance and avoid autoimmunity. Aire-controlled mechanisms of central tolerance are largely dispensable in the adult, as a previously tolerized T cell pool can buffer newly generated autoreactive T cells that might emerge. C1 [Guerau-de-Arellano, Mireia; Martinic, Marianne; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Brigham & Womens Hosp, Sect Immunol & Immunogenet,Joslin Diabet Ctr, Boston, MA 02215 USA. [Guerau-de-Arellano, Mireia; Martinic, Marianne; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. RP Mathis, D (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Sect Immunol & Immunogenet,Joslin Diabet Ctr, Boston, MA 02215 USA. EM cbdm@hms.harvard.edu; cbdm@hms.harvard.edu FU R01 DK60027; NIDDK FX This work was supported by R01 DK60027 and Young Chair funds to D. Mathis and C. Benoist, and by the Joslin's NIDDK- funded Diabetes and Endocrinology Research Center. NR 38 TC 63 Z9 66 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 8 PY 2009 VL 206 IS 6 BP 1245 EP 1252 DI 10.1084/jem.20090300 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 459TS UT WOS:000267133700006 PM 19487417 ER PT J AU Goonetilleke, N Liu, MKP Salazar-Gonzalez, JF Ferrari, G Giorgi, E Ganusov, VV Keele, BF Learn, GH Turnbull, EL Salazar, MG Weinhold, KJ Moore, S Letvin, N Haynes, BF Cohen, MS Hraber, P Bhattacharya, T Borrow, P Perelson, AS Hahn, BH Shaw, GM Korber, BT McMichael, AJ AF Goonetilleke, Nilu Liu, Michael K. P. Salazar-Gonzalez, Jesus F. Ferrari, Guido Giorgi, Elena Ganusov, Vitaly V. Keele, Brandon F. Learn, Gerald H. Turnbull, Emma L. Salazar, Maria G. Weinhold, Kent J. Moore, Stephen Letvin, Norman Haynes, Barton F. Cohen, Myron S. Hraber, Peter Bhattacharya, Tanmoy Borrow, Persephone Perelson, Alan S. Hahn, Beatrice H. Shaw, George M. Korber, Bette T. McMichael, Andrew J. CA CHAVI Clin Core B TI The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CTL ESCAPE MUTATION; IN-VIVO; LYMPHOCYTE ESCAPE; TYPE-1 INFECTION; PERIPHERAL-BLOOD; RHESUS-MONKEYS; IMMUNE CONTROL; VIRAL ESCAPE; GAG AB Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1-specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1-specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell-mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell-driven escape. C1 [Goonetilleke, Nilu; Liu, Michael K. P.; Moore, Stephen; McMichael, Andrew J.] Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England. [Salazar-Gonzalez, Jesus F.; Keele, Brandon F.; Learn, Gerald H.; Salazar, Maria G.; Hahn, Beatrice H.; Shaw, George M.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Ferrari, Guido; Weinhold, Kent J.; Haynes, Barton F.] Duke Univ, Duke Univ Med Res, Durham, NC 27710 USA. [Giorgi, Elena; Ganusov, Vitaly V.; Hraber, Peter; Bhattacharya, Tanmoy; Perelson, Alan S.; Korber, Bette T.] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM 87545 USA. [Turnbull, Emma L.; Borrow, Persephone] Univ Oxford, Jenner Inst, Compton RG20 7NN, England. [Letvin, Norman] Harvard Univ, BIDMC, Boston, MA 02115 USA. [Cohen, Myron S.] Univ N Carolina, HIV Prevent Trials Unit, Chapel Hill, NC 27599 USA. [Bhattacharya, Tanmoy; Korber, Bette T.] Santa Fe Inst, Santa Fe, NM 87501 USA. RP McMichael, AJ (reprint author), Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England. EM andrew.mcmichael@imm.ox.ac.uk RI Bhattacharya, Tanmoy/J-8956-2013; Ferrari, Guido/A-6088-2015; OI Bhattacharya, Tanmoy/0000-0002-1060-652X; Ganusov, Vitaly/0000-0001-6572-1691; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU HIV/AIDS Vaccine Immunology [A1067854-03]; Medical Research Center Human Immunology Unit; National Institute for Health Research Oxford Biomedical Research Center [37874]; Bill and Melinda Gates Foundation; NIDDK [DK049381]; U. S. Department of Energy [DE-AC52-06NA25396] FX This work was supported by the Center for HIV/AIDS Vaccine Immunology grant A1067854-03. Additional support came from the Medical Research Center Human Immunology Unit, the National Institute for Health Research Oxford Biomedical Research Center, and grant 37874 from the Bill and Melinda Gates Foundation. P. Borrow is supported by a Jenner Fellowship and M. S. Cohen is supported by NIDDK Award DK049381. Portions of this work were done under the auspices of the U. S. Department of Energy under contract DE-AC52-06NA25396, and V. V. Ganusov was supported by their Laboratory Directed Research and Development program. NR 63 TC 340 Z9 348 U1 5 U2 24 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 8 PY 2009 VL 206 IS 6 BP 1253 EP 1272 DI 10.1084/jem.20090365 PG 20 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 459TS UT WOS:000267133700007 PM 19487423 ER PT J AU Jinushi, M Sato, M Kanamoto, A Itoh, A Nagai, S Koyasu, S Dranoff, G Tahara, H AF Jinushi, Masahisa Sato, Marimo Kanamoto, Akira Itoh, Akihiko Nagai, Shigenori Koyasu, Shigeo Dranoff, Glenn Tahara, Hideaki TI Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NF-KAPPA-B; APOPTOTIC CELLS; DENDRITIC CELLS; ANTITUMOR IMMUNITY; CANCER DEVELOPMENT; GM-CSF; THERAPY; INFLAMMATION; PROGRESSION; DISEASE AB Carcinogenesis reflects the dynamic interplay of transformed cells and normal host elements, but cancer treatments typically target each compartment separately. Within the tumor micro-environment, the secreted protein milk fat globule epidermal growth factor-8 (MFG-E8) stimulates disease progression through coordinated alpha(v)beta(3) integrin signaling in tumor and host cells. MFG-E8 enhances tumor cell survival, invasion, and angiogenesis, and contributes to local immune suppression. We show that systemic MFG-E8 blockade cooperates with cytotoxic chemotherapy, molecularly targeted therapy, and radiation therapy to induce destruction of various types of established mouse tumors. The combination treatments evoke extensive tumor cell apoptosis that is coupled to efficient dendritic cell cross-presentation of dying tumor cells. This linkage engenders potent antitumor effector T cells but inhibits FoxP3(+) T reg cells, thereby achieving long-term protective immunity. Collectively, these findings suggest that systemic MFG-E8 blockade might intensify the antitumor activities of existing therapeutic regimens through coordinated cell-autonomous and immune-mediated mechanisms. C1 [Jinushi, Masahisa; Sato, Marimo; Kanamoto, Akira; Itoh, Akihiko; Tahara, Hideaki] Univ Tokyo, Inst Med Sci, Adv Clin Res Ctr, Dept Surg & Bioengn, Tokyo 1088639, Japan. [Nagai, Shigenori; Koyasu, Shigeo] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan. [Nagai, Shigenori] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Tokyo 1020075, Japan. [Dranoff, Glenn] Brigham & Womens Hosp, Dept Med Oncol, Boston, MA 02115 USA. [Dranoff, Glenn] Brigham & Womens Hosp, Canc Vaccine Ctr, Dana Farber Canc Inst, Boston, MA 02115 USA. [Dranoff, Glenn] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Dranoff, Glenn] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Tahara, H (reprint author), Univ Tokyo, Inst Med Sci, Adv Clin Res Ctr, Dept Surg & Bioengn, Tokyo 1088639, Japan. EM tahara@ims.u-tokyo.ac.jp RI Jinushi, Masahisa/A-4311-2012; Koyasu, Shigeo/J-5583-2015 OI Koyasu, Shigeo/0000-0001-9585-3038 FU Ministry of Education, Culture, Sports, Science and Technology of Japan [20015016, 20890050]; Melanoma Research Alliance and the Research Foundation FX This study was supported in part by the Grants-in-Aid for Scientific Research on Priority Areas (20015016 to H. Tahara) and for Young Scientists (Start-Up; 20890050 to M. Jinushi) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, as well as by the Melanoma Research Alliance and the Research Foundation for the Treatment of Ovarian Cancer (G. Dranoff). NR 42 TC 40 Z9 40 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 8 PY 2009 VL 206 IS 6 BP 1317 EP 1326 DI 10.1084/jem.20082614 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 459TS UT WOS:000267133700011 PM 19433619 ER PT J AU Van Rhijn, I Young, DC De Jong, A Vazquez, J Cheng, TY Talekar, R Barral, D Leon, L Brenner, MB Katz, JT Riese, R Ruprecht, RM O'Connor, PB Costello, CE Porcelli, SA Briken, V Moody, DB AF Van Rhijn, Ildiko Young, David C. De Jong, Annemieke Vazquez, Jenny Cheng, Tan-Yun Talekar, Rahul Barral, Duarte Leon, Luis Brenner, Michael B. Katz, Joel T. Riese, Richard Ruprecht, Ruth M. O'Connor, Peter B. Costello, Catherine E. Porcelli, Steven A. Briken, Volker Moody, D. Branch TI CD1c bypasses lysosomes to present a lipopeptide antigen with 12 amino acids SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID T-CELL RECOGNITION; MHC CLASS-II; DIFFERENT INTRACELLULAR COMPARTMENTS; MYCOBACTERIUM-TUBERCULOSIS; LIPID ANTIGENS; CRYSTAL-STRUCTURE; CATHEPSIN-S; GLYCOLIPID ANTIGENS; CYSTEINE PROTEASES; VIRAL INFECTIVITY AB The recent discovery of dideoxymycobactin (DDM) as a ligand for CD1a demonstrates how a nonribosomal lipopeptide antigen is presented to T cells. DDM contains an unusual acylation motif and a peptide sequence present only in mycobacteria, but its discovery raises the possibility that ribosomally produced viral or mammalian proteins that commonly undergo lipidation might also function as antigens. To test this, we measured T cell responses to synthetic acylpeptides that mimic lipoproteins produced by cells and viruses. CD1c presented an N-acyl glycine dodecamer peptide (lipo-12) to human T cells, and the response was specific for the acyl linkage as well as the peptide length and sequence. Thus, CD1c represents the second member of the CD1 family to present lipopeptides. lipo-12 was efficiently recognized when presented by intact cells, and unlike DDM, it was inactivated by proteases and augmented by protease inhibitors. Although lysosomes often promote antigen presentation by CD1, rerouting CD1c to lysosomes by mutating CD1 tail sequences caused reduction in lipo-12 presentation. Thus, although certain antigens require antigen processing in lysosomes, others are destroyed there, providing a hypothesis for the evolutionary conservation of large CD1 families containing isoforms that survey early endosomal pathways. C1 [Van Rhijn, Ildiko; Young, David C.; De Jong, Annemieke; Cheng, Tan-Yun; Talekar, Rahul; Barral, Duarte; Leon, Luis; Brenner, Michael B.; Moody, D. Branch] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Katz, Joel T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Riese, Richard] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm Med, Boston, MA 02115 USA. [Vazquez, Jenny; O'Connor, Peter B.; Costello, Catherine E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ruprecht, Ruth M.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Immunol & AIDS, Boston, MA 02115 USA. [Porcelli, Steven A.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Briken, Volker] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Briken, Volker] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. RP Moody, DB (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. EM i.vanrhijn@uu.nl; bmoody@rics.bwh.harvard.edu RI OConnor, Peter/C-2117-2009; Barral, Duarte/E-7548-2013; OI de Jong, Annemieke/0000-0001-6707-6585; Briken, Volker/0000-0001-5830-6107; OConnor, Peter/0000-0002-6588-6274; Barral, Duarte/0000-0001-8867-2407; Costello, Catherine/0000-0003-1594-5122 FU National Institute of Allergy and Infectious Diseases [R01 AI049313, AI45889]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR048632]; American Lung Association [RT-95-N]; National Institutes of Health/National Center for Research Resources [P41 RR10888]; Pew Foundation Scholars in the Biomedical Sciences FX This work was supported by the National Institute of Allergy and Infectious Diseases (grant R01 AI049313 to D. B. Moody and grant AI45889 to S. A. Porcelli), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant R01 AR048632 to D. B. Moody), the American Lung Association (grant RT-95-N to I. Van Rhijn), the National Institutes of Health/National Center for Research Resources (grant P41 RR10888 to C. E. Costello), the Pew Foundation Scholars in the Biomedical Sciences, NR 66 TC 37 Z9 37 U1 1 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 8 PY 2009 VL 206 IS 6 BP 1409 EP 1422 DI 10.1084/jem.20082480 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 459TS UT WOS:000267133700018 PM 19468063 ER PT J AU Nohadani, O Seco, J Martin, BC Bortfeld, T AF Nohadani, Omid Seco, Joao Martin, Benjamin C. Bortfeld, Thomas TI Dosimetry robustness with stochastic optimization SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID INTENSITY-MODULATED RADIOTHERAPY; IMRT OPTIMIZATION; MONTE-CARLO; THERAPY; MOTION AB All radiation therapy treatment planning relies on accurate dose calculation. Uncertainties in dosimetric prediction can significantly degrade an otherwise optimal plan. In this work, we introduce a robust optimization method which handles dosimetric errors and warrants for high-quality IMRT plans. Unlike other dose error estimations, we do not rely on the detailed knowledge about the sources of the uncertainty and use a generic error model based on random perturbation. This generality is sought in order to cope with a large variety of error sources. We demonstrate the method on a clinical case of lung cancer and show that our method provides plans that are more robust against dosimetric errors and are clinically acceptable. In fact, the robust plan exhibits a two-fold improved equivalent uniform dose compared to the non-robust but optimized plan. The achieved speedup will allow computationally extensivemulti-criteria or beam-angle optimization approaches to warrant for dosimetrically relevant plans. C1 [Nohadani, Omid; Seco, Joao; Martin, Benjamin C.; Bortfeld, Thomas] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Nohadani, Omid; Seco, Joao; Martin, Benjamin C.; Bortfeld, Thomas] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nohadani, Omid] MIT, Ctr Operat Res, Cambridge, MA 02139 USA. RP Nohadani, O (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM nohadani@mit.edu; jseco@partners.org; ben.martin@alum.bu.edu; tbortfeld@partners.org RI Seco, Joao/J-4451-2012; Nohadani, Omid/N-8177-2013 FU National Cancer Institute of the United States; NIH [R01 CA 111590]; [R01-CA118200]; [R01-CA103904] FX We would like to thank D Craft and G Sharp for fruitful discussions. We are also very grateful to H Paganetti for his insights as well as computation time. We would also like to thank N Choi for providing the lung patient data. This work was supported by the National Cancer Institute of the United States under grants R01-CA118200 and R01-CA103904. JS also acknowledges support from NIH grant R01 CA 111590. NR 20 TC 9 Z9 9 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUN 7 PY 2009 VL 54 IS 11 BP 3421 EP 3432 DI 10.1088/0031-9155/54/11/010 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 447QZ UT WOS:000266208200010 PM 19436100 ER PT J AU Raskind, WH Matsushita, M Peter, B Biberston, J Wolff, J Lipe, H Burbank, R Bird, TD AF Raskind, Wendy H. Matsushita, Mark Peter, Beate Biberston, Jeffrey Wolff, John Lipe, Hillary Burbank, Ruben Bird, Thomas D. TI Familial Dyskinesia and Facial Myokymia (FDFM): Follow-Up of a Large Family and Linkage to Chromosome 3p21-3q21 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE chorea; movement disorder; episodic disorder ID EPISODIC ATAXIA; CHANNEL; MUTATION; GENE; EPILEPSY; PROTEIN; KCNA1 AB We previously reported a five-generation family manifesting an autosomal dominant disorder of facial myokymia and dystonic/choreic movements (FDFM). The dyskinetic episodes are initially paroxysmal but may become constant. With increasing age they may lessen or even disappear. The previous study excluded nine candidate genes chosen for their association with myokymia or chorea and two regions containing single or clustered ion channel genes. We now report identification by whole genome linkage analysis of a broad region on chromosome 3p21-3q21 that segregates with the disease in all 10 affected members in three generations who participated in the study. GENEHUNTER-MODSCORE Version 2.0.1 provided a maximum multipoint LOD score of 3.099. No other disorders primarily characterized by myokymia, dystonia, or chorea are known to map to this region. Identification of additional families with FDFM may narrow the critical region and facilitate the choice of candidate genes for further analysis. (C) 2008 Wiley-Liss, Inc. C1 [Raskind, Wendy H.; Matsushita, Mark; Biberston, Jeffrey; Wolff, John; Burbank, Ruben] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Raskind, Wendy H.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Raskind, Wendy H.; Matsushita, Mark] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Peter, Beate] Univ Washington, Sch Med, Dept Speech & Hearing Sci, Seattle, WA 98195 USA. [Wolff, John; Lipe, Hillary; Bird, Thomas D.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. [Bird, Thomas D.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA. RP Raskind, WH (reprint author), Univ Washington, Sch Med, Dept Med, Box 35-7720, Seattle, WA 98195 USA. EM wendyrun@u.washington.edu FU Department of Veterans Affairs; NIH [2 T32 DC000033] FX The authors wish to thank the members of the family whose cooperation with, and interest in, the research is essential. The research was supported in part by funds from the Department of Veterans Affairs (W.H.R., M.M., J.W., H.L., and T.D.B.) and NIH 2 T32 DC000033 (B.P.). NR 25 TC 8 Z9 8 U1 0 U2 0 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 JUN 5 PY 2009 VL 150B IS 4 BP 570 EP 574 DI 10.1002/ajmg.b.30879 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 452CD UT WOS:000266516400016 PM 18980218 ER PT J AU Hofmann, I Stover, EH Cullen, DE Mao, J Morgan, KJ Lee, BH Kharas, MG Miller, PG Cornejo, MG Okabe, R Armstrong, SA Ghilardi, N Gould, S de Sauvage, FJ McMahon, AP Gilliland, DG AF Hofmann, Inga Stover, Elizabeth H. Cullen, Dana E. Mao, Junhao Morgan, Kelly J. Lee, Benjamin H. Kharas, Michael G. Miller, Peter G. Cornejo, Melanie G. Okabe, Rachel Armstrong, Scott A. Ghilardi, Nico Gould, Stephen de Sauvage, Frederic J. McMahon, Andrew P. Gilliland, D. Gary TI Hedgehog Signaling Is Dispensable for Adult Murine Hematopoietic Stem Cell Function and Hematopoiesis SO CELL STEM CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; SONIC HEDGEHOG; HUMAN HOMOLOG; BCR-ABL; CANCER; GENE; DIFFERENTIATION; MEDULLOBLASTOMA; PROLIFERATION; MAINTENANCE AB We report the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) in the adult hematopoietic compartment has no apparent effect on adult hematopoiesis, including peripheral blood count, number or cell-cycle status of stem or progenitor cells, hematopoietic colony-forming potential, long-term repopulating activity in competitive repopulation assays, or stress response to serial 5-fluorouracil treatment. Furthermore, pharmacologic inhibition of Hh signaling with a potent and selective small molecule antagonist has no substantive effect on hematopoiesis in the mouse. In addition, Hh signaling is not required for the development of MLL-AF9-mediated acute myeloid leukemia (AML). Taken together, these data demonstrate that Hh signaling is dispensable for normal hematopoietic development and hematopoietic stem cell function, indicating that targeting of Hh signaling in solid tumors is not likely to result in hematopoietic toxicity. Furthermore, the Hh pathway may not be a compelling target in certain hematopoietic malignancies. C1 [Hofmann, Inga; Stover, Elizabeth H.; Cullen, Dana E.; Morgan, Kelly J.; Lee, Benjamin H.; Kharas, Michael G.; Miller, Peter G.; Cornejo, Melanie G.; Okabe, Rachel; Gilliland, D. Gary] Brigham & Womens Hosp, Div Hematol, Dept Med, Boston, MA 02115 USA. [Hofmann, Inga; Armstrong, Scott A.; Gilliland, D. Gary] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hofmann, Inga; Stover, Elizabeth H.; Miller, Peter G.; Cornejo, Melanie G.; Armstrong, Scott A.; Gilliland, D. Gary] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gilliland, D. Gary] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Gilliland, D. Gary] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Mao, Junhao; McMahon, Andrew P.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Hofmann, Inga; Armstrong, Scott A.] Childrens Hosp, Boston, MA 02115 USA. [Ghilardi, Nico; Gould, Stephen; de Sauvage, Frederic J.] Genentech Inc, San Francisco, CA 94080 USA. RP Gilliland, DG (reprint author), Brigham & Womens Hosp, Div Hematol, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM ggilliland@rics.bwh.harvard.edu OI Ghilardi, Nico/0000-0003-4945-3097 FU Leukemia and Lymphoma Society; National Institutes of Health (NIH); NIH/National Institute of Neurological Disorders and Stroke (NINDS) [R37NS033642] FX We thank Emily Chan, Leslie Lee, and Maria Pitsiouni from Genentech and Allison Coburn, Elizabeth McDowell, and Sandra Moore from the Gilliland lab for technical support; and Thomas Mercher, Glen Raffel, Zuzanna Tothova, Claudia Scholl, and Stefan Frohling for valuable discussion. This work was supported in part by the Leukemia and Lymphoma Society and by National Institutes of Health (NIH) grants (D.G.G., E.H.S.). D.G.G is an Investigator of the Howard Hughes Medical Institute. Work in A.P.M.'s laboratory was supported in part by a grant from the NIH/National Institute of Neurological Disorders and Stroke (NINDS), R37NS033642. E.H.S. and I.H.Z. designed and performed research, analyzed data, and wrote the manuscript. F.J.d.S., N.G., and S.G. designed and performed research and analyzed data on the pharmacological experiments, participated in interpretation of data, and reviewed the manuscript. J.M. and A.P.M. generated the Smo mice, participated in design and interpretation of experiments, and reviewed the manuscript. S.A.A. participated in design and interpretation of experiments involving the MLL-AF9 fusion. D.G.G. designed research, analyzed data, and revised the paper. F.J.d.S., N.G., and S.G. are employees of Genentech, Inc. A.P.M. is a consultant for Merck. NR 36 TC 96 Z9 101 U1 1 U2 5 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 JUN 5 PY 2009 VL 4 IS 6 BP 559 EP 567 DI 10.1016/j.stem.2009.03.016 PG 9 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 455UY UT WOS:000266793600018 PM 19497284 ER PT J AU Zhang, XH Halvorsen, K Zhang, CZ Wong, WP Springer, TA AF Zhang, Xiaohui Halvorsen, Kenneth Zhang, Cheng-Zhong Wong, Wesley P. Springer, Timothy A. TI Mechanoenzymatic Cleavage of the Ultralarge Vascular Protein von Willebrand Factor SO SCIENCE LA English DT Article ID FACTOR A2 DOMAIN; VONWILLEBRAND-FACTOR; FACTOR MULTIMERS; SHEAR-STRESS; PLASMA; ADAMTS13; SUBSTRATE; ADHESION; DISEASE; CONFORMATION AB Von Willebrand factor (VWF) is secreted as ultralarge multimers that are cleaved in the A2 domain by the metalloprotease ADAMTS13 to give smaller multimers. Cleaved VWF is activated by hydrodynamic forces found in arteriolar bleeding to promote hemostasis, whereas uncleaved VWF is activated at lower, physiologic shear stresses and causes thrombosis. Single-molecule experiments demonstrate that elongational forces in the range experienced by VWF in the vasculature unfold the A2 domain, and only the unfolded A2 domain is cleaved by ADAMTS13. In shear flow, tensile force on a VWF multimer increases with the square of multimer length and is highest at the middle, providing an efficient mechanism for homeostatic regulation of VWF size distribution by force-induced A2 unfolding and cleavage by ADAMTS13, as well as providing a counterbalance for VWF-mediated platelet aggregation. C1 [Zhang, Xiaohui; Zhang, Cheng-Zhong; Springer, Timothy A.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Halvorsen, Kenneth; Wong, Wesley P.] Harvard Univ, Rowland Inst Harvard, Cambridge, MA 02142 USA. [Zhang, Xiaohui] Chinese Acad Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM wong@rowland.harvard.edu; springer@idi.harvard.edu FU NIH [HL-48675]; Rowland Junior Fellows; American Heart Association [525918T] FX Supported by NIH HL-48675 (T.A.S.), the Rowland Junior Fellows (W.P.W.), and American Heart Association 525918T (X.Z.). The authors thank C. Bustamante, S. Marqusee, and C. Cecconi for protocols for DNA-protein coupling; J. E. Sadler, D. Schaak, J. Kim, J. Seog, C. Lu, and A. Alexander-Katz for reagents and insightful discussions; and G. Dempsey for work on the early stages of this project. NR 32 TC 213 Z9 215 U1 3 U2 46 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 JUN 5 PY 2009 VL 324 IS 5932 BP 1330 EP 1334 DI 10.1126/science.1170905 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 453TF UT WOS:000266635100047 PM 19498171 ER PT J AU Sundrud, MS Koralov, SB Feuerer, M Calado, DP Kozhaya, AE Rhule-Smith, A Lefebvre, RE Unutmaz, D Mazitschek, R Waldner, H Whitman, M Keller, T Rao, A AF Sundrud, Mark S. Koralov, Sergei B. Feuerer, Markus Calado, Dinis Pedro Kozhaya, Aimee ElHed Rhule-Smith, Ava Lefebvre, Rachel E. Unutmaz, Derya Mazitschek, Ralph Waldner, Hanspeter Whitman, Malcolm Keller, Tracy Rao, Anjana TI Halofuginone Inhibits T(H)17 Cell Differentiation by Activating the Amino Acid Starvation Response SO SCIENCE LA English DT Article ID UNFOLDED PROTEIN RESPONSE; REGULATORY T-CELLS; NF-KAPPA-B; GENE-EXPRESSION; ROR-GAMMA; STRESS; INFLAMMATION; GENERATION; INITIATION; INDUCTION AB A central challenge for improving autoimmune therapy is preventing inflammatory pathology without inducing generalized immunosuppression. T helper 17 (T(H)17) cells, characterized by their production of interleukin-17, have emerged as important and broad mediators of autoimmunity. Here we show that the small molecule halofuginone (HF) selectively inhibits mouse and human T(H)17 differentiation by activating a cytoprotective signaling pathway, the amino acid starvation response (AAR). Inhibition of T(H)17 differentiation by HF is rescued by the addition of excess amino acids and is mimicked by AAR activation after selective amino acid depletion. HF also induces the AAR in vivo and protects mice from T(H)17-associated experimental autoimmune encephalomyelitis. These results indicate that the AAR pathway is a potent and selective regulator of inflammatory T cell differentiation in vivo. C1 [Whitman, Malcolm; Keller, Tracy] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Sundrud, Mark S.; Koralov, Sergei B.; Calado, Dinis Pedro; Lefebvre, Rachel E.; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sundrud, Mark S.; Koralov, Sergei B.; Calado, Dinis Pedro; Lefebvre, Rachel E.; Rao, Anjana] Immune Dis Inst, Boston, MA 02115 USA. [Feuerer, Markus] Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. [Kozhaya, Aimee ElHed; Unutmaz, Derya] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Kozhaya, Aimee ElHed; Unutmaz, Derya] NYU, Sch Med, Microbial Pathogenesis Program, New York, NY 10016 USA. [Rhule-Smith, Ava; Waldner, Hanspeter] Penn State Univ, Dept Microbiol & Immunol, Coll Med, Hershey, PA 17033 USA. [Mazitschek, Ralph] Broad Inst, Chem Biol Program, Cambridge, MA 02142 USA. [Mazitschek, Ralph] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02142 USA. RP Whitman, M (reprint author), Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. EM whitman@hms.harvard.edu; tkeller@hms.harvard.edu; arao@idi.harvard.edu RI Mazitschek, Ralph/E-3741-2013 OI Mazitschek, Ralph/0000-0002-1105-689X FU NIH [T32, P01]; Juvenile Diabetes Research Foundation; Irvington Institute fellowship program of the Cancer Research Institute; Portuguese Foundation for Science and Technology fellowship FX D. Littman and A. Rudensky provided reagents for this work, and K. Otipoby prepared recombinant TAT-Cre. We thank J. Hill and K. Leatherbee for technical assistance with microarray data analysis and members of the Rao lab for critical discussion. This work was supported by grants from NIH (to A.R., D.U., and M.W.) and the Juvenile Diabetes Research Foundation (to A.R.). M.S.S. was supported by the Irvington Institute fellowship program of the Cancer Research Institute. D.P.C. was supported by a fellowship from the Portuguese Foundation for Science and Technology. S.K. was supported by an NIH training grant (T32). Further support was provided by a P01 grant to K Rajewsky. M.S.S., A.R., T.K., and M.W. have filed patent applications concerning the use of HF and its derivatives to inhibit TH17 cell differentiation. Array data can be found at www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15624 with the accession number of GSE15624 [NCBI GEO] . NR 29 TC 161 Z9 173 U1 2 U2 16 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 JUN 5 PY 2009 VL 324 IS 5932 BP 1334 EP 1338 DI 10.1126/science.1172638 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 453TF UT WOS:000266635100048 PM 19498172 ER PT J AU Burns, CE Galloway, JL Smith, ACH Keefe, MD Cashman, TJ Paik, EJ Mayhall, EA Amsterdam, AH Zon, LI AF Burns, Caroline E. Galloway, Jenna L. Smith, Alexandra C. H. Keefe, Matthew D. Cashman, Timothy J. Paik, Elizabeth J. Mayhall, Elizabeth A. Amsterdam, Adam H. Zon, Leonard I. TI Agenetic screen in zebrafish defines a hierarchical network of pathways required for hematopoietic stem cell emergence SO BLOOD LA English DT Article ID ENDOTHELIAL-GROWTH-FACTOR; GONAD-MESONEPHROS REGION; DIAMOND-BLACKFAN ANEMIA; DEFINITIVE HEMATOPOIESIS; ARTERIAL DEVELOPMENT; NOTCH; GENE; DIFFERENTIATION; EXPRESSION; SPADETAIL AB Defining the genetic pathways essential for hematopoietic stem cell (HSC) development remains a fundamental goal impacting stem cell biology and regenerative medicine. To genetically dissect HSC emergence in the aorta-gonad-mesonephros (AGM) region, we screened a collection of insertional zebrafish mutant lines for expression of the HSC marker, c-myb. Nine essential genes were identified, which were subsequently binned into categories representing their proximity to HSC induction. Using overexpression and loss-of-function studies in zebrafish, we ordered these signaling pathways with respect to each other and to the Vegf, Notch, and Runx programs. Overexpression of vegf and notch is sufficient to induce HSCs in the tbx16 mutant, despite a lack of axial vascular organization. Although embryos deficient for artery specification, such as the phospholipase C gamma-1 (plc gamma 1) mutant, fail to specify HSCs, overexpression of notch or runx1 can rescue their hematopoietic defect. The most proximal HSC mutants, such as hdac1, were found to have no defect in vessel or artery formation. Further analysis demonstrated that hdac1 acts downstream of Notch signaling but upstream or in parallel to runx1 to promote AGM hematopoiesis. Together, our results establish a hierarchy of signaling programs required and sufficient for HSC emergence in the AGM. (Blood. 2009; 113: 5776-5782) C1 [Burns, Caroline E.; Galloway, Jenna L.; Smith, Alexandra C. H.; Keefe, Matthew D.; Paik, Elizabeth J.; Mayhall, Elizabeth A.; Zon, Leonard I.] Harvard Univ, Sch Med, Stem Cell Program, Boston, MA 02115 USA. [Burns, Caroline E.; Galloway, Jenna L.; Smith, Alexandra C. H.; Keefe, Matthew D.; Paik, Elizabeth J.; Mayhall, Elizabeth A.; Zon, Leonard I.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp, Boston, MA 02115 USA. [Burns, Caroline E.; Galloway, Jenna L.; Smith, Alexandra C. H.; Keefe, Matthew D.; Paik, Elizabeth J.; Mayhall, Elizabeth A.; Zon, Leonard I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Burns, Caroline E.; Cashman, Timothy J.] Harvard Univ, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. [Amsterdam, Adam H.] MIT, Ctr Canc Res, Cambridge, MA 02139 USA. RP Zon, LI (reprint author), Harvard Univ, Sch Med, Stem Cell Program, 320 Longwood Ave,Enders Bldg Rm 761, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU National Heart, Lung, and Blood Institute [5 R01 HL48801]; National Institute of Diabetes and Digestive and Kidney Diseases [1 K01 DK067179]; National Institutes of Health grant from the National Center for Research Resources [2 R01 RR012589]; Howard Hughes Medical Institute FX This work was supported by the National Heart, Lung, and Blood Institute (grant 5 R01 HL48801). C. E. B. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases ( Research Career Award 1 K01 DK067179). A. H. A. is supported by a National Institutes of Health grant from the National Center for Research Resources (2 R01 RR012589). L. I. Z. is supported by Howard Hughes Medical Institute. NR 48 TC 48 Z9 49 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 4 PY 2009 VL 113 IS 23 BP 5776 EP 5782 DI 10.1182/blood-2008-12-193607 PG 7 WC Hematology SC Hematology GA 454BH UT WOS:000266656100017 PM 19332767 ER PT J AU Kisucka, J Chauhan, AK Zhao, BQ Patten, IS Yesilaltay, A Krieger, M Wagner, DD AF Kisucka, Janka Chauhan, Anil K. Zhao, Bing-Qiao Patten, Ian S. Yesilaltay, Ayce Krieger, Monty Wagner, Denisa D. TI Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis SO BLOOD LA English DT Article ID OBSTRUCTIVE SLEEP-APNEA; VASCULAR ENDOTHELIAL-CELLS; DEFICIENT MICE; ISCHEMIC-STROKE; PLATELET ACTIVATION; ALZHEIMERS-DISEASE; CYTOPLASMIC DOMAIN; APOLIPOPROTEIN-E; TISSUE FACTOR; IN-VIVO AB Cerebrovascular and cardiovascular diseases are a major cause of morbidity and mortality. Soluble P-selectin (sP-selectin) is a biomarker for platelet/endothelial activation and is considered a risk factor for vascular disease. sP-selectin enhances procoagulant activity by inducing leukocyte-derived microparticle production and promotes activation of leukocyte integrins. However, it is not known whether it directly contributes to vascular complications. We investigated the effect of in-creased levels of sP-selectin on blood-brain barrier (BBB) function, stroke outcome, and atherosclerosis by comparing wild-type mice with P-sel(Delta CT/Delta CT) mice in which the endogenous P-selectin gene was replaced with a mutant that produces abnormally high plasma levels of sP-selectin. P-sel(Delta CT/Delta CT) mice presented several abnormalities, including (1) higher BBB permeability, with 25% of the animals showing differential permeability between the right and left hemispheres; (2) altered social behavior with increased aggression; (3) larger infarcts in the middle cerebral artery occlusion ischemic stroke model; and (4) increased susceptibility to atherosclerotic, macrophage-rich lesion development in both male and female mice on the apoE(-/-) genetic background. Thus, elevated sP-selectin is not only a biomarker for vascular disease, but also may contribute directly to atherosclerosis and cerebrovascular complications. (Blood. 2009; 113: 6015-6022) C1 [Kisucka, Janka; Chauhan, Anil K.; Zhao, Bing-Qiao; Patten, Ian S.; Wagner, Denisa D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Kisucka, Janka; Chauhan, Anil K.; Zhao, Bing-Qiao; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Yesilaltay, Ayce; Krieger, Monty] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Wagner, DD (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 3 Blackfan Circle,3rd Floor, Boston, MA 02115 USA. EM wagner@idi.harvard.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, MD) [HL056949, HL066105] FX This work was supported by grants HL056949 (to D. D. W.) and HL066105 (to M. K. and D. D. W.) from the National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, MD). NR 56 TC 34 Z9 41 U1 2 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 4 PY 2009 VL 113 IS 23 BP 6015 EP 6022 DI 10.1182/blood-2008-10-186650 PG 8 WC Hematology SC Hematology GA 454BH UT WOS:000266656100044 PM 19349621 ER PT J AU Wilson, D Hurtado, RM Digumarthy, S AF Wilson, Douglas Hurtado, Rocio M. Digumarthy, Subba TI A Woman with AIDS and Tuberculosis with Progressive Cough, Dyspnea, and Wasting Extensively drug-resistant Mycobacterium tuberculosis infection in a patient with HIV/AIDS. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT 2nd Annual Workshop on Advanced Clinical Care - Aids CT IEEE International Conference on Computer Design CY OCT 02, 2008 CY OCT 12-15, 2008 CL Durban, SOUTH AFRICA CL Lake Tahoe, CA SP IEEE, IEEE Circuits & Syst Soc, IEEE Comp Soc ID MULTIDRUG-RESISTANT; PULMONARY TUBERCULOSIS; TREATMENT OUTCOMES; SOUTH-AFRICA; THERAPY; LIMA; PERU; DIAGNOSIS; STRAINS C1 [Wilson, Douglas] Edendale Hosp, Dept Med, Pietermaritzburg, South Africa. [Wilson, Douglas] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Dept Med, Durban, South Africa. [Hurtado, Rocio M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Digumarthy, Subba] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hurtado, Rocio M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Digumarthy, Subba] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Wilson, D (reprint author), Edendale Hosp, Dept Med, Pietermaritzburg, South Africa. NR 29 TC 0 Z9 0 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 4 PY 2009 VL 360 IS 23 BP 2456 EP 2464 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 453DN UT WOS:000266590500013 PM 19494222 ER PT J AU Masaki, K Gu, JW Ghaffari, R Chan, G Smith, RJH Freeman, DM Aranyosi, AJ AF Masaki, Kinuko Gu, Jianwen Wendy Ghaffari, Roozbeh Chan, Gary Smith, Richard J. H. Freeman, Dennis M. Aranyosi, A. J. TI Col11a2 Deletion Reveals the Molecular Basis for Tectorial Membrane Mechanical Anisotropy SO BIOPHYSICAL JOURNAL LA English DT Article ID ARTICULAR-CARTILAGE; HEARING-LOSS; MOTION; COLLAGEN; MOUSE; ORGAN; MODEL; CORTI; LOCALIZATION; ORGANIZATION AB The tectorial membrane (TM) has a significantly larger stiffness in the radial direction than other directions, a prominent mechanical anisotropy that is believed to be critical for the proper functioning of the cochlea. To determine the molecular basis of this anisotropy, we measured material properties of TMs from mice with a targeted deletion of Col11a2, which encodes for collagen XI. In light micrographs, the density of TM radial collagen fibers was lower in Col11a2-/- mice than wild-types. Tone-evoked distortion product otoacoustic emission and auditory brainstem response measurements in Col11a2-/- mice were reduced by 30-50 dB independent of frequency as compared with wild-types, showing that the sensitivity loss is cochlear in origin. Stress-strain measurements made using osmotic pressure revealed no significant dependence of TM bulk compressibility on the presence of collagen XI. Charge measurements made by placing the TM as an electrical conduit between two baths revealed no change in the density of charge affixed to the TM matrix in Col11a2-/- mice. Measurements of mechanical shear impedance revealed a 5.5 +/- 0.8 dB decrease in radial shear impedance and a 3.3 +/- 0.3 dB decrease in longitudinal shear impedance resulting from the Col11a2 deletion. The ratio of radial to longitudinal shear impedance fell from 1.8 +/- 0.7 for TMs from wild-type mice to 1.0 +/- 0.1 for those from Col11a2-/- mice. These results show that the organization of collagen into radial fibrils is responsible for the mechanical anisotropy of the TM. This anisotropy can be attributed to increased mechanical coupling provided by the collagen fibrils. Mechanisms by which changes in TM material properties may contribute to the threshold elevation in Col11a2-/- mice are discussed. C1 [Masaki, Kinuko; Gu, Jianwen Wendy; Ghaffari, Roozbeh; Freeman, Dennis M.; Aranyosi, A. J.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Masaki, Kinuko; Gu, Jianwen Wendy; Ghaffari, Roozbeh; Freeman, Dennis M.; Aranyosi, A. J.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Chan, Gary; Freeman, Dennis M.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Masaki, Kinuko; Gu, Jianwen Wendy; Ghaffari, Roozbeh; Freeman, Dennis M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. [Smith, Richard J. H.] Univ Iowa, Dept Otolaryngol Head & Neck Surg, Iowa City, IA 52242 USA. RP Aranyosi, AJ (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM aja@mit.edu OI Aranyosi, Alexander/0000-0002-8133-5026 FU National Institutes of Health (NIH) [R01-DC00238]; NIH-NIDCD [R01 DC03544] FX G.C., A.J.A., and D.M.F. were Supported by National Institutes of Health (NIH) grant No. R01-DC00238. J.W.G. and R.G. Were Supported by in NIH training grant to the Harvard-MIT Speech and Hearing Biosciences and Technology Program. K.M. and R.J.H.S. were Supported in part by NIH-NIDCD grant No. R01 DC03544. NR 43 TC 10 Z9 10 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN 3 PY 2009 VL 96 IS 11 BP 4717 EP 4724 DI 10.1016/j.bpj.2009.02.056 PG 8 WC Biophysics SC Biophysics GA 453ZC UT WOS:000266650400036 PM 19486694 ER PT J AU Mortensen, EM Copeland, LA Pugh, MJV Restrepo, MI de Molina, RM Nakashima, B Anzueto, A AF Mortensen, Eric M. Copeland, Laurel A. Pugh, Mary Jo V. Restrepo, Marcos I. de Molina, Rosa Malo Nakashima, Brandy Anzueto, Antonio TI Impact of statins and ACE inhibitors on mortality after COPD exacerbations SO RESPIRATORY RESEARCH LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; C-REACTIVE PROTEIN; AIRWAY INFLAMMATION; PROPENSITY SCORE; HEALTH-STATUS; VALIDATION; PROTECTION; PNEUMONIA; MORBIDITY; INFLUENZA AB Background: The purpose of our study was to examine the association of prior outpatient use of statins and angiotensin converting enzyme (ACE) inhibitors on mortality for subjects >= 65 years of age hospitalized with acute COPD exacerbations. Methods: We conducted a retrospective national cohort study using Veterans Affairs administrative data including subjects >= 65 years of age hospitalized with a COPD exacerbation. Our primary analysis was a multilevel model with the dependent variable of 90-day mortality and hospital as a random effect, controlling for preexisting comorbid conditions, demographics, and other medications prescribed. Results: We identified 11,212 subjects with a mean age of 74.0 years, 98% were male, and 12.4% of subjects died within 90-days of hospital presentation. In this cohort, 20.3% of subjects were using statins, 32.0% were using ACE inhibitors or angiotensin II receptor blockers (ARB). After adjusting for potential confounders, current statin use (odds ratio 0.51, 95% confidence interval 0.40-0.64) and ACE inhibitor/ARB use (0.55, 0.46-0.66) were significantly associated with decreased 90-day mortality. Conclusion: Use of statins and ACE inhibitors prior to admission is associated with decreased mortality in subjects hospitalized with a COPD exacerbation. Randomized controlled trials are needed to examine whether the use of these medications are protective for those patients with COPD exacerbations. C1 [Mortensen, Eric M.; Copeland, Laurel A.; Pugh, Mary Jo V.; Restrepo, Marcos I.; de Molina, Rosa Malo; Nakashima, Brandy; Anzueto, Antonio] S Texas Vet Hlth Care Syst, VERDICT Res Unit, San Antonio, TX USA. [Mortensen, Eric M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Gen Internal Med, San Antonio, TX 78229 USA. [Copeland, Laurel A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; de Molina, Rosa Malo; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. RP Mortensen, EM (reprint author), S Texas Vet Hlth Care Syst, VERDICT Res Unit, San Antonio, TX USA. EM mortensene@uthscsa.edu; copelandl@uthscsa.edu; pughm@uthsca.edu; restrepom@uthscsa.edu; rmm02004@yahoo.es; nakashima@uthscsa.edu; anzueto@uthsa.edu RI Restrepo, Marcos/H-4442-2014; OI Pugh, Mary Jo/0000-0003-4196-7763; Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 FU Department of Veterans Affairs [IIR 02-076, MREP 02-267, MREP 05-145] FX Dr. Pugh received funding from the Department of Veterans Affairs IIR 02-076 and MREP 02-267. Dr. Copeland was supported by Department of Veterans Affairs MREP 05-145. This material is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System. The funding agencies had no role in conducting the study, or role in the preparation, review, or approval of the manuscript. NR 38 TC 62 Z9 65 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD JUN 3 PY 2009 VL 10 AR 45 DI 10.1186/1465-9921-10-45 PG 9 WC Respiratory System SC Respiratory System GA 462BR UT WOS:000267320800001 PM 19493329 ER PT J AU Singh, A Greninger, P Rhodes, D Koopman, L Violette, S Bardeesy, N Settleman, J AF Singh, Anurag Greninger, Patricia Rhodes, Daniel Koopman, Louise Violette, Sheila Bardeesy, Nabeel Settleman, Jeff TI A Gene Expression Signature Associated with "K-Ras Addiction" Reveals Regulators of EMT and Tumor Cell Survival SO CANCER CELL LA English DT Article ID PANCREATIC DUCTAL ADENOCARCINOMA; FACTOR RECEPTOR INHIBITION; TO-MESENCHYMAL TRANSITION; TYROSINE KINASE; LUNG-CANCER; SENSITIVITY; GROWTH; AMPLIFICATION; PROGRESSION; GENOME AB K-ras mutations occur frequently in epithelial cancers. Using short hairpin RNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-ras mutations, two classes were identified-lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases. and integrin beta 6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in "K-Ras-addicted" cancers represent candidate therapeutic targets. C1 [Singh, Anurag; Greninger, Patricia; Bardeesy, Nabeel; Settleman, Jeff] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Singh, Anurag; Greninger, Patricia; Bardeesy, Nabeel; Settleman, Jeff] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Rhodes, Daniel] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Rhodes, Daniel] Univ Michigan, Sch Med, Dept Bioinformat, Ann Arbor, MI 48109 USA. [Koopman, Louise] Biogen Idec, Dept Discovery Oncol, Cambridge, MA 02142 USA. [Violette, Sheila] Stromedix Inc, Cambridge, MA 02141 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu RI Singh, Anurag/C-7347-2014 OI Singh, Anurag/0000-0003-4705-8683 FU NRSA T32 postdoctoral fellowship; NIH [R01 CA109447]; Lustgarten Foundation FX A.S. was supported by a NRSA T32 postdoctoral fellowship. The studies were supported by NIH R01 CA109447 and a Lustgarten Foundation grant (to J.S.). We thank Marie Classon, Jeff Engelman, and Rushika Perara for comments on the manuscript. We thank Michael Rothenberg for construction of the pWPI-K-Ras(12V) expression vector and for advice regarding lentiviral use. We thank Maria Varadi for technical assistance. We thank Nathanael Gray for providing the R406 Syk inhibitor. We thank Sridhar Ramaswamy and Andrew Yee for advice with the application of gene expression signatures as predictive tools. We thank Vikram Deshpande for assistance with IHC analysis. S.V. and L.K. have been or are in the employ of Biogen Idec. S.V. is currently employed by Stromedix Inc. These companies currently have an anti-integrin alpha V beta 6 monoclonal antibody in clinical development. NR 42 TC 317 Z9 323 U1 1 U2 16 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 JUN 2 PY 2009 VL 15 IS 6 BP 489 EP 500 DI 10.1016/j.ccr.2009.03.022 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 454MP UT WOS:000266686500007 PM 19477428 ER PT J AU Fu, J Kim, DH Knoll, W AF Fu, Jun Kim, Dong Ha Knoll, Wolfgang TI Aqueous Networks and Toroids of Amphiphilic Block Copolymer with Non-ionic Surfactants SO CHEMPHYSCHEM LA English DT Article DE block copolymers; morphological transformation; responsive; self-assembly; surfactants ID POLYSTYRENE-BLOCK-POLY(ETHYLENE OXIDE); PHASE-SEPARATION; TERNARY-SYSTEM; DRUG-DELIVERY; MICELLES; ASSEMBLIES; TRANSITION; ACID); MICELLIZATION; COMPLEXATION C1 [Fu, Jun; Knoll, Wolfgang] Max Planck Inst Polymer Res, D-55128 Mainz, Germany. [Kim, Dong Ha] Ewha Womans Univ, Dept Chem & Nano Sci, Seoul 120750, South Korea. RP Fu, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,GRJ 1227, Boston, MA 02114 USA. EM jfu1@partners.org RI Fu, Jun/C-1648-2012; Kim, Dong Ha/B-3778-2008 OI Fu, Jun/0000-0002-8723-1439; Kim, Dong Ha/0000-0003-0444-0479 FU Korea government (MEST) [R11-2005-008-00000-0] FX J.F thanks the Max Planck Society (MPG) and the Chinese Academy of Sciences (CAS) for the Max Planck Society Fellowship under the Cooperative Program of Science and Technology between CAS and MPG. D.H.K thanks the Korea Science and Engineering Foundation (KOSEF) for a grant funded by the Korea government (MEST) (No. R11-2005-008-00000-0). NR 39 TC 7 Z9 7 U1 0 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4235 J9 CHEMPHYSCHEM JI ChemPhysChem PD JUN 2 PY 2009 VL 10 IS 8 BP 1190 EP 1194 DI 10.1002/cphc.200900081 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 457SV UT WOS:000266954500004 PM 19334021 ER PT J AU Morrow, DA Wiviott, SD White, HD Nicolau, JC Bramucci, E Murphy, SA Bonaca, MP Ruff, CT Scirica, BM McCabe, CH Antman, EM Braunwald, E AF Morrow, David A. Wiviott, Stephen D. White, Harvey D. Nicolau, Jose C. Bramucci, Ezio Murphy, Sabina A. Bonaca, Marc P. Ruff, Christian T. Scirica, Benjamin M. McCabe, Carolyn H. Antman, Elliott M. Braunwald, Eugene TI Effect of the Novel Thienopyridine Prasugrel Compared With Clopidogrel on Spontaneous and Procedural Myocardial Infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 An Application of the Classification System From the Universal Definition of Myocardial Infarction SO CIRCULATION LA English DT Article DE angioplasty; myocardial infarction; platelets; prasugrel; unstable angina ID PERCUTANEOUS CORONARY INTERVENTION; CARDIAC ENZYME ELEVATION; RANDOMIZED-TRIAL; ADVERSE OUTCOMES; ISCHEMIC EVENTS; AGGREGATION; DISEASE AB Background-Prasugrel is a novel thienopyridine that reduces new or recurrent myocardial infarctions (MIs) compared with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. This effect must be balanced against an increased bleeding risk. We aimed to characterize the effect of prasugrel with respect to the type, size, and timing of MI using the universal classification of MI. Methods and Results-We studied 13 608 patients with acute coronary syndrome undergoing percutaneous coronary intervention randomized to prasugrel or clopidogrel and treated for 6 to 15 months in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). Each MI underwent supplemental classification as spontaneous, secondary, or sudden cardiac death (types 1, 2, and 3) or procedure related (Types 4 and 5) and examined events occurring early and after 30 days. Prasugrel significantly reduced the overall risk of MI (7.4% versus 9.7%; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.67 to 0.85; P < 0.0001). This benefit was present for procedure-related MIs (4.9% versus 6.4%; HR, 0.76; 95% CI, 0.66 to 0.88; P = 0.0002) and nonprocedural (type 1, 2, or 3) MIs (2.8% versus 3.7%; HR, 0.72; 95% CI, 0.59 to 0.88; P = 0.0013) and consistently across MI size, including MIs with a biomarker peak >= 5 times the reference limit (HR. 0.74; 95% CI, 0.64 to 0.86; P = 0.0001). In landmark analyses starting at 30 days, patients treated with prasugrel had a lower risk of any MI (2.9% versus 3.7%; HR, 0.77; P = 0.014), including nonprocedural MI (2.3% versus 3.1%; HR, 0.74; 95% CI, 0.60 to 0.92; P = 0.0069). Conclusion-Treatment with prasugrel compared with clopidogrel for up to 15 months in patients with acute coronary syndrome undergoing percutaneous coronary intervention significantly reduces the risk of MIs that are procedure related and spontaneous and those that are small and large, including new MIs occurring during maintenance therapy. (Circulation. 2009; 119: 2758-2764.) C1 [Morrow, David A.; Wiviott, Stephen D.; Murphy, Sabina A.; Bonaca, Marc P.; Ruff, Christian T.; Scirica, Benjamin M.; McCabe, Carolyn H.; Antman, Elliott M.; Braunwald, Eugene] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, Boston, MA 02115 USA. [White, Harvey D.] Auckland City Hosp, Auckland, New Zealand. [Nicolau, Jose C.] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo, Brazil. [Bramucci, Ezio] Policlin San Matteo, IRCCS, Div Cardiol, I-27100 Pavia, Italy. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org RI Nicolau, Jose/E-1487-2012 FU Daiichi Sankyo Co, Ltd; Eli Lilly and Co FX This study was supported by a grant from Daiichi Sankyo Co, Ltd, and Eli Lilly and Co. NR 12 TC 85 Z9 91 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 2 PY 2009 VL 119 IS 21 BP 2758 EP 2764 DI 10.1161/CIRCULATIONAHA.108.833665 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 452DY UT WOS:000266521400003 PM 19451347 ER PT J AU Chirinos, JA Segers, P Gupta, AK Swillens, A Rietzschel, ER De Buyzere, ML Kirkpatrick, JN Gillebert, TC Wang, Y Keane, MG Townsend, R Ferrari, VA Wiegers, SE Sutton, MSJ AF Chirinos, Julio A. Segers, Patrick Gupta, Amit Kumar Swillens, Abigail Rietzschel, Ernst R. De Buyzere, Marc L. Kirkpatrick, James N. Gillebert, Thierry C. Wang, Yan Keane, Martin G. Townsend, Raymond Ferrari, Victor A. Wiegers, Susan E. Sutton, Martin St John TI Time-Varying Myocardial Stress and Systolic Pressure-Stress Relationship Role in Myocardial-Arterial Coupling in Hypertension SO CIRCULATION LA English DT Article DE hypertension; myocardium; hemodynamics ID LEFT-VENTRICULAR GEOMETRY; WAVE REFLECTION; HEART-FAILURE; WALL STRESS; HYPERTROPHY; ECHOCARDIOGRAPHY; QUANTIFICATION; DISEASE AB Background-Myocardial afterload depends on left ventricular (LV) cavity size, pressure, and wall thickness, all of which change markedly throughout ejection. We assessed the relationship between instantaneous ejection-phase pressure and myocardial stress and the effect of arterial wave reflections on myocardial stress in hypertensive and normotensive adults. Methods and Results-We studied 42 untreated hypertensive, 42 treated hypertensive, and 42 normotensive adults with normal LV ejection fraction. Time-resolved central pressure, flow, and LV geometry were measured with carotid tonometry, Doppler, and speckle-tracking echocardiography for computation of arterial load and time-varying circumferential and longitudinal myocardial stress. In all 3 groups, peak myocardial stress typically occurred in early systole (within the first 100 milliseconds of ejection), followed by a marked midsystolic shift in the pressure-stress relationship, which favored lower late systolic stress values (P < 0.001) relative to pressure. The mean magnitude of this midsystolic shift was quantitatively important in all 3 groups (circumferential stress, 144 to 148 kdynes/cm(2)) and was independently predicted by a higher LV ejection fraction and ratio of LV end-diastolic cavity to wall volume. Time of peak myocardial stress independently correlated with time of the first systolic but not with time of the second systolic central pressure peak. Conclusions-Peak myocardial stress occurs in early systole, before important contributions of reflected waves to central pressure. In the presence of normal LV ejection fraction, a midsystolic shift in the pressure-stress relationship protects cardiomyocytes against excessive late systolic stress (despite pressure augmentation associated with wave reflections), a coupling mechanism that may be altered in various disease states. (Circulation. 2009; 119:2798-2807.) C1 [Chirinos, Julio A.; Gupta, Amit Kumar; Kirkpatrick, James N.; Wang, Yan; Keane, Martin G.; Townsend, Raymond; Ferrari, Victor A.; Wiegers, Susan E.; Sutton, Martin St John] Univ Penn, Philadelphia, PA 19104 USA. [Chirinos, Julio A.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Segers, Patrick; Swillens, Abigail] Univ Ghent, Cardiovasc Mech & Biofluid Dynam Res Unit, IBiTech, B-9000 Ghent, Belgium. [Rietzschel, Ernst R.; De Buyzere, Marc L.; Gillebert, Thierry C.] Ghent Univ Hosp, Dept Cardiovasc Dis, B-9000 Ghent, Belgium. RP Chirinos, JA (reprint author), Childrens Hosp Philadelphia, Div Cardiol, Room 8B111,3900 Woodland Ave, Philadelphia, PA 19104 USA. EM julio.chirinos@uphs.upenn.edu RI Gupta, amit/B-3831-2012; OI Gillebert, Thierry/0000-0002-3832-919X NR 19 TC 32 Z9 32 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 2 PY 2009 VL 119 IS 21 BP 2798 EP U100 DI 10.1161/CIRCULATIONAHA.108.829366 PG 20 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 452DY UT WOS:000266521400008 PM 19451350 ER PT J AU Breitner, JCS Haneuse, SJPA Walker, R Dublin, S Crane, PK Gray, SL Larson, EB AF Breitner, J. C. S. Haneuse, S. J. P. A. Walker, R. Dublin, S. Crane, P. K. Gray, S. L. Larson, E. B. TI Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort SO NEUROLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; ANTIINFLAMMATORY DRUGS; CACHE COUNTY; ONSET; AGE; ROFECOXIB; NAPROXEN AB Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent Alzheimer dementia (AD). Methods: We analyzed the association of prior NSAID exposure with incident dementia and AD in the Adult Changes in Thought population-based cohort aged >= 65 years (median 74.8) at enrollment. Participants were members of Group Health, which provided computerized pharmacy dispensing records from 1977 onward. We studied 2,736 dementia-free enrollees with extensive prior pharmacy data, following them biennially for up to 12 years to identify dementia and AD. Cox proportional hazards regression assessed association of dementia or AD with NSAID use graded in standard daily doses (SDD) dispensed over 2 years (e.g., heavy use = 500 + SDD), with some analyses also adding consecutive biennial self-reports of NSAID use. Results: Pharmacy records identified 351 participants (12.8%) with history of heavy NSAID use at enrollment. Another 107 became heavy users during follow-up. Some 476 individuals developed incident dementia, 356 with AD (median onset ages 83.5 and 83.8 years). Contrary to the hypothesis that NSAIDs protect against AD, pharmacy-defined heavy NSAID users showed increased incidence of dementia and AD, with adjusted hazard ratios of 1.66 (95% confidence interval, 1.24-2.24) and 1.57 (95% confidence interval, 1.10-2.23). Addition of self-reported exposure data did not alter these results. Conclusions: These findings differ from those of other studies with younger cohorts. The results observed elsewhere may reflect delayed onset of Alzheimer dementia (AD) in nonsteroidal anti-inflammatory drug (NSAID) users. Conceivably, such delay could result in increased AD incidence in late old age. The relation of NSAID use and AD pathogenesis needs further investigation. Neurology (R) 2009; 72: 1899-1905 C1 [Breitner, J. C. S.] Geriatr Res Educ & Clin Ctr, Dept Vet Affairs Med Ctr, Seattle, WA USA. [Breitner, J. C. S.; Crane, P. K.] Univ Washington, Sch Med, Seattle, WA USA. [Haneuse, S. J. P. A.; Walker, R.; Dublin, S.; Larson, E. B.] Ctr Hlth Studies, Grp Hlth Cooperat, Seattle, WA USA. [Dublin, S.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Gray, S. L.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. RP Breitner, JCS (reprint author), VA Puget Sound Hlth Care Syst, GRECC S182, 1660 S Columbian Way, Seattle, WA 98108 USA. EM jcsb@u.washington.edu RI Crane, Paul/C-8623-2014; OI Crane, Paul/0000-0003-4278-7465 FU NIA NIH HHS [U01-AG-15477, K23 AG028954, K23 AG028954-01A1, K23-AG-28954, R01-AG-24010, U01 AG006781, U01 AG006781-13, U01-AG-06781] NR 28 TC 99 Z9 102 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 2 PY 2009 VL 72 IS 22 BP 1899 EP 1905 DI 10.1212/WNL.0b013e3181a18691 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 452FD UT WOS:000266524600005 PM 19386997 ER PT J AU Kivisakk, P Healy, BC Viglietta, V Quintana, FJ Hootstein, MA Weiner, HL Khoury, SJ AF Kivisakk, P. Healy, B. C. Viglietta, V. Quintana, F. J. Hootstein, M. A. Weiner, H. L. Khoury, S. J. TI Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells SO NEUROLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; MULTIPLE-SCLEROSIS PATIENTS; CENTRAL-NERVOUS-SYSTEM; TRANSCRIPTION FACTOR; REGULATORY CELLS; EXPRESSION; INTEGRIN; BRAIN; ANTIBODIES AB Background: Natalizumab is an antibody directed against integrin alpha 4 that reduces disease activity in patients with multiple sclerosis (MS) by blocking migration of T and B cells into the CNS. The goal of this study was to characterize the effects of natalizumab treatment on cytokine production and expression of activation markers, costimulatory molecules, and trafficking determinants on CD4(+) and CD8(+) T cells. Methods: In a longitudinal study, we investigated the expression of surface makers and cytokine expression on peripheral blood lymphocytes from 28 patients with MS who started natalizumab treatment and were followed for 1 year. A mixed effects model was used to compare pretreatment to on-treatment measurements. Results: The frequency of CD4(+) T cells producing interferon-gamma, tumor necrosis factor, and interleukin (IL)-17 upon anti-CD3 stimulation increased 6 months after initiation of natalizumab treatment and remained elevated throughout the follow-up. The frequency of CD4(+) T cells expressing CD25, HLA-DR, and CCR6 ex vivo was increased at one or more time points during treatment. Among CD8(+) T cells, the frequency of cells producing IL-2 and IL-17 after stimulation was increased during natalizumab treatment, as was the frequency of CD8(+) T cells expressing CD58 and CCR5 ex vivo. The increase in the frequency of activated cells could not be replicated by in vitro exposure to natalizumab. Conclusion: Natalizumab treatment increases the percentage of activated leukocytes producing proinflammatory cytokines in blood, presumably due to sequestration of activated cells in the peripheral circulation. Neurology (R) 2009; 72:1922-1930 C1 [Khoury, S. J.] Harvard Univ, Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol,Partners MS Ctr,Sch Med,Harvard Inst, Boston, MA 02115 USA. [Healy, B. C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Khoury, SJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol,Partners MS Ctr,Sch Med,Harvard Inst, Room 710,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM skhoury@rics.bwh.harvard.edu OI khoury, samia/0000-0003-3198-6063 FU NIAID NIH HHS [N01 AI05411, U19 AI46130] NR 40 TC 70 Z9 71 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 2 PY 2009 VL 72 IS 22 BP 1922 EP 1930 DI 10.1212/WNL.0b013e3181a8266f PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 452FD UT WOS:000266524600008 PM 19487650 ER PT J AU Landers, JE Melki, J Meininger, V Glass, JD van den Berg, LH van Es, MA Sapp, PC van Vught, PWJ McKenna-Yasek, DM Blauw, HM Cho, TJ Polak, M Shi, LJ Wills, AM Broom, WJ Ticozzi, N Silani, V Ozoguz, A Rodriguez-Leyva, I Veldink, JH Ivinson, AJ Saris, CGJ Hosler, BA Barnes-Nessa, A Couture, N Wokke, JHJ Kwiatkowski, TJ Ophoff, RA Cronin, S Hardiman, O Diekstra, FP Leigh, PN Shaw, CE Simpson, CL Hansen, VK Powell, JF Corcia, P Salachas, F Heath, S Galan, P Georges, F Horvitz, HR Lathrop, M Purcell, S Al-Chalabi, A Brown, RH AF Landers, John E. Melki, Judith Meininger, Vincent Glass, Jonathan D. van den Berg, Leonard H. van Es, Michael A. Sapp, Peter C. van Vught, Paul W. J. McKenna-Yasek, Diane M. Blauw, Hylke M. Cho, Ting-Jan Polak, Meraida Shi, Lijia Wills, Anne-Marie Broom, Wendy J. Ticozzi, Nicola Silani, Vincenzo Ozoguz, Aslihan Rodriguez-Leyva, Ildefonso Veldink, Jan H. Ivinson, Adrian J. Saris, Christiaan G. J. Hosler, Betsy A. Barnes-Nessa, Alayna Couture, Nicole Wokke, John H. J. Kwiatkowski, Thomas J., Jr. Ophoff, Roel A. Cronin, Simon Hardiman, Orla Diekstra, Frank P. Leigh, P. Nigel Shaw, Christopher E. Simpson, Claire L. Hansen, Valerie K. Powell, John F. Corcia, Philippe Salachas, Francois Heath, Simon Galan, Pilar Georges, Franck Horvitz, H. Robert Lathrop, Mark Purcell, Shaun Al-Chalabi, Ammar Brown, Robert H., Jr. TI Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genome-wide association study; single nucleotide polymorphism ID GENOME-WIDE ASSOCIATION; MOTOR-NEURON DISEASE; MULTIPLE-SCLEROSIS; INTERLEUKIN-7 RECEPTOR; SUPEROXIDE-DISMUTASE; AXONAL-TRANSPORT; RISK LOCI; MUTATIONS; ALS; SUSCEPTIBILITY AB Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U. S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result ( P = 1.84 x 10(-8)) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability. C1 [Landers, John E.; Sapp, Peter C.; McKenna-Yasek, Diane M.; Cho, Ting-Jan; Shi, Lijia; Wills, Anne-Marie; Broom, Wendy J.; Ticozzi, Nicola; Rodriguez-Leyva, Ildefonso; Hosler, Betsy A.; Barnes-Nessa, Alayna; Couture, Nicole; Kwiatkowski, Thomas J., Jr.; Brown, Robert H., Jr.] Massachusetts Gen Hosp E, Cecil B Day Neuromuscular Res Lab, Charlestown, MA 02129 USA. [Melki, Judith; Georges, Franck] Univ Evry & Paris 11, Mol Neurogenet Lab, Inst Natl Sante & Rech Med, U798, F-91057 Evry, France. [Meininger, Vincent; Salachas, Francois] Hop La Pitie Salpetriere, Assistance Publ Hop Paris, F-75651 Paris, France. [Glass, Jonathan D.; Polak, Meraida] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [van den Berg, Leonard H.; van Es, Michael A.; van Vught, Paul W. J.; Blauw, Hylke M.; Veldink, Jan H.; Saris, Christiaan G. J.; Wokke, John H. J.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, NL-3584 CX Utrecht, Netherlands. [Ophoff, Roel A.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [Sapp, Peter C.; Horvitz, H. Robert] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. [Ticozzi, Nicola; Silani, Vincenzo] Univ Milan, Sch Med, Dept Neurol,Ist Auxol Italiano, Dino Ferrari Ctr,Ist Di Ricovero & Cura Carattere, I-20149 Milan, Italy. [Ticozzi, Nicola; Silani, Vincenzo] Univ Milan, Sch Med, Lab Neurosci,Ist Auxol Italiano, Dino Ferrari Ctr,Ist Di Ricovero & Cura Carattere, I-20149 Milan, Italy. [Ozoguz, Aslihan] Bogazici Univ, Dept Mol Biol & Genet, Neurodegenerat Res Lab, Istanbul, Turkey. [Rodriguez-Leyva, Ildefonso] Univ Autonoma San Luis Potosi, Fac Med, San Luis Potosi 78210, Mexico. [Ivinson, Adrian J.] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Boston, MA 02115 USA. [Ophoff, Roel A.] Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. [Cronin, Simon; Hardiman, Orla] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland. [Diekstra, Frank P.; Leigh, P. Nigel; Shaw, Christopher E.; Simpson, Claire L.; Hansen, Valerie K.; Powell, John F.; Al-Chalabi, Ammar] Kings Coll London, Dept Clin Neurosci, MRC, Ctr Neurodegenerat Res,Inst Psychiat, London SE5 8AF, England. [Corcia, Philippe] CHU Bretonneau, Serv Neurol, F-37044 Tours, France. [Heath, Simon; Lathrop, Mark] CEA, Ctr Natl Genotypage, Inst Genom, F-91057 Evry, France. [Galan, Pilar] UFR Sante Med & Biol Humaine, Unite Rech Epidemiol Nutr, F-93017 Bobigny, France. [Purcell, Shaun] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Landers, JE (reprint author), Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA. EM john.landers@umassmed.edu RI Al-Chalabi, Ammar/E-5361-2010; Powell, John/G-4412-2011; Ticozzi, Nicola/K-8094-2016; OI Al-Chalabi, Ammar/0000-0002-4924-7712; Powell, John/0000-0001-6124-439X; Ticozzi, Nicola/0000-0001-5963-7426; Silani, Vincenzo/0000-0002-7698-3854; Hardiman, Orla/0000-0003-2610-1291 FU The Netherlands Organisation for Scientific Research; Adessium Foundation; Howard Hughes Medical Institute; Packard Center for ALS Research; Muscular Dystrophy Association; National Center for Research Resources [U54 RR020278-01]; Howard Hughes Medical Institute Investigator; ALS Family Charitable Foundation; Al-Athel ALS Research Foundation; Pierre L. de Bourgknecht ALS Research Foundation; Angel Fund; ALS Therapy Alliance; National Institute of Neurological Disorders and Stroke; American Academy of Neurology Foundation/ALS Association; Harvard Business School Class of 2007; Medical Research Council; Wellcome Trust; Psychiatry Research Trust FX We dedicate this article to the memories of Frieda R. Abraham, Donna Roberts, and Jennifer Estess. We thank Daniel Mirel ( Broad Institute) for all of his assistance, all of the clinicians who assisted in recruiting cases and controls, particularly to clients with ALS and their families, and Jerry Xu and Dennis Gurgul of the Enterprise Research IS group at Partners Healthcare for support and use of the Hewlett-Packard computing facilities. The Boston- based investigations were supported by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation ( R. H. B., J. E. L., D. M. M.- Y., I. R.- L, T. J. K.), the ALS Family Charitable Foundation, the American Academy of Neurology Foundation/ALS Association ( A.-M. W.), the National Institute of Neurological Disorders and Stroke ( R. H. B., T. J. K.), the Harvard Business School Class of 2007, the Yamner family, Avichai Kremer, Guy Yamen, Nate Boaz, and Professor Robert S. Kaplan. London-based investigations were supported by the Motor Neurone Disease Association of Great Britain and Northern Ireland ( A. A.- C.), the Medical Research Council ( A. A.- C.), the Wellcome Trust ( P. N. L. and C. E. S.), and Psychiatry Research Trust ( Tim Perkins Fund) ( P. N. L., A. A.-. C., and C. E. S.). The investigations in France were supported by Assistance Publique, Hopitaux de Paris, Institut National de la Santeet de la Recherche Medicale, GIS-Institut des Maladies Rares and the Ministere de l'Enseignement Superieur et de la Recherche. V. S. was partially suported by a donation of the Peviani Family. We thank DNA banks maintained by the Coriell Institute ( with support from the National Institute of Neurological DisordersandStroke) andGenethon. This study used data from the SNP Database at the National Institute of Neurological Disorders and Stroke Human Genetics Resource CenterDNAand Cell Line Repository (http://ccr.coriell.org/ninds). Investigations in The Netherlands were supported by The Netherlands Organisation for Scientific Research, the "Prinses Beatrix Fonds,'' the Kersten Foundation, the Adessium Foundation, J. R. van Dijk and VSB Fonds ( L. H. v. d. B.). This work was supported by Howard Hughes Medical Institute ( P. S. and H. R. H.), the Packard Center for ALS Research ( J. D. G. and M. P.), The Muscular Dystrophy Association ( U. S.) ( S. C. and O. H.), and National Center for Research Resources Grant U54 RR020278-01 ( to The Broad Institute Center for Genotyping and Analysis). H. R. H. is Howard Hughes Medical Institute Investigator. NR 48 TC 92 Z9 93 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 JUN 2 PY 2009 VL 106 IS 22 BP 9004 EP 9009 DI 10.1073/pnas.0812937106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 452ZU UT WOS:000266580500042 PM 19451621 ER PT J AU Song, LK Sun, ZYJ Coleman, KE Zwick, MB Gach, JS Wang, JH Reinherz, EL Wagner, G Kim, M AF Song, Likai Sun, Zhen-Yu J. Coleman, Kate E. Zwick, Michael B. Gach, Johannes S. Wang, Jia-huai Reinherz, Ellis L. Wagner, Gerhard Kim, Mikyung TI Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE membrane-proximal ectodomain region; neutralizing antibody; vaccine design; AIDS; fusion ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; PROXIMAL EXTERNAL REGION; ENVELOPE GLYCOPROTEIN; MEDIATED FUSION; HIV-1 GP41; EPITOPE; 2F5; RECOGNITION; CONFORMATION AB A vaccine capable of stimulating protective antiviral antibody responses is needed to curtail the global AIDS epidemic caused by HIV-1. Although rarely elicited during the course of natural infection or upon conventional vaccination, the membrane-proximal ectodomain region (MPER) of the HIV-1 glycoprotein of M(r) 41,000 (gp41) envelope protein subunit is the target of 3 such human broadly neutralizing antibodies (BNAbs): 4E10, 2F5, and Z13e1. How these BNAbs bind to their lipid-embedded epitopes and mediate antiviral activity is unclear, but such information might offer important insight into a worldwide health imperative. Here, EPR and NMR techniques were used to define the manner in which these BNAbs differentially recognize viral membrane-encrypted residues configured within the L-shaped helix-hinge-helix MPER segment. Two distinct modes of antibody-mediated interference of viral infection were identified. 2F5, like 4E10, induces large conformational changes in the MPER relative to the membrane. However, although 4E10 straddles the hinge and extracts residues W672 and F673, 2F5 lifts up residues N-terminal to the hinge region, exposing L669 and W670. In contrast, Z13e1 effects little change in membrane orientation or conformation, but rather immobilizes the MPER hinge through extensive rigidifying surface contacts. Thus, BNAbs disrupt HIV-1MPERfusogenic functions critical for virus entry into human CD4 T cells and macrophages either by preventing hinge motion or by perturbing MPER orientation. HIV-1 MPER features important for targeted vaccine design have been revealed, the implications of which extend to BNAb targets on other viral fusion proteins. C1 [Song, Likai; Coleman, Kate E.; Reinherz, Ellis L.] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Song, Likai; Reinherz, Ellis L.; Kim, Mikyung] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Sun, Zhen-Yu J.; Wang, Jia-huai; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Mol Pharmacol & Biochem, Boston, MA 02115 USA. [Zwick, Michael B.; Gach, Johannes S.] Scripps Res Inst, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA. [Wang, Jia-huai; Reinherz, Ellis L.; Kim, Mikyung] Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Wang, Jia-huai; Reinherz, Ellis L.; Kim, Mikyung] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, Jia-huai] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu; mikyung_kim@dfci.harvard.edu OI Gach, Johannes/0000-0002-5043-5710 FU National Institutes of Health [AI43649, AI69993]; Austrian Science Fund [J2845-B13] FX We thank Drs. Barton Haynes (Duke University Human Vaccine Institute) and Munir S. Alam (Duke University Human Vaccine Institute) for providing 13H11 mAb and SP62 peptide, and Kyoung Joon Oh and Piotr G. Fajer for helpful discussions. This work was supported by National Institutes of Health Grants AI43649 (to E. L. R. and G. W.) and AI69993 (to M. B. Z.), as well as Austrian Science Fund Grant J2845-B13 (to J. S. G.). NR 40 TC 78 Z9 78 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 2 PY 2009 VL 106 IS 22 BP 9057 EP 9062 DI 10.1073/pnas.0901474106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 452ZU UT WOS:000266580500051 PM 19458040 ER PT J AU Caterino, JM Weed, SG Espinola, JA Camargo, CA AF Caterino, Jeffrey M. Weed, Sarah Grace Espinola, Janice A. Camargo, Carlos A., Jr. TI National Trends in Emergency Department Antibiotic Prescribing for Elders with Urinary Tract Infection, 1996-2005 SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Scientific Research Forum of the American-College-of-Emergency-Physicians CY OCT 24-28, 2008 CL Chicago, IL SP Amer Coll Emergency Phys DE urinary tract infection; aged; emergency department; antibiotic; elderly ID VENTILATOR-ASSOCIATED PNEUMONIA; INADEQUATE ANTIMICROBIAL TREATMENT; TERM-CARE FACILITY; ESCHERICHIA-COLI; PATIENT OUTCOMES; SEPTIC SHOCK; RISK-FACTORS; WOMEN; MANAGEMENT; THERAPY AB Given reported increases in antibiotic resistance among elders with urinary tract infection (UTI) and pyelonephritis, the authors identified national rates and trends in emergency department (ED) trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolone prescribing for older adults from 1996 to 2005. This was a retrospective analysis utilizing the ED component of the 1996-2005 National Hospital Ambulatory Medical Care Survey (NHAMCS). The authors included NHAMCS ED entries aged >= 18 years with a diagnosis of UTI or pyelonephritis; pregnancy was excluded. Records were divided into 18-64 years ("adults") and >= 65 years ("elders"). Primary outcome measures were prescription of TMP-SMX monotherapy, fluoroquinolone monotherapy, and combination therapy with two or more antibiotics. Estimated visit totals and rates were calculated and trends analyzed. From 1996 to 2005, there were 5 million elder ED visits for UTI or pyelonephritis. Approximately 9.4% (95% confidence interval [CI] = 7.9% to 11%) of elders received TMP-SMX monotherapy with rates decreasing over time (p-value for trend = 0.031). Overall, 35% (95% CI = 32% to 38%) of elders received fluoroquinolone monotherapy, which increased from 21% (95% CI = 14% to 27%) in 1996 to 45% (95% CI = 39% to 50%) in 2005 (p-value for trend < 0.001). Therapy with a fluoroquinolone plus a second antibiotic was used in only 4.2% (95% CI = 3.1% to 5.3%) of older patients. From 1996 to 2005, TMP-SMX monotherapy in elder ED patients decreased while fluoroquinolone therapy increased. The majority of older patients receiving fluoroquinolone therapy received a single agent. Given the continued prevalence of monotherapy for elder ED patients with UTI or pyelonephritis, antibiotic resistance patterns in these patients should be better characterized to ensure institution of appropriate empiric therapy. C1 [Caterino, Jeffrey M.] Ohio State Univ, Dept Emergency Med, Columbus, OH 43210 USA. [Caterino, Jeffrey M.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Weed, Sarah Grace] Duke Univ, Coll Med, Durham, NC USA. [Espinola, Janice A.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Caterino, JM (reprint author), Ohio State Univ, Dept Emergency Med, Columbus, OH 43210 USA. EM jeffrey.caterino@osumc.edu NR 42 TC 12 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD JUN PY 2009 VL 16 IS 6 BP 500 EP 507 DI 10.1111/j.1553-2712.2009.00353.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 453FB UT WOS:000266594600004 PM 19245373 ER PT J AU Grudzen, CR Timmermans, S Koenig, WJ Torres, JM Hoffman, JR Lorenz, KA Asch, SM AF Grudzen, Corita R. Timmermans, Stefan Koenig, William J. Torres, Jacqueline M. Hoffman, Jerome R. Lorenz, Karl A. Asch, Steven M. TI Paramedic and Emergency Medical Technicians Views on Opportunities and Challenges When Forgoing and Halting Resuscitation in the Field SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE resuscitation; ethics; emergency medical services; prehospital care; cardiac arrest ID CARDIAC-ARREST; QUALITY; DEATH AB The objective was to assess paramedic and emergency medical technicians (EMT) perspectives and decision-making after a policy change that allows forgoing or halting resuscitation in prehospital atraumatic cardiac arrest. Five semistructured focus groups were conducted with 34 paramedics and 2 EMTs from emergency medical services (EMS) agencies within Los Angeles County (LAC), 6 months after a policy change that allowed paramedics to forgo or halt resuscitation in the field under certain circumstances. Participants had an overwhelmingly positive view of the policy; felt it empowered their decision-making abilities; and thought the benefits to patients, family, EMS, and the public outweighed the risks. Except under certain circumstances, such as when the body was in public view or when family members did not appear emotionally prepared to have the body left on scene, they felt the policy improved care. Assuming that certain patient characteristics were present, decisions by paramedics about implementing the policy in the field involve many factors, including knowledge and comfort with the new policy, family characteristics (e.g., agreement), and logistics regarding the place of arrest (e.g., size of space). Paramedic and EMT experiences with and attitudes toward forgoing resuscitation, as well as group dynamics among EMS leadership, providers, police, and ED staff, also play a role. Participants view the ability to forgo or halt resuscitation in the field as empowering and do not believe it presents harm to patients or families under most circumstances. Factors other than patient clinical characteristics, such as knowledge and attitudes toward the policy, family emotional preparedness, and location of arrest, affect whether paramedics will implement it. C1 [Grudzen, Corita R.] Mt Sinai Sch Med, Dept Emergency Med, New York, NY 10029 USA. [Timmermans, Stefan] Univ Calif Los Angeles, Dept Sociol, Los Angeles, CA 90024 USA. [Koenig, William J.] Los Angeles Cty, Emergency Med Serv Agcy, Los Angeles, CA USA. [Torres, Jacqueline M.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Hoffman, Jerome R.] Univ Calif Los Angeles, Dept Emergency Med, Los Angeles, CA USA. [Lorenz, Karl A.] Vet Integrated Palliat Care Program, Los Angeles, CA USA. [Lorenz, Karl A.; Asch, Steven M.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Grudzen, Corita R.] Univ Calif Los Angeles, Robert Wood Johnson Clin Scholars Program, Los Angeles, CA USA. RP Grudzen, CR (reprint author), Mt Sinai Sch Med, Dept Emergency Med, New York, NY 10029 USA. EM corita.grudzen@mountsinai.org OI Grudzen, Corita/0000-0003-3039-8497 FU California Health Care Foundation [07-1155] FX This study was funded with a grant from the California Health Care Foundation, Grant 07-1155. NR 14 TC 9 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD JUN PY 2009 VL 16 IS 6 BP 532 EP 538 DI 10.1111/j.1553-2712.2009.00427.x PG 7 WC Emergency Medicine SC Emergency Medicine GA 453FB UT WOS:000266594600009 PM 19438412 ER PT J AU Lebedev, AY Cheprakov, AV Sakadzic, S Boas, DA Wilson, DF Vinogradov, SA AF Lebedev, Artem Y. Cheprakov, Andrei V. Sakadzic, Sava Boas, David A. Wilson, David F. Vinogradov, Sergei A. TI Dendritic Phosphorescent Probes for Oxygen Imaging in Biological Systems SO ACS APPLIED MATERIALS & INTERFACES LA English DT Review DE phosphorescence; oxygen; porphyrins; dendrimers; quenching; imaging ID ELECTRON-TRANSFER REACTIONS; NEAR-INFRARED PHOSPHORS; IN-VIVO; PHOTOPHYSICAL PROPERTIES; PEGYLATED DENDRIMERS; OPTICAL NANOSENSORS; MOLECULAR-OXYGEN; O-2 UPTAKE; PORPHYRINS; COMPLEXES AB Oxygen levels in biological systems can be measured by the phosphorescence quenching method using probes with controllable quenching parameters and defined biodistributions. We describe a general approach to the construction of phosphorescent nanosensors with tunable spectral characteristics, variable degrees of quenching, and a high selectivity for oxygen. The probes are based on bright phosphorescent Pt and Pd complexes of porphyrins and symmetrically pi-extended porphyrins (tetrabenzoporphyrins and tetranaphthoporphyrins). pi-Extension of the core macrocycle allows tuning of the spectral parameters of the probes in order to meet the requirements of a particular imaging application (e.g., oxygen tomography versus planar microscopic imaging). Metalloprophyrins are encapsulated into poly(arylglycine) dendrimers, which fold in aqueous environments and create diffusion barriers for oxygen, making it possible to regulate the sensitivity and the dynamic range of the method. The periphery of the dendrimers is modified with poly(ethylene glycol) residues, which enhance the probe's solubility, diminish toxicity, and help prevent interactions of the probes with the biological environment. The probe's parameters were measured under physiological conditions and shown to be unaffected by the presence of biomacromolecules. The performance of the probes was demonstrated in applications, including in vivo microscopy of vascular pO(2) in the rat brain. C1 [Lebedev, Artem Y.; Wilson, David F.; Vinogradov, Sergei A.] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. [Cheprakov, Andrei V.] Moscow MV Lomonosov State Univ, Dept Chem, Moscow, Russia. [Sakadzic, Sava; Boas, David A.] Harvard Univ, Sch Med, Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Vinogradov, SA (reprint author), Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. EM vinograd@mail.med.upenn.edu RI Cheprakov, Andrey/D-7255-2015; OI Cheprakov, Andrey/0000-0001-9589-4104; Wilson, David F/0000-0002-2626-5838; Lebedev, Artem/0000-0001-5366-9793 FU NHLBI NIH HHS [R01 HL081273-04, HL081273, R01 HL081273]; NIBIB NIH HHS [EB007279, R01 EB007279, R01 EB007279-03]; NINDS NIH HHS [NS031465, R01 NS031465, R01 NS031465-16] NR 100 TC 118 Z9 119 U1 4 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD JUN PY 2009 VL 1 IS 6 BP 1292 EP 1304 DI 10.1021/am9001698 PG 13 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 464NX UT WOS:000267513100024 PM 20072726 ER PT J AU De Witte, PB Wijffels, M Jupiter, JB Ring, D AF De Witte, Pieter Bas Wijffels, Mathieu Jupiter, Jesse B. Ring, David TI The Darrach procedure for post-traumatic reconstruction SO ACTA ORTHOPAEDICA BELGICA LA English DT Article DE distal ulna resection; Darrach ID DISTAL RADIOULNAR JOINT; SAUVE-KAPANDJI PROCEDURE; ULNAR IMPINGEMENT; FOLLOW-UP; RESECTION; HEMIRESECTION AB Over a 6-year-period, 15 women and It men with a mean age of 53 years (range, 24 to 80 years) had resection of the distal part of the ulna (Darrach's procedure) to address stiffness, instability, non-union, or substantial radioulnar length discrepancy after trauma. At an average follow-up of 21 months (range, 4 to 60 months), the improvement in total arc of forearm rotation averaged 87 degrees (range, 0 degrees to 160 degrees), from an average of 49 degrees to an average of 136 degrees (p < 0.001). The proportion of patients with occasional or continuous pain after the Darrach procedure (7 after vs. 16 prior; p = 0.04) was significantly reduced. Only two patients had reoperation related to the residual ulna. In this study, the Darrach procedure improved forearm rotation and pain in patients with posttraumatic stiffness, instability, nonunion, or substantial radio-ulnar length discrepancy with a low complication and re-operation rate. C1 [De Witte, Pieter Bas; Wijffels, Mathieu; Jupiter, Jesse B.; Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Dept Orthopaed Surg, Yawkey Ctr Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 28 TC 11 Z9 11 U1 0 U2 1 PU ACTA MEDICA BELGICA PI BRUSSELS PA AVENUE WINSTON CHURCHILL, WINSTON CHURCHILL-LAAN, 11 BOX 30, B-1180 BRUSSELS, BELGIUM SN 0001-6462 J9 ACTA ORTHOP BELG JI Acta Orthop. Belg. PD JUN PY 2009 VL 75 IS 3 BP 316 EP 322 PG 7 WC Orthopedics SC Orthopedics GA 465SV UT WOS:000267608600005 PM 19681316 ER PT J AU Henderson, DC Fan, X Sharma, B Copeland, PM Borba, CP Boxill, R Freudenreich, O Cather, C Evins, AE Goff, DC AF Henderson, D. C. Fan, X. Sharma, B. Copeland, P. M. Borba, C. P. Boxill, R. Freudenreich, O. Cather, C. Evins, A. Eden Goff, D. C. TI A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with Schizophrenia SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE clozapine; rosiglitazone; metabolic syndrome; lipids ID TYPE-2 DIABETES-MELLITUS; CORONARY-ARTERY-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; INSULIN-RESISTANCE SYNDROME; MINIMAL MODEL ANALYSIS; INTRAVENOUS GLUCOSE; WEIGHT-GAIN; PEROXISOME-PROLIFERATOR; BLOOD-PRESSURE; TOLERANCE TEST AB Henderson DC, Fan X, Sharma B, Copeland PM, Borba CP, Boxill R, Freudenreich O, Cather C, Eden Evins A, Goff DC. A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with Schizophrenia. The primary purpose of this 8-week double-blind, placebo-controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine-treated subjects with schizophrenia with insulin resistance. Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI. Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non-significant improvement in SG (0.016 +/- 0.006-0.018 +/- 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 +/- 2.8-7.8 +/- 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low-density lipoprotein cholesterol (LDL-C) particle number (987 +/- 443-694 +/- 415, effect size = 0.30, P = 0.04). Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine. C1 [Henderson, D. C.; Fan, X.; Sharma, B.; Borba, C. P.; Boxill, R.; Freudenreich, O.; Cather, C.; Evins, A. Eden; Goff, D. C.] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Henderson, D. C.; Fan, X.; Copeland, P. M.; Boxill, R.; Freudenreich, O.; Cather, C.; Evins, A. Eden; Goff, D. C.] Harvard Univ, Sch Med, Boston, MA USA. RP Henderson, DC (reprint author), Freedom Trail Clin, 25 Staniford St, Boston, MA USA. EM dchenderson@partners.org FU Stanley Foundation; National Institute of Health (NIH/NCRR) [5MO1RR01066-24]; NARSAD New Investigator Award FX This study was funded by Stanley Foundation, National Institute of Health (NIH/NCRR) Grant 5MO1RR01066-24 (General Clinical Research Center) and a NARSAD New Investigator Award (DCH). NR 63 TC 21 Z9 21 U1 3 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD JUN PY 2009 VL 119 IS 6 BP 457 EP 465 DI 10.1111/j.1600-0447.2008.01325.x PG 9 WC Psychiatry SC Psychiatry GA 447CR UT WOS:000266169700006 PM 19183127 ER PT J AU Watkins, LE O'Farrell, TJ Suvak, MK Murphy, CM Taft, CT AF Watkins, Laura E. O'Farrell, Timothy J. Suvak, Michael K. Murphy, Christopher M. Taft, Casey T. TI Parenting satisfaction among fathers with alcoholism SO ADDICTIVE BEHAVIORS LA English DT Article DE Parenting satisfaction; Alcohol use; Alcoholism AB This study examined parenting satisfaction among a clinical sample of 88 men with alcoholism at baseline and 6-month and 12-month follow-up. Findings indicated no overall improvements in parenting satisfaction from the outset of treatment across assessments. Alcohol consumption variables were associated with parenting satisfaction at the bivariate level, and changes in alcohol consumption from pre to post treatment emerged as a significant predictor of changes in parenting satisfaction over the course of the study. Greater decreases in alcohol consumption were associated with greater improvement in parenting satisfaction. (C) 2009 Elsevier Ltd. All rights reserved. C1 [O'Farrell, Timothy J.] Harvard Univ, Sch Med, Families & Addict Program, Dept Psychiat,VA Boston Healthcare Syst,VAMC, Brockton, MA 02301 USA. [Watkins, Laura E.; Suvak, Michael K.; Taft, Casey T.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Suvak, Michael K.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Taft, Casey T.] Boston Univ, Dept Psychiat, Sch Med, Boston, MA 02215 USA. [Murphy, Christopher M.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21250 USA. RP O'Farrell, TJ (reprint author), Harvard Univ, Sch Med, Families & Addict Program, Dept Psychiat,VA Boston Healthcare Syst,VAMC, 116B-1,940 Belmont St, Brockton, MA 02301 USA. EM timothy_ofarrell@hms.harvard.edu FU National Institute on Alcohol Abuse and Alcoholism [R01AA10796, K02AA00234]; Department of Veterans Affairs FX This research was supported by grants to Timothy O'Farrell from the National Institute on Alcohol Abuse and Alcoholism (R01AA10796 and K02AA00234) and by the Department of Veterans Affairs. NR 11 TC 1 Z9 1 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUN-JUL PY 2009 VL 34 IS 6-7 BP 610 EP 612 DI 10.1016/j.addbeh.2009.01.006 PG 3 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 455DU UT WOS:000266738400020 PM 19232833 ER PT J AU Lee, S Van Remmen, H Csete, M AF Lee, Sukkyoo Van Remmen, Holly Csete, Marie TI Sod2 overexpression preserves myoblast mitochondrial mass and function, but not muscle mass with aging SO AGING CELL LA English DT Article DE hydrogen peroxide; mitochondria; muscle aging; myoblast; PI3 kinase-Akt signaling; superoxide ID MANGANESE SUPEROXIDE-DISMUTASE; FOXO TRANSCRIPTION FACTORS; PROTEIN-KINASE B; DNA COPY NUMBER; SKELETAL-MUSCLE; SATELLITE-CELL; MUTANT MICE; DILATED CARDIOMYOPATHY; OXIDATIVE STRESS; COMPLEX I AB Mice lacking superoxide dismutase-2 (SOD2 or MnSOD) die during embryonic or early neonatal development, with diffuse superoxide-induced mitochondrial damage. Although stem and progenitor cells are exquisitely sensitive to oxidant stress, they have not been well studied in MnSOD2-manipulated mouse models. Patterns of proliferation and differentiation of cultured myoblasts (muscle progenitor cells), PI3-Akt signaling during differentiation, and the maintenance of mitochondrial mass with aging using myoblasts from young (3-4 week old) and aged (27-29 months old) MnSOD2-overexpressing (Sod2-Tg) and heterozygote (Sod2(+/-)) mice were characterized by us. Overexpression of MnSOD2 in myoblasts had a protective effect on mitochondrial DNA abundance and some aspects of mitochondrial function with aging, and preservation of differentiation potential. Sod2 deficiency resulted in defective signaling in the PI3-Akt pathway, specifically impaired phosphorylation of Akt at Ser473 and Thr308 in young myoblasts, and decreased differentiation potential. Compared with young myoblasts, aged myoblast Akt was constitutively phosphorylated, unresponsive to mitogen signaling, and indifferent to MnSOD2 levels. These data suggest that specific sites in the PI3K-Akt pathway are more sensitive to increased superoxide levels than to the increased hydrogen peroxide levels generated in Sod2-transgenic myoblasts. In wild-type myoblasts, aging was associated with significant loss of mitochondrial DNA relative to chromosomal DNA, but MnSOD2 overexpression was associated with maintained myoblast mitochondrial DNA with aging. C1 [Lee, Sukkyoo; Csete, Marie] Emory Univ, Sch Med, Dept Anesthesiol, Atlanta, GA 30322 USA. [Lee, Sukkyoo; Csete, Marie] Emory Univ, Sch Med, Program Biochem Cell & Dev Biol, Atlanta, GA 30322 USA. [Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Van Remmen, Holly] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Csete, M (reprint author), Calif Inst Regenerat Med, 210 King St, San Francisco, CA 94107 USA. EM mcsete@cirm.ca.gov FU Emory Anesthesiology; [PO1 NIA 1-386003609] FX The authors thank Dr Charles Epstein for supplying mice for these studies. The authors acknowledge Drs Russ Price (Emory), David Lambeth (Emory), Tom Burkholder (GaTech) and Karl Saxe (American Cancer Society) for helpful discussions. This work was supported by PO1 NIA 1-386003609 (MC, HVR), and Emory Anesthesiology. NR 63 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD JUN PY 2009 VL 8 IS 3 BP 296 EP 310 DI 10.1111/j.1474-9726.2009.00477.x PG 15 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 450RE UT WOS:000266417700009 PM 19627269 ER PT J AU Gardner, EM Burman, WJ Steiner, JF Anderson, PL Bangsberg, DR AF Gardner, Edward M. Burman, William J. Steiner, John F. Anderson, Peter L. Bangsberg, David R. TI Antiretroviral medication adherence and the development of class-specific antiretroviral resistance SO AIDS LA English DT Editorial Material DE adherence; antiretroviral resistance; antiretroviral therapy; genetic barrier to resistance; HIV; potency; replication capacity ID HIV DRUG-RESISTANCE; REVERSE-TRANSCRIPTASE INHIBITORS; IMMUNODEFICIENCY-VIRUS TYPE-1; TREATMENT-NAIVE PATIENTS; VIROLOGICAL FAILURE; VIRAL LOAD; COMBINATION THERAPY; PROTEASE INHIBITORS; INITIAL TREATMENT; INFECTED PATIENTS AB Objective: To assess the association between antiretroviral adherence and the development of class-specific antiretroviral medication resistance. Design and methods: Literature and conference abstract review of studies assessing the association between adherence to antiretroviral therapy and the development of antiretroviral medication resistance. Results: Factors that determine class-specific adherence-resistance relationships include antiretroviral regimen potency, viral fitness or, more specifically, the interplay between the fold-change in resistance and fold-change in fitness caused by drug resistance mutations, and the genetic barrier to antiretroviral resistance. During multidrug therapy, differential drug exposure increases the likelihood of developing resistance. In addition, antiretroviral medications with higher potency and higher genetic barriers to resistance decrease the incidence of resistance for companion antiretroviral medications at all adherence levels. Conclusion: Knowledge of class-specific adherence-resistance relationships may help clinicians and patients tailor therapy to match individual patterns of adherence in order to minimize the development of resistance at failure. In addition, this information may guide the selection of optimal drug combinations and regimen sequences to improve the durability of antiretroviral therapy. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Gardner, Edward M.; Burman, William J.] Denver Publ Hlth, Denver, CO 80204 USA. [Gardner, Edward M.; Burman, William J.] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Anderson, Peter L.] Univ Colorado Denver, Dept Pharmaceut Sci, Aurora, CO USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Initiat Global Hlth, Boston, MA USA. RP Gardner, EM (reprint author), Denver Publ Hlth, 605 Bannock St, Denver, CO 80204 USA. EM edward.m.gardner@dhha.org FU NIAID NIH HHS [K01 AI067063, K01 AI067063-05, R01 AI 64029, R01 AI064029]; NIMH NIH HHS [R01 MH054907]; PHS HHS [NIAAA 015287, NIMH 54907] NR 57 TC 70 Z9 72 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 1 PY 2009 VL 23 IS 9 BP 1035 EP 1046 DI 10.1097/QAD.0b013e32832ba8ec PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 452VN UT WOS:000266569400001 PM 19381075 ER PT J AU Gonzalez, JS Hendriksen, ES Collins, EM Duran, RE Safren, SA AF Gonzalez, Jeffrey S. Hendriksen, Ellen Setsuko Collins, Erin Marie Duran, Ron E. Safren, Steven A. TI Latinos and HIV/AIDS: Examining Factors Related to Disparity and Identifying Opportunities for Psychosocial Intervention Research SO AIDS AND BEHAVIOR LA English DT Review DE HIV/AIDS; Latino/Hispanic; Treatment adherence; Mental health; Substance abuse; Disparities ID HUMAN-IMMUNODEFICIENCY-VIRUS; BEHAVIORAL STRESS-MANAGEMENT; SELF-REPORTED ADHERENCE; ILLICIT DRUG-USE; ACTIVE ANTIRETROVIRAL THERAPY; HIV-SEROPOSITIVE WOMEN; PRIMARY-CARE PATIENTS; QUALITY-OF-LIFE; HEALTH LITERACY; SOCIAL SUPPORT AB Latinos maintain an AIDS case rate more than 3 times higher than whites, a greater rate of progression to AIDS, and a higher rate of HIV/AIDS-related deaths. Three broad areas are reviewed related to these disparities: (1) relevant demographic, socioeconomic, and socio-cultural factors among Latinos; (2) drug abuse and mental health problems in Latinos relevant to HIV/AIDS outcomes; and (3) opportunities for psychosocial intervention. Latinos living with HIV are a rapidly growing group, are more severely impacted by HIV than whites, and confront unique challenges in coping with HIV/AIDS. A body of research suggests that depression, substance abuse, treatment adherence, health literacy, and access to healthcare may be fruitful targets for intervention research in this population. Though limited, the current literature suggests that psychosocial interventions that target these factors could help reduce HIV/AIDS disparities between Latinos and whites and could have important public health value. C1 [Gonzalez, Jeffrey S.; Hendriksen, Ellen Setsuko; Collins, Erin Marie; Safren, Steven A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gonzalez, Jeffrey S.; Hendriksen, Ellen Setsuko; Safren, Steven A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Duran, Ron E.] Alliant Int Univ, Dept Psychol, Los Angeles, CA USA. RP Gonzalez, JS (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,ACC 812, Boston, MA 02114 USA. EM jsgonzalez@partners.org FU NIDA NIH HHS [R01DA018603, R01 DA018603] NR 149 TC 32 Z9 32 U1 9 U2 20 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD JUN PY 2009 VL 13 IS 3 BP 582 EP 602 DI 10.1007/s10461-008-9402-4 PG 21 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 449NI UT WOS:000266336900021 PM 18498050 ER PT J AU Byakika-Tusiime, J Crane, J Oyugi, JH Ragland, K Kawuma, A Musoke, P Bangsberg, DR AF Byakika-Tusiime, Jayne Crane, Johanna Oyugi, Jessica H. Ragland, Kathleen Kawuma, Annet Musoke, Philippa Bangsberg, David R. TI Longitudinal Antiretroviral Adherence in HIV plus Ugandan Parents and Their Children Initiating HAART in the MTCT-Plus Family Treatment Model: Role of Depression in Declining Adherence Over Time SO AIDS AND BEHAVIOR LA English DT Article; Proceedings Paper CT Conference on Switching Gears in HIV Research CY APR 21-23, 2008 CL Soweto, SOUTH AFRICA DE Uganda; Adherence; Antiretroviral therapy; Household; MTCT-Plus ID FIXED-DOSE COMBINATION; HIV-1-INFECTED ADULTS; POSITIVE INDIVIDUALS; SOUTHWEST ETHIOPIA; THERAPY; NEVIRAPINE; BARRIERS; AFRICA; DETERMINANTS; FACILITATORS AB We conducted a study to assess the effect of family-based treatment on adherence amongst HIV-infected parents and their HIV-infected children attending the Mother-To-Child-Transmission Plus program in Kampala, Uganda. Adherence was assessed using home-based pill counts and self-report. Mean adherence was over 94%. Depression was associated with incomplete adherence on multivariable analysis. Adherence declined over time. Qualitative interviews revealed lack of transportation money, stigma, clinical response to therapy, drug packaging, and cost of therapy may impact adherence. Our results indicate that providing ART to all eligible HIV-infected members in a household is associated with excellent adherence in both parents and children. Adherence to ART among new parents declines over time, even when patients receive treatment at no cost. Depression should be addressed as a potential barrier to adherence. Further study is necessary to assess the long-term impact of this family treatment model on adherence to ART in resource-limited settings. C1 [Byakika-Tusiime, Jayne] Univ Calif Berkeley, Sch Publ Hlth, Dept Epidemiol, Berkeley, CA 94720 USA. [Crane, Johanna] Cornell Univ, Dept Sci & Technol Studies, Ithaca, NY USA. [Oyugi, Jessica H.] Infect Dis Inst, Kampala, Uganda. [Ragland, Kathleen] Univ Calif San Francisco, San Francisco Gen Hosp, Epidemiol & Prevent Intervent Ctr, Div Infect Dis, San Francisco, CA USA. [Kawuma, Annet] Mbarara Univ Sci & Technol, Dept Community Hlth, Mbarara, Uganda. [Musoke, Philippa] Makerere Univ, Dept Pediat & Child Hlth, Kampala, Uganda. [Musoke, Philippa] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Initiat Global Hlth, Boston, MA USA. RP Byakika-Tusiime, J (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Dept Epidemiol, Berkeley, CA 94720 USA. EM tusiimej@berkeley.edu FU FIC NIH HHS [1D43 TW00003]; NIAAA NIH HHS [K24 AA015287, R21 AA015897]; NIMH NIH HHS [K24 MH087227, R0-1 MH54907, R01 MH054907] NR 53 TC 71 Z9 71 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD JUN PY 2009 VL 13 BP S82 EP S91 DI 10.1007/s10461-009-9546-x PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 473CG UT WOS:000268181900012 PM 19301113 ER PT J AU Kaida, A Lima, VD Andia, I Kabakyenga, J Mbabazi, P Emenyonu, N Patterson, TL Hogg, RS Bangsberg, DR AF Kaida, Angela Lima, Viviane Dias Andia, Irene Kabakyenga, Jerome Mbabazi, Pamela Emenyonu, Nneka Patterson, Thomas L. Hogg, Robert S. Bangsberg, David R. TI The WHOMEN's Scale (Women's HAART Optimism Monitoring and EvaluatioN Scale v.1) and the Association with Fertility Intentions and Sexual Behaviours Among HIV-Positive Women in Uganda SO AIDS AND BEHAVIOR LA English DT Article; Proceedings Paper CT Conference on Switching Gears in HIV Research CY APR 21-23, 2008 CL Soweto, SOUTH AFRICA DE HIV; HAART; Uganda; Scale; HAART optimism; Women; Fertility intentions; Sexual behaviour; HAART optimism scale ID ACTIVE ANTIRETROVIRAL THERAPY; RISK BEHAVIOR; COMBINATION THERAPIES; BISEXUAL MEN; GAY MEN; PREVENTION; MORTALITY; MORBIDITY; SURVIVAL; CONTEXT AB The objective of this study was to develop a reliable HAART optimism scale among HIV-positive women in Uganda and to test the scale's validity against measures of fertility intentions, sexual activity, and unprotected sexual intercourse. We used cross-sectional survey data of 540 women (18-50 years) attending Mbarara University's HIV clinic in Uganda. Women were asked how much they agreed or disagreed with 23 statements about HAART. Data were subjected to a principal components and factor analyses. Subsequently, we tested the association between the scale and fertility intentions and sexual behaviour using Wilcoxon rank sum test. Factor analysis yielded three factors, one of which was an eight-item HAART optimism scale with moderately high internal consistency (alpha = 0.70). Women who reported that they intended to have (more) children had significantly higher HAART optimism scores (median = 13.5 [IQR: 12-16]) than women who did not intend to have (more) children (median = 10.5 [IQR: 8-12]; P < 0.0001). Similarly, women who were sexually active and who reported practicing unprotected sexual intercourse had significantly higher HAART optimism scores than women who were sexually abstinent or who practiced protected sexual intercourse. Our reliable and valid scale, termed the Women's HAART Optimism Monitoring and EvaluatioN scale (WHOMEN's scale), may be valuable to broader studies investigating the role of HAART optimism on reproductive intentions and sexual behaviours of HIV-positive women in high HIV prevalence settings. C1 [Kaida, Angela; Lima, Viviane Dias; Hogg, Robert S.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Kaida, Angela] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Andia, Irene; Kabakyenga, Jerome; Mbabazi, Pamela] MUST, Mbarara, Uganda. [Emenyonu, Nneka] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Patterson, Thomas L.] Univ Calif San Diego, San Diego, CA 92103 USA. [Hogg, Robert S.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Kaida, A (reprint author), BC Ctr Excellence HIV AIDS, 608-1081 Burrard St, Vancouver, BC, Canada. EM akaida@interchange.ubc.ca RI Hogg, Robert/B-2783-2012; OI Hogg, Robert/0000-0003-3463-5488 FU NIMH NIH HHS [R01 MH054907]; PHS HHS [NIAAA 015287, NIMH 54907] NR 46 TC 10 Z9 10 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD JUN PY 2009 VL 13 BP S72 EP S81 DI 10.1007/s10461-009-9553-y PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 473CG UT WOS:000268181900011 PM 19387819 ER PT J AU Kaida, A Bangsberg, DR Gray, G Hogg, RS King, R Miller, CL AF Kaida, Angela Bangsberg, David R. Gray, Glenda Hogg, Robert S. King, Rachel Miller, Cari L. TI Editorial: Introduction to the Supplement on HIV, HAART, and Fertility in sub-Saharan Africa SO AIDS AND BEHAVIOR LA English DT Editorial Material C1 [Kaida, Angela; Hogg, Robert S.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Kaida, Angela] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Gray, Glenda] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Hogg, Robert S.; Miller, Cari L.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [King, Rachel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [King, Rachel] Karolinska Inst, Stockholm, Sweden. RP Kaida, A (reprint author), BC Ctr Excellence HIV AIDS, 608-1081 Burrard St, Vancouver, BC, Canada. EM akaida@interchange.ubc.ca RI Hogg, Robert/B-2783-2012; OI Hogg, Robert/0000-0003-3463-5488 FU NIMH NIH HHS [K24 MH087227, R01 MH054907] NR 3 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD JUN PY 2009 VL 13 BP S1 EP S4 DI 10.1007/s10461-009-9568-4 PG 4 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 473CG UT WOS:000268181900001 PM 19434488 ER PT J AU Crothers, K Goulet, JL Rodriguez-Barradas, MC Gibert, CL Oursler, KAK Goetz, MB Crystal, S Leaf, DA Butt, AA Braithwaite, RS Peck, R Justice, AC AF Crothers, Kristina Goulet, Joseph L. Rodriguez-Barradas, Maria C. Gibert, Cynthia L. Oursler, Kris Ann K. Goetz, Matthew Bidwell Crystal, Stephen Leaf, David A. Butt, Adeel A. Braithwaite, R. Scott Peck, Robin Justice, Amy C. TI IMPACT OF CIGARETTE SMOKING ON MORTALITY IN HIV-POSITIVE AND HIV-NEGATIVE VETERANS SO AIDS EDUCATION AND PREVENTION LA English DT Article; Proceedings Paper CT Workshop on Current Issues in Cigarette Smoking and HIV/AIDS CY OCT 08, 2007 CL Bethesda, MD SP Natl Inst Hlth ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTH-CARE-SYSTEM; QUALITY-OF-LIFE; BACTERIAL PNEUMONIA; RANDOMIZED-TRIAL; ALCOHOL-USE; INFECTION; CESSATION; OUTCOMES; DISEASE AB It is unknown whether smoking confers similar mortality risk in HIV-positive as in HIV-negative patients. We compared overall mortality stratified by HIV and smoking of 1,034 HIV-positive block-matched to 739 HIV-negative veterans, enrolled 2001-2002 in the Veterans Aging Cohort 5 Site Study. Adjusted incidence rate ratios (IRR) for mortality were calculated using Poisson regression. Mortality was significantly increased in HIV-positive veterans according to both smoking status and pack-years in unadjusted and adjusted analyses (adjusted IRR 2.31, 95% confidence interval [CI] 1.53-3.49 for HIV-positive current smokers and IRR 1.32, 95% CI 0.67-2.61 for HIV-negative current smokers). Comorbid diseases were also significantly increased according to smoking status and pack-years. Current smoking is associated with poor outcomes; even lower levels of exposure appear to be detrimental in HIV-infected veterans. These findings support the need for improvements in smoking cessation and for studies of mechanisms and diseases underlying increased mortality in smokers with HIV. C1 [Crothers, Kristina; Goulet, Joseph L.; Rodriguez-Barradas, Maria C.; Justice, Amy C.] VA Connecticut Healthcare Syst, Dept Internal Med, New Haven, CT USA. [Crothers, Kristina; Goulet, Joseph L.; Rodriguez-Barradas, Maria C.; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Med Serv, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Gibert, Cynthia L.; Peck, Robin] George Washington Univ, Dept Med, Washington, DC USA. [Gibert, Cynthia L.; Peck, Robin] VA Med Ctr, Washington, DC USA. [Oursler, Kris Ann K.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Oursler, Kris Ann K.] Baltimore VA Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD USA. [Goetz, Matthew Bidwell; Leaf, David A.] VA Greater Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Goetz, Matthew Bidwell; Leaf, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Crystal, Stephen] Rutgers State Univ, Ctr Pharmacotherapy Chron Dis Management & Outcom, New Brunswick, NJ 08903 USA. [Crystal, Stephen] Rutgers State Univ, Inst Hlth, New Brunswick, NJ 08903 USA. [Crystal, Stephen] Rutgers State Univ, Sch Social Work, New Brunswick, NJ 08903 USA. [Butt, Adeel A.] VA Pittsburgh Healthcare Syst, Dept Internal Med, Pittsburgh, PA USA. [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Crothers, K (reprint author), VA Connecticut Healthcare Syst, 950 Campbell Ave,11 ACSLG, West Haven, CT 06516 USA. EM kristina.crothers@yale.edu OI Goetz, Matthew/0000-0003-4542-992X; Goulet, Joseph/0000-0002-0842-804X; Crothers, Kristina/0000-0001-9702-0371 FU AHRQ HHS [U18 HS016097, U18-HS016097]; NCRR NIH HHS [1KL2 RR024138, KL2 RR024138]; NHLBI NIH HHS [1R01 HL090342, R01 HL090342]; NIAAA NIH HHS [3U01AA13566, U01 AA013566, U10 AA013566, U10 AA013566-08]; NIMH NIH HHS [MH058984, R01 MH058984] NR 37 TC 53 Z9 54 U1 0 U2 1 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0899-9546 J9 AIDS EDUC PREV JI Aids Educ. Prev. PD JUN PY 2009 VL 21 IS 3 BP 40 EP 53 PG 14 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 456XT UT WOS:000266888500005 PM 19537953 ER PT J AU Applebaum, AJ Reilly, LC Gonzalez, JS Richardson, MA Leveroni, CL Safren, SA AF Applebaum, Allison J. Reilly, Laura C. Gonzalez, Jeffrey S. Richardson, Mark A. Leveroni, Catherine L. Safren, Steven A. TI The Impact of Neuropsychological Functioning on Adherence to HAART in HIV-Infected Substance Abuse Patients SO AIDS PATIENT CARE AND STDS LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; METHADONE-MAINTENANCE PATIENTS; PSYCHOMOTOR SPEED PERFORMANCE; INJECTING DRUG-USERS; COGNITIVE IMPAIRMENT; NEUROCOGNITIVE IMPAIRMENT; MEDICATION ADHERENCE; VIRAL LOAD; PREDICTORS; ADULTS AB This study assessed the frequency of neuropsychological impairment and its relationship to adherence in a sample of HIV-infected injection drug users (IDUs) in treatment. One hundred eight participants recruited between September 2006 and October 2008 completed psychodiagnostic and neuropsychological assessments and monitored HAART adherence over a 2-week period via the use of Medication Event Monitoring System (MEMS) electronic pill caps and self-report. Assessment of concurrent functioning included clinician-rated scales of depression and substance use severity, and a battery of neuropsychological tests. Findings from individual neuropsychological tests were converted to Z scores relative to standard norms and averaged to form a composite score (NPZ). NPZ was generally poor (mean = -1.505, standard deviation = 1.120), with 76.9% of the sample being classified as highly impaired. Self-reported adherence was significantly higher than MEMS cap adherence. In contrast with previous studies, overall neuropsychological functioning was not a significant predictor of electronically monitored or self-reported adherence. However, examiner-rated current global severity of substance use and delayed word list recall emerged as significant predictors of self-reported adherence. Additionally, estimated premorbid verbal intelligence emerged as a significant predictor of the discrepancy between electronically monitored and self-reported adherence. Given the extent of neuropsychological impairment in this sample, future studies should examine the degree to which the impact of neuropsychological impairment may moderate interventions for this population, and the extent to which skills to cope with neuropsychological problems may boost the potential efficacy of such interventions. C1 [Applebaum, Allison J.; Reilly, Laura C.; Gonzalez, Jeffrey S.; Leveroni, Catherine L.; Safren, Steven A.] Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. [Applebaum, Allison J.; Richardson, Mark A.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Richardson, Mark A.] Boston Univ, Sch Med, Div Psychiat, Boston, MA 02215 USA. [Gonzalez, Jeffrey S.; Leveroni, Catherine L.; Safren, Steven A.] Harvard Univ, Sch Med, Boston, MA USA. [Gonzalez, Jeffrey S.] Yeshiva Univ, Bronx, NY USA. RP Safren, SA (reprint author), Massachusetts Gen Hosp, Behav Med Serv, 1 Bowdoin Sq,BS07-B, Boston, MA 02114 USA. EM ssafren@partners.org OI Richardson, Mark/0000-0003-4730-3431 FU National Institute of Drug Abuse [DA018603-03] FX This project was funded by grant number DA018603-03 from the National Institute of Drug Abuse to Dr. Steven Safren. NR 72 TC 16 Z9 17 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD JUN PY 2009 VL 23 IS 6 BP 455 EP 462 DI 10.1089/apc.2008.0181 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 457GB UT WOS:000266915400008 PM 19519229 ER PT J AU Denmark, DL Buck, KJ AF Denmark, D. L. Buck, K. J. TI A POSSIBLE ROLE FOR THE MITOCHONDRIAL RESPIRATORY CHAIN IN GENETIC VULNERABILITY TO SEVERE ALCOHOL WITHDRAWAL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Portland Alcohol Res Ctr, Portland, OR 97239 USA. Portland VA Med Ctr, Portland, OR 97239 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 18A EP 18A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100030 ER PT J AU Hashimoto, JG Forquer, MR Wiren, KM AF Hashimoto, J. G. Forquer, M. R. Wiren, K. M. TI SEXUALLY DIMORPHIC HORMONE PROFILES AFTER CHRONIC ALCOHOL EXPOSURE IN WSP AND WSR MICE: TESTOSTERONE LEVELS DROP IN MALES BUT INCREASE IN FEMALES SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 Portland VA Med Ctr, Res Serv, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Portland, OR 97239 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 32A EP 32A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100086 ER PT J AU Kelly, JF Stout, RL Tonigan, JS Magill, M AF Kelly, J. F. Stout, R. L. Tonigan, J. S. Magill, M. TI NEGATIVE AFFECT, RELAPSE, AND ALCOHOLICS ANONYMOUS: DOES AA WORK BY REDUCING DEPRESSIVE SYMPTOMS? SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Kelly, J. F.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Kelly, J. F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tonigan, J. S.] Univ New Mexico, Albuquerque, NM 87131 USA. [Magill, M.] Brown Univ, Sch Med, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 47A EP 47A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100147 ER PT J AU Kelly, JF Magill, M Stout, RL AF Kelly, J. F. Magill, M. Stout, R. L. TI HOW DO PEOPLE RECOVER FROM ALCOHOL DEPENDENCE? A SYSTEMATIC REVIEW OF THE RESEARCH ON MECHANISMS OF BEHAVIOR CHANGE IN ALCOHOLICS ANONYMOUS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Kelly, J. F.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Kelly, J. F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Magill, M.] Brown Univ, Sch Med, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 48A EP 48A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100150 ER PT J AU Hawkins, EH Malte, CA Baer, JS Kivlahan, DR AF Hawkins, E. H. Malte, C. A. Baer, J. S. Kivlahan, D. R. TI PREVALENCE AND CHARACTERISTICS OF PATIENTS WITH MULTIPLE ALCOHOL USE DISORDER TREATMENT EPISODES SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Hawkins, E. H.; Malte, C. A.; Baer, J. S.; Kivlahan, D. R.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 57A EP 57A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100188 ER PT J AU Gazdzinski, S Mon, A Durazzo, TC Meyerhoff, DJ AF Gazdzinski, S. Mon, A. Durazzo, T. C. Meyerhoff, D. J. TI ELEVATED BODY MASS INDEX IS ASSOCIATED WITH BRAIN INJURY IN ALCOHOL DEPENDENCE - A MAGNETIC RESONANCE STUDY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 Univ Calif San Francisco, San Francisco VA Med Ctr, CIND, San Francisco, CA 94121 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 90A EP 90A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100321 ER PT J AU Batki, SL Dimmock, JA Ploutz-Snyder, R Meszaros, ZS Canfield, K AF Batki, S. L. Dimmock, J. A. Ploutz-Snyder, R. Meszaros, Z. S. Canfield, K. TI DIRECTLY MONITORED NALTREXONE REDUCES HEAVY DRINKING IN SCHIZOPHRENIA: PRELIMINARY ANALYSIS OF A CONTROLLED TRIAL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 UCSF, Dept Psychiat, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA 94121 USA. SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 113A EP 113A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100412 ER PT J AU Hahn, JA Dobkin, LM Mayanja, B Emenyonu, N Kigozi, IM Bangsberg, DR Weinmann, W Yegles, M Wurst, FM AF Hahn, Judith A. Dobkin, Loren M. Mayanja, Bernard Emenyonu, Nneka Kigozi, Isaac M. Bangsberg, David R. Weinmann, Wolfgang Yegles, Michel Wurst, Friedrich M. TI VALIDATION OF DIRECT METABOLITES OF ALCOHOL CONSUMPTION IN HIV POSITIVES IN UGANDA SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Emenyonu, Nneka; Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weinmann, Wolfgang] Univ Hosp Freiburg, Freiburg, Germany. [Yegles, Michel] Univ Luxembourg, Luxembourg, Luxembourg. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 126A EP 126A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100462 ER PT J AU Kelly, JF Dow, SJ AF Kelly, J. F. Dow, S. J. TI STIGMA IN ADDICTION: DOES IT MATTER HOW WE REFER TO INDIVIDUALS WITH SUBSTANCE-RELATED CONDITIONS? SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Kelly, J. F.; Dow, S. J.] Massachusetts Gen Hosp, Ctr Addict Med, Boston, MA 02114 USA. [Kelly, J. F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 129A EP 129A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100475 ER PT J AU Milner, LC Giardino, W Buck, KJ AF Milner, L. C. Giardino, W. Buck, K. J. TI DEVELOPMENT OF A NOVEL MURINE BEHAVIORAL BATTERY: EFFECTS OF ETHANOL WITHDRAWAL AND KCNJ9 ALLELIC STATUS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 Portland VA Med Ctr, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Portland Alcohol Res Ctr, Dept Behav Neurosci, Portland, OR 97239 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 141A EP 141A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100525 ER PT J AU Rasmussen, DD Federoff, D Froehlich, JC AF Rasmussen, D. D. Federoff, D. Froehlich, J. C. TI PRAZOSIN REDUCES ALCOHOL DRINKING IN AN ANIMAL MODEL OF ALCOHOL RELAPSE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Rasmussen, D. D.] VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Rasmussen, D. D.] Univ Washington, Seattle, WA 98195 USA. [Federoff, D.; Froehlich, J. C.] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. NR 0 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 146A EP 146A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100543 ER PT J AU Dou, X Menkari, CE Charness, ME AF Dou, X. Menkari, C. E. Charness, M. E. TI ALCOHOL BINDING SITES ON L1 REGULATE L1-MEDIATED CELL ADHESION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Dou, X.; Menkari, C. E.; Charness, M. E.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. NR 0 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 165A EP 165A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100621 ER PT J AU Pedrelli, P Shyu, I Kelly, J Farabaugh, A Fava, M AF Pedrelli, P. Shyu, I. Kelly, J. Farabaugh, A. Fava, M. TI GENDER, DEPRESSIVE SYMPTOMS AND ALCOHOL CONSUMPTION AMONG COLLEGE STUDENTS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Pedrelli, P.; Shyu, I.; Kelly, J.; Farabaugh, A.; Fava, M.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 184A EP 184A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100694 ER PT J AU Mckay, JR Lynch, KG Van Horn, D Ivey, M Oslin, D Drapkin, M AF McKay, J. R. Lynch, K. G. Van Horn, D. Ivey, M. Oslin, D. Drapkin, M. TI EFFECTIVENESS OF EXTENDED TELEPHONE CONTINUING CARE: 18 MONTH OUTCOMES SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NR 0 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 197A EP 197A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100747 ER PT J AU Leite-Morris, KA Kerestes, HB Colombo, G AF Leite-Morris, K. A. Kerestes, H. B. Colombo, G. TI INTRA-VENTRAL TEGMENTAL AREA INJECTION OF THE GABA B RECEPTOR POSITIVE ALLOSTERIC MODULATOR GS39783 INHIBITS ETHANOL SEEKING BEHAVIOR IN RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 Boston Univ, Sch Med & Res Serv, Boston VA Healthcare Syst, Div Psychiat, Boston, MA 02130 USA. Boston Univ, Sch Med & Res Serv, Boston VA Healthcare Syst, Dept Pharmacol & Expt Therapeut, Boston, MA 02130 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 226A EP 226A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100863 ER PT J AU Durazzo, TC Pathik, V Gazdzinski, S Mon, A Meyerhoff, DJ AF Durazzo, T. C. Pathik, V. Gazdzinski, S. Mon, A. Meyerhoff, D. J. TI METABOLITE LEVELS IN THE BRAIN REWARD PATHWAY AT TREATMENT ENTRY DIFFERENTIATE FUTURE ABSTAINERS AND RELAPERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Durazzo, T. C.; Pathik, V.; Gazdzinski, S.; Mon, A.; Meyerhoff, D. J.] Univ Calif San Francisco, San Francisco VA Med Ctr, Ctr Neuroimaging Neurodegenerat Dis, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 231A EP 231A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335100883 ER PT J AU Kelly, JF Stout, RL Tonigan, S Magill, M Pagano, ME AF Kelly, John F. Stout, Robert L. Tonigan, Scott Magill, Molly Pagano, Maria E. TI DOES AA WORK BY REDUCING ANGER? SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Kelly, John F.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Tonigan, Scott] Univ New Mexico, Albuquerque, NM 87131 USA. [Magill, Molly] Brown Univ, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 302A EP 302A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335101160 ER PT J AU Raskind, MA AF Raskind, M. A. TI SUSTAINED RECOVERY FROM CHRONIC ALCOHOL DEPENDENCE WITH PRAZOSIN TREATMENT OF PTSD SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Raskind, M. A.] Univ Washington, Mental Hlth Serv, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Raskind, M. A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA. NR 0 TC 2 Z9 2 U1 3 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 311A EP 311A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335101195 ER PT J AU Walker, B Rasmussen, D Raskind, M Koob, G AF Walker, B. Rasmussen, D. Raskind, M. Koob, G. TI THE EFFECT OF ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISM ON EXCESSIVE ALCOHOL SELF-ADMINISTRATION DURING ACUTE WITHDRAWAL IN DEPENDENT SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Walker, B.] Washington State Univ, Pullman, WA 99164 USA. [Rasmussen, D.; Raskind, M.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Rasmussen, D.; Raskind, M.] Univ Washington, Seattle, WA 98195 USA. [Koob, G.] Scripps Res Inst, La Jolla, CA 92037 USA. RI koob, george/P-8791-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 311A EP 311A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335101196 ER PT J AU Rasmussen, DD Federoff, D Froehlich, JC AF Rasmussen, D. D. Federoff, D. Froehlich, J. C. TI PRAZOSIN REDUCES VOLUNTARY ALCOHOL DRINKING IN BOTH NON-DEPRIVED AND ALCOHOL-DEPRIVED RATS SELECTIVELY BRED FOR ALCOHOL PREFERENCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Rasmussen, D. D.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Federoff, D.; Froehlich, J. C.] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. NR 0 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 312A EP 312A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335101197 ER PT J AU Simpson, TL Saxon, AJ Meredith, CW Malte, CA McBride, B Ferguson, LC Gross, CA Hart, KL Raskind, M AF Simpson, T. L. Saxon, A. J. Meredith, C. W. Malte, C. A. McBride, B. Ferguson, L. C. Gross, C. A. Hart, K. L. Raskind, M. TI A PILOT TRIAL OF THE ALPHA-1 ADRENERGIC ANTAGONIST, PRAZOSIN, FOR ALCOHOL DEPENDENCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2009 CL San Diego, CA SP Res Soc Alcoholism C1 [Simpson, T. L.; Saxon, A. J.; Meredith, C. W.; Malte, C. A.; McBride, B.; Ferguson, L. C.; Gross, C. A.; Hart, K. L.; Raskind, M.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2009 VL 33 IS 6 BP 312A EP 312A PG 1 WC Substance Abuse SC Substance Abuse GA 449MQ UT WOS:000266335101198 ER PT J AU Gheorghiade, M Adams, KF Cleland, JGF Cotter, G Felker, GM Filippatos, GS Fonarow, GC Greenberg, BH Hernandez, AF Khan, S Komajda, M Konstam, MA Liu, PP Maggioni, AP Massie, BM McMurray, JJ Mehra, M Metra, M O'Connell, J O'Connor, CM Pang, PS Pina, IL Sabbah, HN Teerlink, JR Udelson, JE Yancy, CW Zannad, F Stockbridge, N AF Gheorghiade, Mihai Adams, Kirkwood F. Cleland, John G. F. Cotter, Gad Felker, G. Michael Filippatos, Gerasimos S. Fonarow, Gregg C. Greenberg, Barry H. Hernandez, Adrian F. Khan, Sadiya Komajda, Michel Konstam, Marvin A. Liu, Peter P. Maggioni, Aldo P. Massie, Barry M. McMurray, John J. Mehra, Mandeep Metra, Marco O'Connell, John O'Connor, Christopher M. Pang, Peter S. Pina, Ileana L. Sabbah, Hani N. Teerlink, John R. Udelson, James E. Yancy, Clyde W. Zannad, Faiez Stockbridge, Norman CA Acute Heart Failure Syndromes Int TI Phase III clinical trial end points in acute heart failure syndromes: A virtual roundtable with the acute heart failure syndromes international working group SO AMERICAN HEART JOURNAL LA English DT Editorial Material C1 [Gheorghiade, Mihai; Khan, Sadiya; O'Connell, John; Pang, Peter S.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Adams, Kirkwood F.] Univ N Carolina, Chapel Hill, NC USA. [Cleland, John G. F.] Univ Hull, Castle Hill Hosp, Kingston Upon Hull, Yorks, England. [Cotter, Gad] Momentum Res Inc, Durham, NC USA. [Felker, G. Michael; Hernandez, Adrian F.; O'Connor, Christopher M.] Duke Univ, Med Ctr, Durham, NC USA. [Filippatos, Gerasimos S.] Univ Athens, Athens, Greece. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles Med Ctr, Los Angeles, CA USA. [Greenberg, Barry H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Komajda, Michel] Univ Paris 06, Paris, France. [Komajda, Michel] Hosp Pitie Salpetriere, Paris, France. [Konstam, Marvin A.] Tufts Med Ctr, Boston, MA USA. [Liu, Peter P.] UHN, Toronto Gen Hosp, Toronto, ON, Canada. [Maggioni, Aldo P.] Assoc Nazl Med Cardiol Osped, Florence, Italy. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [McMurray, John J.] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Mehra, Mandeep] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Metra, Marco] Univ Brescia, Brescia, Italy. [Pina, Ileana L.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Sabbah, Hani N.] Henry Ford Hosp, Henry Ford Heart & Vasc Inst, Detroit, MI 48202 USA. [Teerlink, John R.] Univ Calif San Francisco, Vet Adm Med Ctr, San Francisco, CA USA. [Yancy, Clyde W.] Baylor Heart & Vasc Inst, Dallas, TX USA. [Zannad, Faiez] INSERM, Nancy, France. [Stockbridge, Norman] US FDA, Silver Spring, MD USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Feinberg Sch Med, 676 N St Clair St,Suite 600, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu RI Teerlink, John/D-2986-2012; Lainscak, Mitja/F-3237-2015; Hernandez, Adrian F./A-7818-2016; OI Mehra, Mandeep/0000-0001-8683-7044; Hernandez, Adrian F./0000-0003-3387-9616; Cleland, John/0000-0002-1471-7016; Metra, Marco/0000-0001-6691-8568; mcmurray, john/0000-0002-6317-3975 NR 0 TC 37 Z9 37 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 JUN PY 2009 VL 157 IS 6 BP 957 EP 970 DI 10.1016/j.ahj.2009.04.010 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 454GD UT WOS:000266669500002 PM 19464405 ER PT J AU Dokholyan, RS Muhlbaier, LH Falletta, JM Jacobs, JP Shahian, D Haan, CK Peterson, ED AF Dokholyan, Rachel S. Muhlbaier, Lawrence H. Falletta, John M. Jacobs, Jeffrey P. Shahian, David Haan, Constance K. Peterson, Eric D. TI Regulatory and ethical considerations for linking clinical and administrative databases SO AMERICAN HEART JOURNAL LA English DT Article ID HEALTH-CARE; IMPROVEMENT; QUALITY; PRIVACY; HIPAA AB Clinical data registries are valuable tools that support evidence development, performance assessment, comparative effectiveness studies, and the adoption of new treatments into routine clinical practice. Although these registries do not have important information on long-term therapies or clinical events, administrative claims databases offer a potentially valuable complement. This article focuses on the regulatory and ethical considerations that arise from the use of registry data for research, including linkage of clinical and administrative data sets. (1) Are such activities primarily designed for quality assessment and improvement, research, or both, as this determines the appropriate ethical and regulatory standards? (2) Does the submission of data to a central registry, which may subsequently be linked to other data sources, require review by the institutional review board (IRB) of each participating organization? (3) What levels and mechanisms of IRB oversight are appropriate for the existence of a linked central data repository and the specific studies that may subsequently be developed using it? (4) Under what circumstances are waivers of informed consent and Health Insurance Portability and Accountability Act authorization required? (5) What are the requirements for a limited data set that would qualify a research activity as not involving human subjects and thus not subject to further IRB review? The approaches outlined in this article represent a local interpretation of the regulations in the context of several clinical data registry projects and focuses on a specific case study of the Society of Thoracic Surgeons National Database. (Am Heart J 2009;157:971-82.) C1 [Dokholyan, Rachel S.; Muhlbaier, Lawrence H.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC 27705 USA. [Falletta, John M.] Duke Univ, Sch Med, Durham, NC USA. [Jacobs, Jeffrey P.] CHIF, St Petersburg, FL USA. [Jacobs, Jeffrey P.] CHIF, Tampa, FL USA. [Shahian, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Haan, Constance K.] Univ Florida, Coll Med, Jacksonville, FL USA. RP Dokholyan, RS (reprint author), Duke Clin Res Inst, Room 0311 Terrace Level,2400 Pratt St, Durham, NC 27705 USA. EM rachel.dokholyan@duke.edu NR 20 TC 45 Z9 45 U1 2 U2 5 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 JUN PY 2009 VL 157 IS 6 BP 971 EP 982 DI 10.1016/j.ahj.2009.03.023 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 454GD UT WOS:000266669500003 PM 19464406 ER PT J AU Forman, DE Cannon, CP Hernandez, AF Liang, L Yancy, C Fonarow, GC AF Forman, Daniel E. Cannon, Christopher P. Hernandez, Adrian F. Liang, Li Yancy, Clyde Fonarow, Gregg C. CA Get Guidelines Steering Comm Hosp TI Influence of age on the management of heart failure: Findings from Get With the Guidelines-Heart Failure (GWTG-HF) SO AMERICAN HEART JOURNAL LA English DT Article ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; INITIATE LIFESAVING TREATMENT; ACUTE MYOCARDIAL-INFARCTION; EARLY INVASIVE MANAGEMENT; ACUTE CORONARY SYNDROMES; QUALITY-OF-CARE; HOSPITALIZED-PATIENTS; ORGANIZED PROGRAM; OPTIMIZE-HF; PART II AB Background Heart failure (HF) is common among elderly adults. Although multiple studies demonstrate age-related declines in the utilization of evidence-based therapies for coronary artery disease, there are few analyses of HF patients to distinguish possible age-related management differences. Methods We analyzed 57,937 HF admissions from January 2005 through April 2007 in 257 hospitals participating in the American Heart Association's Get With The Guidelines-Heart Failure program. Patient characteristics and management were stratified by age groups <= 65, 66-75, 76-85, and >85 years. Multivariable regression analyses were used to assess the influence of age on use of therapies and inhospital mortality. Results The mean patient age was 73 +/- 14 years; 18.7% were >85 years of age. Prescriptions of most HF therapies were relatively reduced with age but still remained high overall. Although 88.6% of patients <= 65 years of age with left ventricular systolic dysfunction were prescribed angiotensin-converting enzyme inhibitor or angiotensin receptor blacker and 90.9% were prescribed beta-blockers, among those >85 years of age with left ventricular systolic dysfunction, 79% were prescribed angiotensin-converting enzyme inhibitor or angiotensin receptor blacker and 82.7% were prescribed beta-blockers. Regression analysis that accounted for typical confounders demonstrated that older age was associated with diminished utilization of most evidence-based treatment measures as well as increased mortality. Conclusions Get With The Guidelines-Heart Failure data demonstrate that guidelines recommended therapies are frequently utilized for older patients with HF, including patients >85 years old. Nonetheless, age-related differences in therapy persist, suggesting that opportunities to improve care still remain. (Am Heart J 2009; 157:1010-7.) C1 [Forman, Daniel E.; Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Forman, Daniel E.] VA Boston Healthcare Syst, Boston, MA USA. [Hernandez, Adrian F.] Duke Univ, Med Ctr, Durham, NC USA. [Liang, Li] Duke Clin Res Inst, Durham, NC USA. [Yancy, Clyde] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. RP Forman, DE (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM deforman@partners.org RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 NR 28 TC 30 Z9 31 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUN PY 2009 VL 157 IS 6 BP 1010 EP 1017 DI 10.1016/j.ahj.2009.03.010 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 454GD UT WOS:000266669500008 PM 19464411 ER PT J AU Sorensen, SV Dewilde, S Singer, DE Goldhaber, SZ Monz, BU Plumb, JM AF Sorensen, Sonja V. Dewilde, Sarah Singer, Daniel E. Goldhaber, Samuel Z. Monz, Brigitta U. Plumb, Jonathan M. TI Cost-effectiveness of warfarin: Trial versus "real-world" stroke prevention in atrial fibrillation SO AMERICAN HEART JOURNAL LA English DT Article ID ANTITHROMBOTIC THERAPY; ISCHEMIC-STROKE; ORAL ANTICOAGULATION; CLINICAL-PRACTICE; HEART-DISEASE; RISK; METAANALYSIS; ASPIRIN; INTENSITY; PROPHYLAXIS AB Background and Purpose Previous cost-effectiveness analyses analyzed warfarin for stroke prevention in randomized trial settings. Given the complexities of warfarin treatment, cost-effectiveness should be examined within a real-world setting. Methods Our model followed patients with atrial fibrillation at moderate to high risk of stroke through primary and recurrent ischemic stroke, hemorrhages-intracranial and extracranial, and the resulting disability. Four scenarios were examined: (1) all patients start on warfarin with perfect control, that is, international normalized ratio (INR) values always within range; (2) all patients start on warfarin with trial-like control, where INR can fall outside the recommended range; (3) all patients start on warfarin with real-world INR control; and (4) real-world prescription (and control) of warfarin, aspirin, or neither for warfarin-eligible patients. Reported warfarin discontinuation rates were used. Main outcomes were total number of events, quality adjusted life years, and costs in a US setting. Results The total number of primary and recurrent ischemic strokes in a 1000-patient cohort (age 70 years, lifetime analysis) was 626, 832, 984, and 1,171 in scenarios 1 to 4, respectively. The corresponding mean quality adjusted life years per patient were 7.21, 6.92, 6.75, and 6.67 for scenarios 1 to 4, respectively. Costs per patient were $68,039, $77,764, $84,518, and $87,248 in scenarios 1 to 4, respectively. If "perfect" adherence to warfarin was assumed, except for discontinuations for clinical reasons, strokes would decrease to 503, 737, 909, and 1,120 in scenarios 1 to 4, respectively. Conclusions Clinical and cost outcomes are strongly dependent on the quality of anticoagulation and rates of warfarin discontinuation. Clinicians should work to improve both. Policy makers should use real-world INR control and warfarin discontinuation rates when assessing cost-effectiveness. (Am Heart J 2009; 157:1064-73.) C1 [Sorensen, Sonja V.] United BioSource Corp, Bethesda, MD USA. [Dewilde, Sarah] United BioSource Corp, Brussels, Belgium. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.; Goldhaber, Samuel Z.] Harvard Univ, Sch Med, Boston, MA USA. [Goldhaber, Samuel Z.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Monz, Brigitta U.; Plumb, Jonathan M.] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. RP Sorensen, SV (reprint author), 7101 Wisconsin Ave,Suite 600, Bethesda, MD 20814 USA. EM sonja.sorensen@unitedbiosource.com NR 55 TC 40 Z9 41 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUN PY 2009 VL 157 IS 6 BP 1064 EP 1073 DI 10.1016/j.ahj.2009.03.022 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 454GD UT WOS:000266669500015 PM 19464418 ER PT J AU Mendez, MF McMurtray, AM Licht, EA Saul, RE AF Mendez, Mario F. McMurtray, Aaron M. Licht, Eliot A. Saul, Ronald E. TI Frontal-executive Versus Posterior-perceptual Mental Status Deficits in Early-onset Dementias SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE dementia; Alzheimer's disease; vascular dementia; frontotemporal dementia; frontal-executive functions; perceptual disturbances ID FRONTOTEMPORAL LOBAR DEGENERATION; DIAGNOSED PRESENILE-DEMENTIA; ISCHEMIC VASCULAR DEMENTIA; ALZHEIMERS-DISEASE; ASSESSMENT BATTERY; NEUROPSYCHOLOGICAL FEATURES; CLINICAL CHARACTERISTICS; COGNITIVE IMPAIRMENT; PREVALENCE; MEMORY AB Background: Compared to late-onset dementias, early-onset dementias (EODs) may have greater focal cognitive involvement with differences in frontal-executive compared to posterior-perceptual deficits. Objective: This study evaluated whether mental status screening based on this frontal-posterior axis can distinguish EODs. Methods: Twenty-three patients each with early-onset Alzheimer's disease (eAD), frontotemporal dementia (FTD), or subcortical ischemic vascular disease (SIVD), and 20 normal controls underwent the Frontal Assessment Battery (FAB) and the Perceptual Assessment Battery (PAB). Results: Compared to controls, SIVD and FTD groups were impaired on the FAB whereas eAD and SIVD groups were impaired on the PAB. The FAB/PAB ratio further differentiated the groups (F(3,85) = 26.49, P < .001). For sensitivities and specificities of 93%, a cut-off score of 1.25 on the FAB/PAB distinguished eAD, and a cut-off of 0.83 distinguishing FTD. Conclusion: Although preliminary, this study indicates that mental status screening based on frontal versus posterior cortical functions may help clinicians diagnose EODs. C1 [Mendez, Mario F.; McMurtray, Aaron M.; Licht, Eliot A.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, Neurobehav Unit, Los Angeles, CA 90073 USA. [Mendez, Mario F.; McMurtray, Aaron M.; Saul, Ronald E.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Mendez, MF (reprint author), VA Greater Los Angeles Healthcare Syst, Neurobehav Unit 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM mmendez@ucla.edu NR 56 TC 5 Z9 5 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD JUN-JUL PY 2009 VL 24 IS 3 BP 220 EP 227 DI 10.1177/1533317509332626 PG 8 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA 464NL UT WOS:000267511700005 PM 19329784 ER PT J AU Baruch, L Agarwal, S Gupta, B Haynos, A Eng, C AF Baruch, Lawrence Agarwal, Sanjay Gupta, Bhanu Haynos, Ann Eng, Calvin TI Effect on Serum Lipid Levels of Switching Dose of Ezetimibe from 10 to 5 mg SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CHOLESTEROL ABSORPTION INHIBITOR; TREATMENT PANEL-III; PRIMARY HYPERCHOLESTEROLEMIA; CLINICAL-TRIALS; TOLERABILITY AB Although during its initial development, lower doses of ezetimibe reduced low-density lipoprotein (LDL) significantly, ezetimibe is available only in 10-mg form. Compliant patients receiving ezetimibe 10 mg were randomized in a blinded fashion to continue therapy with ezetimibe 10 mg or to convert to a split-tablet 5-mg dose. Lipid panels were collected at baseline and after 4 weeks of therapy. The impact of the 2 ezetimibe dosing strategies on LDL and the achievement of the Adult Treatment Panel III LDL goal was evaluated. One hundred thirty patients receiving ezetimibe 10 mg were screened for eligibility. Thirty-nine of the 130 patients were randomized; 36 patients successfully completed the study. All patients who had achieved their Adult Treatment Panel III LDL goals at baseline remained at their LDL goals after conversion to 5 mg. In conclusion, conversion to the lower dose of ezetimibe did not result in any clinically meaningful or statistically significant changes in any lipid parameter. (C) 2009 Published by Elsevier Inc. (Am J Cardiol 2009;103:1568-1571) C1 [Baruch, Lawrence; Agarwal, Sanjay; Gupta, Bhanu; Haynos, Ann; Eng, Calvin] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Baruch, Lawrence; Agarwal, Sanjay; Gupta, Bhanu; Eng, Calvin] Mt Sinai Sch Med, New York, NY USA. RP Baruch, L (reprint author), James J Peters Vet Affairs Med Ctr, Bronx, NY USA. EM lawrence.baruch@va.gov NR 10 TC 1 Z9 1 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 1 PY 2009 VL 103 IS 11 BP 1568 EP 1571 DI 10.1016/j.amjcard.2009.01.365 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 456ZR UT WOS:000266894300015 PM 19463517 ER PT J AU Aizer, A Gaziano, JM Cook, NR Manson, JE Buring, JE Albert, CM AF Aizer, Anthony Gaziano, J. Michael Cook, Nancy R. Manson, Joann E. Buring, Julie E. Albert, Christine M. TI Relation of Vigorous Exercise to Risk of Atrial Fibrillation SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LONG-DISTANCE RUNNERS; PHYSICAL-ACTIVITY; SPORT PRACTICE; FOLLOW-UP; ABLATION; ASPIRIN; TONE; MEN AB Limited data suggest that athletes may have a higher risk of developing atrial fibrillation (AF); however, there has been no large prospective assessment of the relation between vigorous exercise and AF. Logistic regression analyses stratified by time were used to assess the association between frequency of vigorous exercise and risk of developing AF in 16,921 apparently healthy men in the Physicians' Health Study. During 12 years of follow-up, 1,661 men reported developing AF. With increasing frequency of vigorous exercise (0, 1, 1 to 2, 3 to 4, 5 to 7 days/week), multivariate relative risks for the full cohort were 1.0 (referent), 0.90, 1.09, 1.04, and 1.20 (p = 0.04). This risk was not significantly increased when exercise habits were updated or in models excluding variables that may be in the biological pathway through which exercise influences AF risk. In subgroup analyses, this increased risk was observed only in men <50 years of age (1.0, 0.94, 1.20, 1.05, 1.74, p <0.01) and joggers (1.0, 0.91, 1.03, 1.30, 1.53, p <0.01), where risks remained increased in all analyses. In conclusion, frequency of vigorous exercise was associated with an increased risk of developing AF in young men and joggers. This risk decreased as the population aged and was offset by known beneficial effects of vigorous exercise on other AF risk factors. (C) 2009 Elsevier Inc. (Am J Cardiol 2009;103:1572-1577) C1 [Aizer, Anthony; Albert, Christine M.] Brigham & Womens Hosp, Dept Med, Ctr Arrhythmia Prevent, Boston, MA 02115 USA. [Aizer, Anthony; Gaziano, J. Michael; Cook, Nancy R.; Manson, Joann E.; Buring, Julie E.; Albert, Christine M.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Gaziano, J. Michael; Albert, Christine M.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Gaziano, J. Michael; Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] MAVERIC, VA Boston Healthcare Syst, Boston, MA USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Cook, Nancy R.; Manson, Joann E.; Buring, Julie E.; Albert, Christine M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Aizer, Anthony] NYU, Med Ctr, Dept Med, Leon H Charney Div Cardiol, New York, NY 10016 USA. RP Aizer, A (reprint author), Brigham & Womens Hosp, Dept Med, Ctr Arrhythmia Prevent, 75 Francis St, Boston, MA 02115 USA. EM anthony.aizer@nyumc.org OI Aizer, Anthony/0000-0001-6550-0178 FU NCI NIH HHS [R01 CA097193, CA097193, CA34944, CA40360, R01 CA040360, R01 CA040360-17, R01 CA047988, R01 CA097193-07]; NHLBI NIH HHS [HL26490, HL34595, R01 HL043851] NR 23 TC 120 Z9 125 U1 2 U2 12 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 JUN 1 PY 2009 VL 103 IS 11 BP 1572 EP 1577 DI 10.1016/j.amjcard.2009.01.374 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 456ZR UT WOS:000266894300016 PM 19463518 ER PT J AU Shea, MK O'Donnell, CJ Hoffmann, U Dallal, GE Dawson-Hughes, B Ordovas, JM Price, PA Williamson, MK Booth, SL AF Shea, M. Kyla O'Donnell, Christopher J. Hoffmann, Udo Dallal, Gerard E. Dawson-Hughes, Bess Ordovas, Jose M. Price, Paul A. Williamson, Matthew K. Booth, Sarah L. TI Vitamin K supplementation and progression of coronary artery calcium in older men and women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID MATRIX GLA PROTEIN; GAMMA-CARBOXYGLUTAMIC ACID; VASCULAR CALCIFICATION; ASYMPTOMATIC SUBJECTS; POSTMENOPAUSAL WOMEN; ATHEROSCLEROSIS MESA; COMPUTED-TOMOGRAPHY; RISK-FACTORS; WARFARIN; ATORVASTATIN AB Background: Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. Objective: The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. Design: CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 mu g phylloquinone/d (treatment), and 188 received a multivitamin alone (control). Results: In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/- SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were >= 85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. Conclusions: Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials. gov as NCT00183001. Am J Clin Nutr 2009; 89: 1799-807. C1 [Shea, M. Kyla; Dawson-Hughes, Bess; Ordovas, Jose M.; Booth, Sarah L.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Bethesda, MD USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, CIMIT, Boston, MA 02114 USA. [Price, Paul A.; Williamson, Matthew K.] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92103 USA. RP Booth, SL (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM sarah.booth@tufts.edu OI Ordovas, Jose/0000-0002-7581-5680 FU US Department of Agriculture, Agricultural Research Service [58-1950-7-707]; National Institutes of Health [AG14759, HL69272, T32HL69772]; American Heart Association [0515605T] FX Supported by the US Department of Agriculture, Agricultural Research Service, under Cooperative Agreement no. 58-1950-7-707; National Institutes of Health (AG14759, HL69272, and T32HL69772); and the American Heart Association (0515605T). NR 37 TC 65 Z9 67 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN 1 PY 2009 VL 89 IS 6 BP 1799 EP 1807 DI 10.3945/ajcn.2008.27338 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 448EI UT WOS:000266245500014 PM 19386744 ER PT J AU Shaikh, S Van Cott, EM AF Shaikh, Salima Van Cott, Elizabeth M. TI The Effect of Argatroban on Activated Protein C Resistance SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Argatroban; Anticoagulation; Activated protein C resistance; Interference ID FACTOR-V-LEIDEN; LUPUS ANTICOAGULANTS; THROMBOSIS; THERAPY; RISK AB Activated protein C (APC) resistance is commonly tested in hypercoagulation evaluations, and argatroban is an anticoagulant therapy used in hypercoagulable patients. The effect of argatroban on APC resistance testing is unknown. We studied 100 ex vivo specimens from 44 patients treated with argatroban. Argatroban increased the APC resistance ratio in all but 1 patient. The effect was seen even in the specimens containing subtherapeutic argatroban levels. For patients without APC resistance, the mean APC resistance ratio significantly increased from 2.43 without argatroban to 3.10 with argatroban. For patients with APC resistance due to factor V Leiden, argatroban significantly increased the mean ratio from 1.73 to 2.13, falsely raising it into the normal range (> 2). Argatroban increases the APC resistance ratio, which can mask a diagnosis of APC resistance and, therefore, factor V Leiden. Clinicians should be advised that APC resistance testing for patients receiving argatroban is not valid. C1 [Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Van Cott, EM (reprint author), Massachusetts Gen Hosp, Dept Pathol, Gray Jackson 235,55 Fruit St, Boston, MA 02114 USA. NR 13 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUN PY 2009 VL 131 IS 6 BP 828 EP 833 DI 10.1309/AJCPVMUS77ZMBEHJ PG 6 WC Pathology SC Pathology GA 448CB UT WOS:000266238600012 PM 19461089 ER PT J AU de Fucio, SBP Puppin-Rontani, RM de Carvalho, FG Mattos-Graner, RD Correr-Sobrinho, L Garcia-Godoy, F AF Portugal de Fucio, Suzana Beatriz Puppin-Rontani, Regina Maria de Carvalho, Fabiola Galbiatti Mattos-Graner, Renata de Oliveira Correr-Sobrinho, Lourenco Garcia-Godoy, Franklin TI Analyses of biofilms accumulated on dental restorative materials SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID LASER-SCANNING MICROSCOPY; GLASS-IONOMER CEMENTS; STREPTOCOCCUS-MUTANS; IN-VITRO; ANTIBACTERIAL ACTIVITY; SPATIAL-DISTRIBUTION; CONFOCAL MICROSCOPY; PLAQUE-FORMATION; BACTERIA; COMPOSITE AB Purpose: To qualitatively and quantitatively assess the architectural arrangement of microorganisms in biofilm developed on the surface of different restorative materials: ceramic (C), resin composite (RC), conventional (CGIC) and resin-modified glass-ionomer cements (RMGIC). Methods: Streptococcus mutans was used to develop a biofilm that adhered to the surfaces of the selected material disks in 30 days. The specimens were stained and analyzed by confocal laser scanning microscopy and COMSTAT. Among biofilm properties, mean thickness, total bio-volume, roughness coefficient and surface-to-volume ratio were investigated, as well as characteristics of the distribution and architecture of viable/nonviable cells in the biofilm. Results: Only the mean biofilm thickness was statistically significantly different among the restorative materials tested. C and RC accumulated the thickest biofilms. Qualitative analysis showed cellular aggregates and fluid-filled channels penetrating to a considerable depth of the biofilm. In addition, images demonstrated a progression of more viable cells in superficial regions of the biofilm to proportionally more nonviable cells in the deeper regions of the biofilms near the disk. (Am J Dent 2009;22:131-136). C1 [Puppin-Rontani, Regina Maria] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Pediat Dent, UNICAMP, BR-13414018 Piracicaba, SP, Brazil. [Puppin-Rontani, Regina Maria] Univ Estadual Campinas, Piracicaba Dent Sch, Pre & Postgrad Program Dent Mat, BR-13414018 Piracicaba, SP, Brazil. [Portugal de Fucio, Suzana Beatriz; de Carvalho, Fabiola Galbiatti] Univ Estadual Campinas, Piracicaba Dent Sch, Dent Mat Program, BR-13414018 Piracicaba, SP, Brazil. [Mattos-Graner, Renata de Oliveira] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Microbiol & Immunol, BR-13414018 Piracicaba, SP, Brazil. [Correr-Sobrinho, Lourenco] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Operat Dent, BR-13414018 Piracicaba, SP, Brazil. [Garcia-Godoy, Franklin] Univ Tennessee, Coll Dent, Biosci Res Ctr, Memphis, TN USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. RP Puppin-Rontani, RM (reprint author), Univ Estadual Campinas, Piracicaba Dent Sch, Dept Pediat Dent, UNICAMP, Av Limeira 901, BR-13414018 Piracicaba, SP, Brazil. EM rmpuppin@fop.unicamp.br RI PUPPIN-RONTANI, regina/C-3994-2012; Mattos-Graner, Renata/C-9410-2012 OI PUPPIN-RONTANI, regina/0000-0002-1218-5159; Mattos-Graner, Renata/0000-0001-8309-8135 FU CAPES (Coordenacao de Aperfeicoamento Profissional de Nivel Superior) FX The research was Supported by CAPES (Coordenacao de Aperfeicoamento Profissional de Nivel Superior). All authors claim no conflict of interest. NR 42 TC 9 Z9 9 U1 0 U2 7 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD JUN PY 2009 VL 22 IS 3 BP 131 EP 136 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 475FM UT WOS:000268344000001 PM 19650591 ER PT J AU Aspinall, SL Good, CB Metlay, JP Mor, MK Fine, MJ AF Aspinall, Sherrie L. Good, Chester B. Metlay, Joshua P. Mor, Maria K. Fine, Michael J. TI Antibiotic prescribing for presumed nonbacterial acute respiratory tract infections SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article CT National Annual Meeting of the US-Department-of-Veterans-Affairs-Health-Services-Research-and-Developme nt-Service CY FEB, 2005 CL Baltimore, MD SP US Dept Vet Affairs Hlth Serv Res & Dev Serv ID ACUTE BRONCHITIS; STREPTOCOCCUS-PNEUMONIAE; EMERGENCY-DEPARTMENTS; AMBULATORY PRACTICE; CARE PHYSICIANS; UNITED-STATES; ADULTS; TRENDS; PREDICTORS; MANAGEMENT AB Objective: The objective of the study was to identify patient and provider factors associated with prescribing antibiotics for outpatients with acute respiratory tract infections of likely nonbacterial etiology. Methods: We identified outpatients who were diagnosed in the emergency department with nonspecific upper respiratory tract infections (URIs) and acute bronchitis at the VA Pittsburgh Healthcare System from June 15, 2003, to June 14, 2004, and the Philadelphia VA Medical Center from November 30, 2003, to March 31, 2004. Stepwise logistic regression was used to identify factors independently associated with antibiotic prescribing. Results: Overall, 26% of the 667 eligible patients with URIs and/or acute bronchitis received antibiotics. Antibiotics were prescribed significantly more frequently for acute bronchitis at one site (97% vs 65%, P < .001). Using multivariable analysis, the following factors were independently associated with antibiotic prescribing (odds ratio, 95% confidence interval): presence of I or more comorbidities (2.1, 1.2-3.5), fever (2.5, 1.4-4.4), purulent sputum (2.5, 1.5-4.4), shortness of breath (2.8, 1.4-5.4), altered breath sounds (4.6, 2.4-8.6), diagnosis of acute bronchitis (15.9, 8.0-31.8), provider age >= 30 years (2.6, 1.1-6.3), and noninternal medicine specialty (2.7, 1.2-6.0). Conclusions: Antibiotic use was high and varied substantially for URN and acute bronchitis. Specific signs and symptoms, a diagnosis of acute bronchitis, and provider age and specialty were associated with antibiotic prescribing. Interventions to decrease inappropriate prescribing should address the perceived utility of antibiotics in acute bronchitis and the accuracy of signs and symptoms in diagnosing a bacterial respiratory infection. Published by Elsevier Inc. C1 [Aspinall, Sherrie L.; Good, Chester B.; Mor, Maria K.; Fine, Michael J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Aspinall, Sherrie L.; Good, Chester B.] VA Ctr Medicat Safety, Hines VA, Hines, IL 60141 USA. [Aspinall, Sherrie L.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA 15261 USA. [Good, Chester B.; Fine, Michael J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15261 USA. [Metlay, Joshua P.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 19104 USA. [Metlay, Joshua P.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Mor, Maria K.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. RP Aspinall, SL (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 151C-H, Pittsburgh, PA 15206 USA. EM sherrie.aspinall@va.gov FU PHS HHS [5K24 A101769] NR 31 TC 12 Z9 12 U1 2 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JUN PY 2009 VL 27 IS 5 BP 544 EP 551 DI 10.1016/j.ajem.2008.04.015 PG 8 WC Emergency Medicine SC Emergency Medicine GA 457OH UT WOS:000266940800005 PM 19497459 ER PT J AU Levin, SK Metlay, JP Maselli, JH Kersey, AS Camargo, CA Gonzales, R AF Levin, Sara K. Metlay, Joshua P. Maselli, Judith H. Kersey, Ayanna S. Camargo, Carlos A., Jr. Gonzales, Ralph CA IMPAACT Project Investigators TI Perceived social support among adults seeking care for acute respiratory tract infections in US EDs SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID MULTIDIMENSIONAL SCALE; MEDICAL-CARE; COMMON COLD; EMERGENCY; EXPERIENCE; ILLNESS; STRESS; HEALTH AB Emergency departments (EDs) provide a disproportionate amount of care to disenfranchised and vulnerable populations. We examined social support levels among a diverse population of adults seeking ED care for acute respiratory tract infections. A convenience sample of adults seeking care in I of 15 US EDs was telephone interviewed 1 to 6 weeks postvisit. The Multidimensional Scale of Perceived Social Support (7-point Likert) assessed social support across 3 domains: friends, family, and significant others. Higher scores indicate higher support. Of 1104 subjects enrolled, 704 (64%) completed the follow-up interview. Factor analysis yielded 3 factors. Mean social support score was 5.54 (SD 1.04). Female sex, greater household income, and better health status were independently associated with higher levels of social support. Social support levels among adults seeking care in the ED for acute respiratory tract infections are similar to general population cohorts, suggesting that social support is not a strong determinant of health care seeking in EDs. (C) 2009 Elsevier Inc. All rights reserved. C1 [Levin, Sara K.; Maselli, Judith H.; Gonzales, Ralph] Univ Calif San Francisco, Dept Med, San Francisco, CA 94118 USA. [Metlay, Joshua P.] Univ Penn, Sch Med, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot,Dept Med, Philadelphia, PA 19104 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Gonzales, R (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94118 USA. EM ralphg@medicine.ucsf.edu FU Translating Research Into Practice Initiative; Agency for Healthcare Research and Quality [1 R01 HS013915]; Health Services Research and Development Service of the Department of Veteran Affairs [AVA-03-239] FX This project was supported by the Translating Research Into Practice Initiative, jointly sponsored by the Agency for Healthcare Research and Quality (grant 1 R01 HS013915) and the Health Services Research and Development Service of the Department of Veteran Affairs (AVA-03-239). NR 18 TC 0 Z9 0 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JUN PY 2009 VL 27 IS 5 BP 582 EP 587 DI 10.1016/j.ajem.2008.05.013 PG 6 WC Emergency Medicine SC Emergency Medicine GA 457OH UT WOS:000266940800011 PM 19497465 ER PT J AU Freedland, SJ Aronson, WJ AF Freedland, Stephen J. Aronson, William J. TI Invited Commentary: Lower Urinary Tract Symptoms and Inflammation - Weighing the Evidence SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE inflammation; prostate; urinary tract physiological phenomena ID MEN AB Lower urinary tract symptoms (LUTS) are a common condition, particularly among older men. The etiology of these symptoms is often obscure and not always clearly related to prostatic enlargement or benign prostatic hyperplasia. St. Sauver et al. (Am J Epidemiol. 2009;169(11):1281-1290) hypothesized that systemic inflammation may be associated with LUTS and benign prostatic hyperplasia. Using a well-defined cohort, they found that, in general, inflammation was not related to LUTS or to benign prostatic hyperplasia progression. However, men with the highest amount of systemic inflammation, as measured by C-reactive protein levels, were at increased risk of a rapid change in irritative voiding symptoms and decreased urinary flow but not obstructive voiding symptoms or prostate size. To what degree systemic inflammation relates to inflammation within the urinary system and specifically the bladder and/or prostate is unclear. Furthermore, to what degree inflammation within the urinary system contributes to LUTS is unclear. Given that clinical trials of antiinflammatory drugs for LUTS have been largely unsuccessful, the role of inflammation as a contributor to LUTS remains an interesting hypothesis that requires further study. C1 [Freedland, Stephen J.] Durham VA Med Ctr, Dept Surg, Durham, NC USA. [Freedland, Stephen J.] Duke Prostate Ctr, Durham, NC USA. [Freedland, Stephen J.] Duke Univ, Med Ctr, Div Urol Surg, Dept Surg, Durham, NC 27710 USA. [Freedland, Stephen J.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Aronson, William J.] Greater Los Angeles VA Hlth Syst, Dept Surg, Los Angeles, CA USA. [Aronson, William J.] Univ Calif Los Angeles, Med Ctr, Dept Urol, Los Angeles, CA 90024 USA. RP Freedland, SJ (reprint author), Duke Univ, Med Ctr, Div Urol Surg, Dept Surg, Box 2626, Durham, NC 27710 USA. EM steve.freedland@duke.edu NR 8 TC 4 Z9 4 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 JUN 1 PY 2009 VL 169 IS 11 BP 1291 EP 1293 DI 10.1093/aje/kwp084 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 446GF UT WOS:000266109400002 PM 19395692 ER PT J AU Hassanein, T Blei, AT Perry, W Hilsabeck, R Stange, J Larsen, FS Brown, RS Caldwell, S McGuire, B Nevens, F Fontana, R AF Hassanein, Tarek Blei, Andres T. Perry, William Hilsabeck, Robin Stange, Jan Larsen, Fin S. Brown, Robert S., Jr. Caldwell, Stephen McGuire, Brendan Nevens, Frederik Fontana, Robert TI Performance of the Hepatic Encephalopathy Scoring Algorithm in a Clinical Trial of Patients With Cirrhosis and Severe Hepatic Encephalopathy SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID PORTAL-SYSTEMIC ENCEPHALOPATHY; DOUBLE-BLIND; ALBUMIN DIALYSIS; FLUMAZENIL; PLACEBO; MULTICENTER; LACTULOSE; NEOMYCIN; COMA AB OBJECTIVES: The grading of hepatic encephalopathy (HE) is based on a combination of indicators that reflect the state of consciousness, intellectual function, changes in behavior, and neuromuscular alterations seen in patients with liver failure. METHODS: We modified the traditional West Haven criteria (WHC) to provide an objective assessment of the cognitive parameters to complement the subjective clinical ratings for the performance of extracorporeal albumin dialysis (ECAD) using a molecular adsorption recirculating system in patients with cirrhosis and severe (grade III/IV) encephalopathy. The HE Scoring Algorithm (HESA) combined clinical indicators with those derived from simple neuropsychological tests, the latter more often used in milder grades of HE (I/II). The performance of each indicator was compared across grades and sites. RESULTS: Results of HESA were also compared with the Glasgow Coma Scale. A total of 597 evaluations were performed in patients randomized to ECAD plus standard medical therapy or the latter only. Most parameters exhibited significant separation between grades; the most effective indicators were lack of verbal, eye, and motor response (grade IV), somnolence and disorientation to place (grade III), and lethargy and disorientation to time (grade II). Two clinical and four neuropsychological indicators were useful to classify patients as grade I. The Glasgow Coma Scale differed among the four stages of the WHC, but the differences between grades I and II were small and not clinically useful. CONCLUSION: HESA extends the traditional WHC for grading HE. In the absence of a "gold" standard, the most useful indicators noted in this trial should be further validated. C1 [Hassanein, Tarek] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Blei, Andres T.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Perry, William; Hilsabeck, Robin] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Hilsabeck, Robin] S Texas Vet Hlth Care Syst, Psychol Serv, San Antonio, TX USA. [Hilsabeck, Robin] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Stange, Jan] Univ Rostock, Dept Internal Med, D-2500 Rostock, Germany. [Larsen, Fin S.] Univ Copenhagen Hosp, Rigshosp, Dept Hepatol, DK-2100 Copenhagen, Denmark. [Brown, Robert S., Jr.] Columbia Univ, Dept Med, New York, NY USA. [Caldwell, Stephen] Univ Virginia, Dept Med, Charlottesville, VA USA. [McGuire, Brendan] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Nevens, Frederik] Univ Hosp Gasthuisberg, Dept Hepatol, B-3000 Louvain, Belgium. [Fontana, Robert] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. RP Hassanein, T (reprint author), Univ Calif San Diego, Dept Med, 200 W Arbor Dr,MC 8423, San Diego, CA 92103 USA. EM thassanein@ucsd.edu OI Larsen, Fin Stolze/0000-0003-2205-8265 FU Teraklin FX The authors acknowledge Dr Je C Gornbein from the Department of Biostatistics at the University of California at Los Angeles for invaluable statistical assistance. The authors also thank Fatma Barakat and Deanna L. Oliver for their support in preparation of the manuscript. This study was supported by research grants from Teraklin. NR 29 TC 28 Z9 29 U1 0 U2 1 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 JUN PY 2009 VL 104 IS 6 BP 1392 EP 1400 DI 10.1038/ajg.2009.160 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 457DR UT WOS:000266906900017 PM 19455117 ER PT J AU Khandwalla, HE Fasakin, Y El-Serag, HB AF Khandwalla, Hashim E. Fasakin, Yemi El-Serag, Hashem B. TI The Utility of Evaluating Low Serum Albumin Gradient Ascites in Patients With Cirrhosis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID PERITONITIS; DIAGNOSIS; PROTEIN; FLUID AB OBJECTIVES: Serum-ascites albumin gradient (SAAG) has been used extensively in the diagnostic workup of patients with ascites. A SAAG level of <1.1 g/dl is usually thought of as a result of nonportal hypertension etiologies, including malignancies, tuberculous peritonitis, and nephrotic syndrome. However, the predictive value of a low SAAG in patients with existing cirrhosis in whom the pretest probability of portal hypertension is high is not clear. METHODS: We identified all patients with a SAAG of <1.1 g/dl during a 5-year period at a single large veterans affairs medical center. Cirrhosis was defined by clinical, histological, and radiological features. Nonportal hypertension causes of low SAAG were identified, including bacterial peritonitis, peritoneal carcinomatosis, nephrogenous ascites, tuberculous peritonitis, chylous ascites, and pancreatic ascites. RESULTS: We identified 92 patients (76 with cirrhosis and 16 with no cirrhosis) with ascites and a SAAG of <1.1 g/dl. Of the 76 patients with cirrhosis, only 29 (38%) had an identifiable cause, most commonly primary bacterial peritonitis (11, 38%), followed by peritoneal carcinomatosis or malignant ascites (8, 28%) and nephrotic syndrome (5, 17%). There were 47 patients with cirrhosis and a low SAAG for whom no etiology was identified. Thirty-three patients underwent a repeat paracentesis, 24 (73%) of whom changed to a high SAAG. On the other hand, the 16 patients with no cirrhosis had significantly lower SAAG (0.66 vs. 0.81), and most (12, 75 %) had an identifiable cause of ascites. CONCLUSIONS: Evaluation of a SAAG <1.1 g/dl in patients with known cirrhosis has low yield and is less likely to be helpful than that in patients without cirrhosis. A repeat paracentesis as part of the workup is recommended. Further studies of low SAAG cutoffs are needed. C1 [El-Serag, Hashem B.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. [Khandwalla, Hashim E.; Fasakin, Yemi; El-Serag, Hashem B.] Michael E DeBakey Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX USA. RP El-Serag, HB (reprint author), Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Gastroenterol Sect, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hasheme@bcm.tmc.edu FU Houston VA HSR&D Center of Excellence [HFP90-020]; NIH/NIDDK Center [P30 DK56338]; Dr El-Serag [K24DK078154-03] FX This is work was supported in part by the Houston VA HSR&D Center of Excellence (HFP90-020) and NIH/NIDDK Center Grant P30 DK56338. Dr El-Serag is supported by NIH K24DK078154-03. NR 15 TC 7 Z9 8 U1 0 U2 0 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 JUN PY 2009 VL 104 IS 6 BP 1401 EP 1405 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 457DR UT WOS:000266906900018 PM 19491852 ER PT J AU Lembo, AJ Conboy, L Kelley, JM Schnyer, RS McManus, CA Quilty, MT Kerr, CE Drossman, D Jacobson, EE Davis, RB Kaptchuk, TJ AF Lembo, Anthony J. Conboy, Lisa Kelley, John M. Schnyer, Rosa S. McManus, Claire A. Quilty, Mary T. Kerr, Catherine E. Drossman, Doug Jacobson, Eric E. Davis, Roger B. Kaptchuk, Ted J. TI A Treatment Trial of Acupuncture in IBS Patients SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID IRRITABLE-BOWEL-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; PLACEBO RUN-IN; LOW-BACK-PAIN; CLINICAL-TRIALS; ALTERNATIVE MEDICINE; DIARRHEA-PREDOMINANT; END-POINT; ADEQUATE RELIEF AB OBJECTIVES: This study aimed to compare the effects of true and sham acupuncture in relieving symptoms of irritable bowel syndrome (IBS). METHODS: A total of 230 adult IBS patients (75% females, average age: 38.4 years) were randomly assigned to 3 weeks of true or sham acupuncture (6 treatments) after a 3-week "run-in" with sham acupuncture in an "augmented" or "limited" patient-practitioner interaction. A third arm of the study included a waitlist control group. The primary outcome was the IBS Global Improvement Scale (IBS-GIS) (range: 1-7); secondary outcomes included the IBS Symptom Severity Scale (IBS-SSS), the IBS Adequate Relief (IBS-AR), and the IBS Quality of Life (IBS-QOL). RESULTS: Although there was no statistically significant difference between acupuncture and sham acupuncture on the IBS-GIS (41 vs. 32%, P=0.25), both groups improved significantly compared with the waitlist control group (37 vs. 4%, P=0.001). Similarly, small differences that were not statistically significant favored acupuncture over the other three outcomes: IBS-AR (59 vs. 57%, P=0.83), IBS-SSS (31 vs. 21%, P=0.18), and IBS-QOL (17 vs. 13%, P=0.56). Eliminating responders during the run-in period did not substantively change the results. Side effects were generally mild and only slightly greater in the acupuncture group. CONCLUSIONS: This study did not find evidence to support the superiority of acupuncture compared with sham acupuncture in the treatment of IBS. C1 [Lembo, Anthony J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Conboy, Lisa; Schnyer, Rosa S.; McManus, Claire A.; Quilty, Mary T.; Kerr, Catherine E.; Davis, Roger B.; Kaptchuk, Ted J.] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA USA. [Kelley, John M.] Massachusetts Gen Hosp, Dept Psychol, Boston, MA 02114 USA. [Kelley, John M.] Endicott Coll, Dept Math & Psychol, Beverly, MA USA. [Drossman, Doug] Harvard Univ, Sch Med, Dept Social Med, Boston, MA 02115 USA. [Jacobson, Eric E.] Univ N Carolina, Ctr Funct GI & Motil Disorders, Chapel Hill, NC USA. RP Lembo, AJ (reprint author), 330 Brookline Ave,Rabb Rose 1, Boston, MA 02215 USA. EM alembo@bidmc.harvard.edu RI Kerr, Catherine/D-3299-2009 FU NCCIH NIH HHS [R21 AT002860, 1 R21 AT 002564, 1K24 AT 004095, 1R01 AT 001414-01, 1R21 AT 002860-01, K24 AT004095, R01 AT001414, R21 AT002860-02]; NCRR NIH HHS [M01 RR001032, RR 01032] NR 47 TC 46 Z9 50 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUN PY 2009 VL 104 IS 6 BP 1489 EP 1497 DI 10.1038/ajg.2009.156 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 457DR UT WOS:000266906900030 PM 19455132 ER PT J AU Kastrinos, F Allen, JI Stockwell, DH Stoffel, EM Cook, EF Mutinga, ML Balmana, J Syngal, S AF Kastrinos, Fay Allen, John I. Stockwell, David H. Stoffel, Elena M. Cook, Earl F. Mutinga, Muthoka L. Balmana, Judith Syngal, Sapna TI Development and Validation of a Colon Cancer Risk Assessment Tool for Patients Undergoing Colonoscopy SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; REVISED BETHESDA GUIDELINES; REGRESSION TREE ANALYSIS; LYNCH-SYNDROME; MICROSATELLITE INSTABILITY; FAMILY-HISTORY; COST-EFFECTIVENESS; SCORING SYSTEM; CHEST PAIN; SURVEILLANCE AB OBJECTIVES: Diagnostic criteria for hereditary colorectal cancer (CRC) are complex. "Open-access" colonoscopy makes it challenging to identify who needs genetic evaluation, intensive surveillance, and screening for extracolonic tumors. Our aim was to develop a simple, preprocedural risk assessment tool to identify who may be at highest risk for CRC. METHODS: A total of 631 outpatients undergoing colonoscopy at two academic practices completed a questionnaire assessing personal and family histories of CRC, polyps, and Lynch syndrome (LS)-associated malignancies. Subjects were considered to be high-risk if one of the nine prespecified characteristics of hereditary CRC syndromes was met. Through recursive partitioning analysis, an algorithm of fewest questions needed to capture the most high-risk individuals was developed. The results were validated in 5,335 individuals undergoing colonoscopy at five private endoscopy centers and tested in 285 carriers of mismatch repair mutations associated with LS. RESULTS: About 17.7% and 20.0% of individuals were classified as high-risk in the development and validation cohorts, respectively. Recursive partitioning revealed three questions that were most informative for identifying high-risk patients: (i) "Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50?" (ii) "Have you had CRC or polyps diagnosed before age 50?" (iii) "Do you have >= 3 relatives with CRC?" When asked successively, these questions identified 77% of high-risk individuals in both cohorts and 271 of 285 (95%) of mutation carriers. CONCLUSIONS: Approximately one in five individuals undergoing colonoscopy would benefit from further risk assessment. We developed a simple, three-question CRC Risk Assessment Tool to identify the majority of patients who require additional assessment and possible genetic evaluation. C1 [Kastrinos, Fay; Stockwell, David H.; Stoffel, Elena M.; Syngal, Sapna] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Kastrinos, Fay] Columbia Univ, Med Ctr, Div Digest & Liver Dis, New York, NY USA. [Allen, John I.] Minnesota Gastroenterol, Minneapolis, MN USA. [Stockwell, David H.; Stoffel, Elena M.; Cook, Earl F.; Mutinga, Muthoka L.; Syngal, Sapna] Harvard Univ, Sch Med, Boston, MA USA. [Stockwell, David H.; Mutinga, Muthoka L.] Faulkner Hosp, Div Gastroenterol, Boston, MA USA. [Stoffel, Elena M.; Syngal, Sapna] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Cook, Earl F.] Harvard Univ, Sch Publ Hlth, Div Epidemiol, Boston, MA 02115 USA. [Balmana, Judith] Univ Autonoma Barcelona, Hosp Vall Hebron, Dept Med Oncol, E-08193 Barcelona, Spain. RP Syngal, S (reprint author), Dana Farber Canc Inst, Div Populat Sci, 1 Jimmy Fund Way,SM 209, Boston, MA 02115 USA. EM fk18@columbia.edu; ssyngal@partners.org FU NCI NIH HHS [K07 CA120448, K07 CA 120448-01A1, K24 CA 113433, K24 CA113433] NR 42 TC 24 Z9 24 U1 1 U2 4 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 JUN PY 2009 VL 104 IS 6 BP 1508 EP 1518 DI 10.1038/ajg.2009.135 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 457DR UT WOS:000266906900032 PM 19491864 ER PT J AU Castle, NG Hanlon, JT Handler, SM AF Castle, Nicholas G. Hanlon, Joseph T. Handler, Steven M. TI Results of a Longitudinal Analysis of National Data to Examine Relationships Between Organizational and Market Characteristics and Changes in Antipsychotic Prescribing in US Nursing Homes From 1996 Through 2006 SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Article DE aged; antipsychotics; elderly; nursing homes; prescribing patterns ID QUALITY-OF-CARE; RANDOMIZED-TRIAL; DRUG-USE; DEMENTIA; RESIDENTS; PLACEBO; RISK; REGULATIONS; MEDICATIONS; RISPERIDONE AB Objective: The aim of this work was to examine the association between organizational characteristics, market characteristics, and changes in antipsychotic medication use in US nursing homes over time. Methods: This was a longitudinal study comparing antipsychotic use in US nursing homes from 1996 through 2006 using Medicare and Medicaid data (the Online Survey Certification And Reporting system) and US Department of Health and Human Resources Health Resources and Services Administration data (the Area Resource File). The 3 outcomes of interest were increasing, decreasing, or stable use of antipsychotic medications. The primary independent variables were organizational characteristics (eg, for-profit status, chain membership) and market characteristics (eg, Medicaid reimbursement, levels of competition). Results: Antipsychotic use increased from 16.4% in 1996 to 25.9% in 2006 (P < 0.05). A multinomial generalized estimating equations model, controlling for facility, staffing, and resident factors, suggested that increased antipsychotic use was associated with for-profit facilities (adjusted odds ratio [AOR], 1.58; 95% CI, 1.51-1.65; P <= 0.001). Decreased antipsychotic use was associated with chain membership (AOR, 0.82; 95% CI, 0.79-0.85; P <= 0.001), higher levels of competition (AOR, 1.22; 95% CI, 1.16-1.29; P <= 0.001), and a higher Medicaid reimbursement rate (AOR, 0.88; 95% CI, 0.85-0.92; P <= 0.001). Conclusions: Antipsychotic use increased in US nursing homes from 1996 through 2006 and was associated with certain organizational characteristics and market characteristics. Future interventions to reduce antipsychotic use in nursing homes will have to focus Oil these factors. (Am J Geriatr Pharmacother. 2009;7:143-150) (C) 2009 Excerpta Medica Inc. C1 [Castle, Nicholas G.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.; Handler, Steven M.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15213 USA. [Handler, Steven M.] Univ Pittsburgh, Sch Med, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Castle, NG (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15213 USA. EM castlen@pitt.edu OI Handler, Steven/0000-0002-3940-3224 FU National Institute of Aging [R01AG027896, R01AG027017, P30AG024827, 5KL2RR024154]; Agency for Health Care Research and Quality grants [R01HS016808, R03HS016547]; Veterans Administration Health Services Research grant [IIR-06-062] FX This study was supported by National Institute of Aging grants (R01 AG027896,R01AG027017,P30AG024827, 5KL2RR024154), Agency for Health Care Research and Quality grants (R01HS016808, R03HS016547), and a Veterans Administration Health Services Research grant (IIR-06-062). NR 36 TC 17 Z9 17 U1 2 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD JUN PY 2009 VL 7 IS 3 BP 143 EP 150 DI 10.1016/j.amjopharm.2009.05.001 PG 8 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 470MF UT WOS:000267978100001 PM 19616182 ER PT J AU LoboPrabhu, SM Molinari, VA Hamilton, JD Lomax, JW AF LoboPrabhu, Sheila M. Molinari, Victor A. Hamilton, Joseph D. Lomax, James W. TI The Aging Physician With Cognitive Impairment: Approaches to Oversight, Prevention, and Remediation SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Aging; physician; dementia; dyscompetence; impairment AB There are many important unanswered issues regarding the occurrence of cognitive impairment in physicians, such as detection of deficits, remediation efforts, policy implications for safe medical practice, and the need to safeguard quality patient care. The authors review existing literature on these complex issues and derive heuristic formulations regarding how to help manage the professional needs of the aging physician with dementia. To ensure safe standards of medical care while also protecting the needs of physicians and their families, state regulatory or licensing agencies in collaboration with state medical associations and academic medical centers should generate evaluation guidelines to assure continued high levels of functioning. The authors also raise the question of whether age should be considered as a risk factor that merits special screening for adequate functioning. Either age-related screening for cognitive impairment should be initiated or rigorous evaluation after lapses in standard of care should be the norm regardless of age. Ultimately, competence rather than mandatory retirement due to age per se should be the deciding factor regarding whether physicians should be able to continue their practice. Finally, the authors issue a call for an expert consensus panel to convene to make recommendations concerning aging physicians with cognitive impairment who are at risk for medical errors. (Am J Geriatr Psychiatry 2009; 17: 445-454) C1 [LoboPrabhu, Sheila M.] Michael E DeBakey Dept Vet Affairs Med Ctr, Mental Hlth Care Line & MIRECC, Houston, TX 77030 USA. [LoboPrabhu, Sheila M.; Hamilton, Joseph D.; Lomax, James W.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Molinari, Victor A.] Univ S Florida, Dept Aging & Mental Hlth Dispar, Louis de la Parte Florida Mental Hlth Inst, Tampa, FL USA. RP LoboPrabhu, SM (reprint author), Michael E DeBakey Dept Vet Affairs Med Ctr, Mental Hlth Care Line & MIRECC, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM SheilaM.Loboprabhu@med.va.gov NR 37 TC 7 Z9 7 U1 2 U2 5 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 JUN PY 2009 VL 17 IS 6 BP 445 EP 454 DI 10.1097/JGP.0b013e31819e2d7e PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V21XU UT WOS:000208241100001 PM 19461256 ER PT J AU Wetherell, JL Ayers, CR Sorrell, JT Thorp, SR Nuevo, R Belding, W Gray, E Stanley, MA Arean, PA Donohue, M Unutzer, J Ramsdell, J Xu, RH Patterson, TL AF Wetherell, Julie Loebach Ayers, Catherine R. Sorrell, John T. Thorp, Steven R. Nuevo, Roberto Belding, Wendy Gray, Emily Stanley, Melinda A. Arean, Patricia A. Donohue, Michael Unutzer, Jurgen Ramsdell, Joe Xu, Ronghui Patterson, Thomas L. TI Modular Psychotherapy for Anxiety in Older Primary Care Patients SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Aged; elderly; generalized anxiety disorder; cognitive-behavioral therapy ID LATE-LIFE ANXIETY; COGNITIVE-BEHAVIORAL TREATMENT; GENERALIZED ANXIETY; ELDERLY-PATIENTS; INVENTORY-II; OPEN TRIAL; DISORDER; ADULTS; DEPRESSION; HEALTH AB Objective: To develop and test a modular psychotherapy protocol in older primary care patients with anxiety disorders. Design: Randomized, controlled pilot study. Setting: University-based geriatric medicine clinics. Participants: Thirty-one elderly primary care patients with generalized anxiety disorder or anxiety disorder not otherwise specified. Intervention: Modular form of psychotherapy compared with enhanced community treatment. Measurements: Self-reported, interviewer-rated, and qualitative assessments of anxiety, worry, depression, and mental health-related quality of life. Results: Both groups showed substantial improvements in anxiety symptoms, worry, depressive symptoms, and mental health-related quality of life. Most individuals in the enhanced community treatment condition reported receiving medications or some other form of professional treatment for anxiety. Across both conditions, individuals who reported major life events or stressors and those who used involvement in activities as a coping strategy made smaller gains than those who did not. Conclusions: Results suggest that modular psychotherapy and other treatments can be effective for anxiety in older primary care patients. Results further suggest that life events and coping through increased activity may play a role in the maintenance of anxiety in older adults. (Am J Geriatr Psychiatry 2009; 17:483-492) C1 [Wetherell, Julie Loebach; Ayers, Catherine R.; Thorp, Steven R.; Belding, Wendy; Gray, Emily; Patterson, Thomas L.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Wetherell, Julie Loebach; Ayers, Catherine R.; Thorp, Steven R.; Belding, Wendy; Gray, Emily] VA San Diego Healthcare Syst, Psychol Serv, San Diego, CA USA. [Sorrell, John T.] San Mateo Med Ctr, San Mateo, CA USA. [Nuevo, Roberto] Hosp Univ Princesa, Dept Psychiat, Madrid, Spain. [Stanley, Melinda A.] Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Stanley, Melinda A.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Arean, Patricia A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Donohue, Michael; Xu, Ronghui] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Unutzer, Jurgen] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Ramsdell, Joe] Univ Calif San Diego, Dept Internal Med, San Diego, CA 92103 USA. RP Wetherell, JL (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr,Dept 9116B, La Jolla, CA 92093 USA. EM jwetherell@ucsd.edu OI Nuevo, Roberto/0000-0003-3385-2747 FU NIMH [MH067643] FX The authors gratefully acknowledge the contributions of Georgia Birchler, Debora Goodman, Dilip V. Jeste, M. D., Laura Otis, Ph. D., and Murray B. Stein, M. D., M. P. H. This research was supported by NIMH grant MH067643. NR 41 TC 31 Z9 31 U1 2 U2 12 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 JUN PY 2009 VL 17 IS 6 BP 483 EP 492 DI 10.1097/JGP.0b013e3181a31fb5 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 451YC UT WOS:000266505800005 PM 19461257 ER PT J AU Nathan, DG AF Nathan, David G. TI The rewards of patience in bone marrow transplantation SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Nathan, DG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM david_nathan@dfci.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUN PY 2009 VL 84 IS 6 BP 319 EP 319 DI 10.1002/ajh.21430 PG 1 WC Hematology SC Hematology GA 452VW UT WOS:000266570300001 PM 19425069 ER PT J AU Cheng, S Wang, TJ AF Cheng, Susan Wang, Thomas J. TI Predicting Incident CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; POPULATION C1 [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cheng, Susan] Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. [Cheng, Susan; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. RP Wang, TJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org NR 13 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2009 VL 53 IS 6 BP 936 EP 939 DI 10.1053/j.ajkd.2009.04.004 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 456RY UT WOS:000266866600008 PM 19463762 ER PT J AU Coca, SG Yusuf, B Shlipak, MG Garg, AX Parikh, CR AF Coca, Steven G. Yusuf, Bushra Shlipak, Michael G. Garg, Amit X. Parikh, Chirag R. TI Long-term Risk of Mortality and Other Adverse Outcomes After Acute Kidney Injury: A Systematic Review and Meta-analysis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Acute renal failure; chronic kidney disease; prognosis ID ACUTE-RENAL-FAILURE; CRITICALLY-ILL PATIENTS; QUALITY-OF-LIFE; PERCUTANEOUS CORONARY INTERVENTION; INTENSIVE-CARE-UNIT; CONTINUOUS VENOVENOUS HEMODIALYSIS; ACUTE TUBULAR-NECROSIS; REPLACEMENT THERAPY; HOSPITAL MORTALITY; PERITUBULAR CAPILLARIES AB Background: Acute kidney injury (AKI) is common in hospitalized patients. The impact of AKI on long-term outcomes is controversial. Study Design: Systematic review and meta-analysis. Setting & Participants: Persons with AKI. Selection Criteria for Studies: MEDLINE and EMBASE databases were searched from 1985 through October 2007. Original studies describing outcomes of AKI for patients who survived hospital discharge were included. Studies were excluded from review when participants were followed up for less than 6 months. Predictor: AKI, defined as acute changes in serum creatinine level or acute need for renal replacement therapy. Outcomes: Chronic kidney disease (CKD), cardiovascular disease, and mortality. Results: 48 studies that contained a total of 47,017 participants were reviewed; 15 studies reported long-term data for patients without AKI. The incidence rate of mortality was 8.9 deaths/100 person-years in survivors of AKI and 4.3 deaths/100 patient-years in survivors without AKI (rate ratio [RR], 2.59; 95% confidence interval, 1.97 to 3.42). AKI was associated independently with mortality risk in 6 of 6 studies that performed multivariate adjustment (adjusted RR, 1.6 to 3.9) and with myocardial infarction in 2 of 2 studies (RR, 2.05; 95% confidence interval, 1.61 to 2.61). The incidence rate of CKD after an episode of AKI was 7.8 events/100 patient-years, and the rate of end-stage renal disease was 4.9 events/100 patient-years. Limitations: The relative risk for CKD and end-stage renal disease after AKI was unattainable because of lack of follow-up of appropriate controls without AKI. Conclusions: The development of AKI, defined as acute changes in serum creatinine level, characterizes hospitalized patients at increased risk of long-term adverse outcomes. Am J Kidney Dis 53:961-973. Published by Elsevier Inc on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Coca, Steven G.; Yusuf, Bushra; Parikh, Chirag R.] Yale Univ, Nephrol Sect, West Haven, CT 06516 USA. [Coca, Steven G.; Yusuf, Bushra; Parikh, Chirag R.] Vet Affairs Med Ctr, West Haven, CT USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Garg, Amit X.] Univ Western Ontario, London, ON, Canada. RP Parikh, CR (reprint author), Yale Univ, Nephrol Sect, 950 Campbell Ave,Mail Code 151B,Bldg 35 A,Rm 219, West Haven, CT 06516 USA. EM chirag.parikh@yale.edu FU National Institutes of Health [K23DK08013, DK082185]; Canadian Institutes of Health Research; AKI [RO1 HL085757] FX Support: Dr Coca is funded by the career development grant K23DK08013 from the National Institutes of Health and is Supported by the American Heart Association's Established investigator Award. Dr Garg is funded by the Clinical Scientist Award from the Canadian Institutes of Health Research. Dr Parikh is Supported by the AKI grants RO1 HL085757 and UOI-DK082185 from the National Institutes of Health. NR 77 TC 359 Z9 390 U1 2 U2 16 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 JUN PY 2009 VL 53 IS 6 BP 961 EP 973 DI 10.1053/j.ajkd.2008.11.034 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 456RY UT WOS:000266866600011 PM 19346042 ER PT J AU Anderka, MT Lin, AE Abuelo, DN Mitchell, AA Rasmussen, SA AF Anderka, Marlene T. Lin, Angela E. Abuelo, Dianne N. Mitchell, Allen A. Rasmussen, Sonja A. TI Reviewing the Evidence for Mycophenolate Mofetil as a New Teratogen: Case Report and Review of the Literature SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE CellCept (R); cleft lip and palate; coloboma; malformation; microtia; mycophenolate mofetil; teratogenesis ID ACROFACIAL DYSOSTOSIS; PREGNANCY; EXPOSURE; IMMUNOSUPPRESSION; TRANSPLANTATION; MALFORMATIONS; EMBRYOPATHY; RECIPIENTS; OUTCOMES; EDITORS AB Mycophenolate mofetil (MMF) (CellCept (R)) is an immunosuppressant drug that is teratogenic in rats and rabbits. Reports of malformations in 13 offspring of women exposed to MMF in pregnancy raise concern that MMF is also a human teratogen. We report an additional child with malformations following prenatal exposure to MMF and review the other 13 reports. We identified a Cambodian male born at 31 weeks' gestation to a mother who had been treated for lupus nephritis with MMF from before conception to 12 weeks' gestational age. He had bilateral moderate-to-severe microtia, external auditory canal atresia, bilateral conductive hearing loss, mild microcephaly, and apparently normal development. Among the 14 MMF-exposed offspring now reported, the underlying maternal conditions were kidney transplantation (7), lupus nephritis (4), liver transplantation (1), heart transplantation (1), and recurrent erythema. multiforme (1). All were exposed in early pregnancy. The most distinctive malformation was moderate-to-severe microtia. or anotia (12), with external auditory canal atresia in 9. Other common craniofacial malformations and minor anomalies included orofacial clefts (7), hypertelorism (3), coloboma (3), and micrognathia (3). Six had cardiovascular malformations, of which three were either conotruncal or aortic arch defects. MMF dose, reported in 12 patients, was <1 g/day in 4 and 1 g or more/day in 8; no correlation between dose and phenotype severity was apparent. While case reports have limited value in identifying human teratogens, the unusual distribution of malformations among the 14 reported exposed offspring identifies a phenotype suggesting that MMF is likely a human teratogen. (C) 2009 Wiley-Liss, Inc. C1 [Anderka, Marlene T.; Lin, Angela E.] Massachusetts Ctr Birth Defects Res & Prevent, Massachusetts Dept Publ Hlth, Boston, MA 02108 USA. [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA USA. [Abuelo, Dianne N.] Rhode Isl Hosp, Div Genet, Providence, RI USA. [Abuelo, Dianne N.] Hasbro Childrens Hosp, Providence, RI USA. [Abuelo, Dianne N.] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. [Mitchell, Allen A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Rasmussen, Sonja A.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Anderka, MT (reprint author), Massachusetts Ctr Birth Defects Res & Prevent, Massachusetts Dept Publ Hlth, 250 Washington St,5th Floor, Boston, MA 02108 USA. EM marlene.anderka@state.ma.us OI Mitchell, Allen/0000-0003-0950-6799 NR 43 TC 95 Z9 101 U1 0 U2 3 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 JUN PY 2009 VL 149A IS 6 BP 1241 EP 1248 DI 10.1002/ajmg.a.32685 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 454LT UT WOS:000266684200019 PM 19441125 ER PT J AU Lehman, SJ Abbara, S Cury, RC Nagurney, JT Hsu, J Goela, A Schlett, CL Dodd, JD Brady, TJ Bamberg, F Hoffmann, U AF Lehman, Sam J. Abbara, Suhny Cury, Ricardo C. Nagurney, John T. Hsu, Joe Goela, Aashish Schlett, Christopher L. Dodd, Jonathan D. Brady, Thomas J. Bamberg, Fabian Hoffmann, Udo TI Significance of Cardiac Computed Tomography Incidental Findings in Acute Chest Pain SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Chest pain; Computed tomography; Incidental findings ID EMERGENCY-DEPARTMENT PATIENTS; ACUTE CORONARY SYNDROMES; NONCARDIAC FINDINGS; COST-EFFECTIVENESS; CT ANGIOGRAPHY; CARE-UNIT; PREVALENCE; SCANS; MDCT AB BACKGROUND: Coronary computed tomography angiography might improve the management of patients presenting to the emergency department with acute chest pain; however, noncoronary incidental findings are frequently detected. The prevalence and clinical significance of these findings have not been well described. METHODS: Consecutive patients presenting to the emergency department with acute chest pain and inconclusive initial evaluation between May 2005 and May 2007 underwent 64-slice coronary computed tomography angiography before hospital admission with noncoronary incidental findings immediately reported. An expert panel adjudicated which incidental findings changed in-hospital patient management, and projections for additional testing were based on standard medical practice. RESULTS: Among 395 patients (37.0% were female, mean age 53 +/- 12 years), incidental findings were detected in 44.8% (n = 177): noncalcified pulmonary nodules (n = 94, 23.8%), simple liver cysts (n = 26, 6.6%), calcified pulmonary nodules (n = 16, 4.1%), and contrast-enhancing liver lesions (n = 9, 2.3%). In-hospital management was changed because of incidental finding reporting in 5 patients (1.3%), and a potential alternative diagnosis was offered in another 16 patients (4.1%). Subsequent diagnostic imaging tests were recommended in 81 patients (20.5%), including 74 chest computed tomography scans. After 6 months, biopsy was performed in 3 patients, revealing cancer in 2 (0.5%) who underwent successful tumor resection. CONCLUSION: Clinically important findings are detected in up to 5% of patients with a lead symptom of acute chest pain and low to intermediate likelihood of acute coronary syndrome, but only few directly change patient management; 21% are recommended for further imaging tests, resulting in invasive procedures and detection of cancer in few patients. (C) 2009 Elsevier Inc. All rights reserved. The American Journal of Medicine (2009) 122, 543-549 C1 [Lehman, Sam J.; Abbara, Suhny; Cury, Ricardo C.; Hsu, Joe; Schlett, Christopher L.; Dodd, Jonathan D.; Brady, Thomas J.; Bamberg, Fabian; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Lehman, Sam J.; Abbara, Suhny; Cury, Ricardo C.; Nagurney, John T.; Hsu, Joe; Schlett, Christopher L.; Dodd, Jonathan D.; Brady, Thomas J.; Bamberg, Fabian; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lehman, Sam J.] Flinders Univ S Australia, Dept Cardiol, Adelaide, SA, Australia. [Abbara, Suhny; Cury, Ricardo C.; Hsu, Joe; Goela, Aashish; Dodd, Jonathan D.; Brady, Thomas J.; Bamberg, Fabian; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Charles River Plaza,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org NR 26 TC 51 Z9 51 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUN PY 2009 VL 122 IS 6 BP 543 EP 549 DI 10.1016/j.amjmed.2008.10.039 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 451XG UT WOS:000266503600012 PM 19486717 ER PT J AU Cruz-Gonzalez, I Sanchez-Ledesma, M Sanchez, PL Martin-Moreiras, J Jneid, H Rengifo-Moreno, P Inglessis-Azuaje, I Maree, AO Palacios, IF AF Cruz-Gonzalez, Ignacio Sanchez-Ledesma, Maria Sanchez, Pedro L. Martin-Moreiras, Javier Jneid, Hani Rengifo-Moreno, Pablo Inglessis-Azuaje, Ignacio Maree, Andrew O. Palacios, Igor F. TI Predicting Success and Long-Term Outcomes of Percutaneous Mitral Valvuloplasty: A Multifactorial Score SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Percutaneous mitral valvuloplasty; Prognosis; Score ID BALLOON VALVOTOMY; FOLLOW-UP; COMMISSUROTOMY; IMMEDIATE; STENOSIS; DISEASE; COMPLICATIONS; DILATATION; VARIABLES; VALVE AB BACKGROUND: Percutaneous mitral valvuloplasty (PMV) success depends on appropriate patient selection. A multifactorial score derived from clinical, anatomic/echocardiographic, and hemodynamic variables would predict procedural success and clinical outcome. METHODS: Demographic data, echocardiographic parameters (including echocardiographic score), and procedure-related variables were recorded in 1085 consecutive PMVs. Long-term clinical follow-up (death, mitral valve replacement, redo PMV) was performed. Multivariate regression analysis of the first 800 procedures was performed to identify independent predictors of procedural success. Significant variables were formulated into a risk score and validated prospectively. RESULTS: Six independent predictors of PMV success were identified: age less than 55 years, New York Heart Association classes I and II, pre-PMV mitral area of 1 cm(2) or greater, pre-PMV mitral regurgitation grade less than 2, echocardiographic score of 8 or greater, and male sex. A score was constructed from the arithmetic sum of variables present per patient. Procedural success rates increased incrementally with increasing score (0% for 0/6, 39.7% for 1/6, 54.4% for 2/6, 77.3% for 3/6, 85.7% for 4/6, 95% for 5/6, and 100% for 6/6; P < .001). In a validation cohort (n = 285 procedures), the multifactorial score remained a significant predictor of PMV success (P < .001). Comparison between the new score and the echocardiographic score confirmed that the new index was more sensitive and specific (P < .001). This new score also predicts long-term outcomes (P < .001). CONCLUSION: Clinical, anatomic, and hemodynamic variables predict PMV success and clinical outcome and may be formulated in a scoring system that would help to identify the best candidates for PMV. (C) 2009 Elsevier Inc. All rights reserved. The American Journal of Medicine (2009) 122, 581.e11-581.e19 C1 [Cruz-Gonzalez, Ignacio] Harvard Univ, Cardiac Catheterizat Lab, Massachusetts Gen Hosp, Cardiol Div,Med Sch, Boston, MA 02114 USA. [Sanchez, Pedro L.] Hosp Univ Gregorio Maranon, Serv Cardiol, Madrid, Spain. [Martin-Moreiras, Javier] Hosp Univ Salamanca, Serv Cardiol, Salamanca, Spain. RP Cruz-Gonzalez, I (reprint author), Harvard Univ, Cardiac Catheterizat Lab, Massachusetts Gen Hosp, Cardiol Div,Med Sch, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM i-cruz@secardiologia.es RI 2009, Secribsal/A-1266-2012; OI Sanchez, Pedro L/0000-0002-4288-345X NR 24 TC 1 Z9 1 U1 0 U2 1 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 JUN PY 2009 VL 122 IS 6 AR 581.e11 DI 10.1016/j.amjmed.2008.10.038 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 451XG UT WOS:000266503600018 PM 19486721 ER PT J AU Roukoz, H Bavry, AA Sarkees, ML Mood, GR Kumbhani, DJ Rabbat, MG Bhatt, DL AF Roukoz, Henri Bavry, Anthony A. Sarkees, Michael L. Mood, Girish R. Kumbhani, Dharam J. Rabbat, Mark G. Bhatt, Deepak L. TI Comprehensive Meta-Analysis on Drug-Eluting Stents versus Bare-Metal Stents during Extended Follow-up SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Bare-metal stent; Drug-eluting stent; Percutaneous coronary intervention; Stent thrombosis ID ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CLINICAL-TRIALS; CORONARY-ARTERY LESIONS; DOUBLE-BLIND TRIAL; DIABETIC-PATIENTS; UNCOATED STENTS; STANDARD STENT; SLOW-RELEASE; CANADIAN MULTICENTER; LATE THROMBOSIS AB BACKGROUND: Several observational reports have documented both increased and decreased cardiac mortality or Q-wave myocardial infarction with drug-eluting stents compared with bare-metal stents. METHODS: We sought to evaluate the safety and efficacy of drug-eluting stents compared with bare-metal stents early after intervention (<1 year) and late (>1 year) among a broad population of patients, using a meta-analysis of randomized clinical trials. RESULTS: We identified 28 trials with a total of 10,727 patients and a mean follow-up of 29.6 months. For early outcomes (<1 year), all-cause mortality for drug-eluting stents versus bare-metal stents was 2.1% versus 2.4% (risk ratio [RR] 0.91, [95% confidence interval (CI), 0.70-1.18]; P = .47), non-Q-wave myocardial infarction was 3.3% versus 4.4% (RR 0.78 [95% CI, 0.61-1.00]; P = .055), target lesion revascularization was 5.8% versus 18.4% (RR 0.28 [95% CI, 0.21-0.38]; P = .001), and stent thrombosis was 1.1% versus 1.3% (RR 0.87 [95% CI, 0.60-1.26]; P = .47). For late outcomes (>1 year), all-cause mortality for drug-eluting stents versus bare-metal stents was 5.9% versus 5.7% (RR 1.03 [95% CI, 0.83-1.28]; P = .79), target lesion revascularization was 4.0% versus 3.3% (RR 1.22 [95% CI, 0.92-1.60]; P = .16), non-Q-wave myocardial infarction was 1.6% versus 1.2% (RR 1.36 [95% CI, 0.74-2.53]; P = .32) and stent thrombosis was 0.7% versus 0.1% (RR 4.57 [95% CI, 1.54-13.57]; P = .006). CONCLUSIONS: There was no excess mortality with drug-eluting stents. Within 1 year, drug-eluting stents appear to be safe and efficacious with possibly decreased non-Q-wave myocardial infarction compared with bare-metal stents. After 1 year, drug-eluting stents still have similar mortality, despite increased stent thrombosis. The reduction in target lesion revascularization with drug-eluting stents mainly happens within 1 year, but is sustained thereafter. Published by Elsevier Inc. The American Journal of Medicine (2009) 122, 581.e1-581.e10 C1 [Bhatt, Deepak L.] Brigham & Womens Hosp, Integrated Intervent Cardiovasc Program, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Roukoz, Henri] Univ Minnesota, Dept Cardiovasc Med, Minneapolis, MN USA. [Bavry, Anthony A.] Univ Florida, Div Cardiovasc Med, Gainesville, FL USA. [Sarkees, Michael L.] Cleveland Clin, Dept Internal Med, Cleveland, OH 44106 USA. [Mood, Girish R.; Kumbhani, Dharam J.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Rabbat, Mark G.] Loyola Univ, Med Ctr, Cardiovasc Inst, Maywood, IL 60153 USA. RP Bhatt, DL (reprint author), Brigham & Womens Hosp, Integrated Intervent Cardiovasc Program, VA Boston Healthcare Syst, 75 Francis St,PBB-146, Boston, MA 02115 USA. EM dlbhattmd@alum.mit.edu NR 80 TC 9 Z9 10 U1 0 U2 2 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 JUN PY 2009 VL 122 IS 6 AR 581.e1 DI 10.1016/j.amjmed.2008.12.019 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 451XG UT WOS:000266503600017 PM 19486720 ER PT J AU Almandoz, JED Schaefer, PW Forero, NP Falla, JR Gonzalez, RG Romero, JM AF Almandoz, J. E. Delgado Schaefer, P. W. Forero, N. P. Falla, J. R. Gonzalez, R. G. Romero, J. M. TI Diagnostic Accuracy and Yield of Multidetector CT Angiography in the Evaluation of Spontaneous Intraparenchymal Cerebral Hemorrhage SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Neuroradiology CY JUN 09-11, 2007 CL Chicago, IL SP Amer Soc Neuroradiol ID INTRACEREBRAL HEMORRHAGE; ARTERIOVENOUS-MALFORMATIONS; AMYLOID ANGIOPATHY; RISK-FACTORS; INTRACRANIAL HEMORRHAGE; COMPUTED-TOMOGRAPHY; NATURAL-HISTORY; ANEURYSMS; BRAIN; HEMATOMA AB BACKGROUND AND PURPOSE: Multidetector CT angiography (MDCTA) is emerging as the favored initial diagnostic examination in the evaluation of patients presenting with spontaneous intraparenchymal hemorrhage (IPH). This study aims to evaluate the diagnostic accuracy and yield of MDCTA for the detection of vascular etiologies in adult patients presenting to the emergency department with IPH. MATERIALS AND METHODS: We conducted a retrospective study of 623 consecutive adult patients presenting to the emergency department with IPH, who were evaluated with MDCTA during a 9-year period. CT angiograms were reviewed by 2 neuroradiologists to determine the IPH site and the presence of a vascular etiology. Patients with associated subarachnoid hemorrhage in the basal cisterns were excluded from the study. Medical records were reviewed for risk factors and correlation with final diagnosis. The diagnostic accuracy of MDCTA compared with conventional angiography, intraoperative evaluation, and pathologic findings was determined, when available. Multiple-variable logistic regression analysis was performed to determine clinical and radiologic factors that predict a higher yield of MDCTA. RESULTS: MDCTA demonstrated a vascular etiology in 91 patients (14.6%), with a sensitivity of 96%, specificity of 99%, and diagnostic accuracy of 98%. We found independent, statistically significant higher yields of MDCTA in patients with the following characteristics: 1) age younger than 46 years (47%); 2) lobar (20%) or infratentorial (16%) IPH, especially lobar IPH with associated intraventricular hemorrhage (25%); 3) female sex (18%); or 4) neither known hypertension nor impaired coagulation at presentation (33%). CONCLUSIONS: MDCTA is an accurate diagnostic examination in the evaluation of adult patients presenting with spontaneous IPH and should be performed in all patients with the aforementioned clinical and radiologic characteristics. C1 [Almandoz, J. E. Delgado; Schaefer, P. W.; Forero, N. P.; Falla, J. R.; Gonzalez, R. G.; Romero, J. M.] Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02114 USA. RP Almandoz, JED (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Founders 216,55 Fruit St, Boston, MA 02114 USA. EM jdelgadoalmandoz@partners.org NR 27 TC 40 Z9 41 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUN-JUL PY 2009 VL 30 IS 6 BP 1213 EP 1221 DI 10.3174/ajnr.A1546 PG 9 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 461IL UT WOS:000267258400025 ER PT J AU Stefancyk, AL AF Stefancyk, Amanda L. TI Improving Processes of Care SO AMERICAN JOURNAL OF NURSING LA English DT Editorial Material C1 Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. RP Stefancyk, AL (reprint author), Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. EM astefancyk@partners.org NR 2 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-936X J9 AM J NURS JI Am. J. Nurs. PD JUN PY 2009 VL 109 IS 6 BP 36 EP 37 PG 2 WC Nursing SC Nursing GA 453XW UT WOS:000266647200015 PM 19478603 ER PT J AU Ohishi, M Chiusaroli, R Ominsky, M Asuncion, F Thomas, C Khatri, R Kostenuik, P Schipani, E AF Ohishi, Masanobu Chiusaroli, Riccardo Ominsky, Michael Asuncion, Frank Thomas, Clare Khatri, Richa Kostenuik, Paul Schipani, Ernestina TI Osteoprotegerin Abrogated Cortical Porosity and Bone Marrow Fibrosis in a Mouse Model of Constitutive Activation of the PTH/PTHrP Receptor SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; GROWTH-FACTOR-BETA; PRIMARY HYPERPARATHYROIDISM; PARATHYROID-HORMONE; IN-VIVO; CYNOMOLGUS MONKEYS; TARGETED DELETION; CANCELLOUS BONE; MEDICAL THERAPY; TRABECULAR BONE AB Intracortical porosities and marrow fibrosis are hallmarks of hyperparathyroidism and are present in bones of transgenic mice expressing constitutively active parathyroid hormone/parathyroid hormone-related protein receptors (PPR*Tg). Cortical porosity is the result of osteoclast activity; however, the etiology of marrow fibrosis is poorly understood. While osteoclast numbers and activity are regulated by osteoprotegerin (OPG), bisphosphonates suppress osteoclast activity but not osteoclast numbers. We therefore used OPG and bisphosphonates to evaluate the extent to which osteoclasts, as opposed to bone resorption, regulate marrow fibrosis in PPR*Tg mice after treatment of animals with vehicle, OPG, alendronate, or zoledronate. All three agents similarly increased trabecular bone volume in both PPR*Tg and control mice, suggesting that trabecular bone resorption was comparably suppressed by these agents. However, the number of trabecular osteoclasts was greatly decreased by OPG but not by either alendronate or zoledronate. Furthermore, intracortical porosity and marrow fibrosis were virtually abolished by OPG treatment, whereas alendronate and zoledronate only partially reduced these two parameters. The greater reductions in cortical porosity and increments in cortical bone mineral density with OPG in PPR*Tg mice were associated with greater improvements in bone strength. The differential effect of OPG versus bisphosphonates on marrow fibrosis, despite similar effects on trabecular bone volume, suggests that marrow fibrosis was related not only to bone resorption but also to the presence of osteoclasts. (Am J Pathol 2009, 174:2160-2171; DOI:10.2353/ajpath.2009.081026) C1 [Ohishi, Masanobu; Chiusaroli, Riccardo; Thomas, Clare; Khatri, Richa; Kostenuik, Paul; Schipani, Ernestina] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA USA. [Ominsky, Michael; Asuncion, Frank; Kostenuik, Paul] Amgen Inc, Metab Disorders, Thousand Oaks, CA 91320 USA. RP Schipani, E (reprint author), Thier 11-MGH,50 Blossom St, Boston, MA 02114 USA. EM paulk@amgen.com FU Amgen Inc FX Supported by a grant from Amgen Inc to E.S. NR 54 TC 16 Z9 16 U1 1 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2009 VL 174 IS 6 BP 2160 EP 2171 DI 10.2353/ajpath.2009.081026 PG 12 WC Pathology SC Pathology GA 449ZT UT WOS:000266370600020 PM 19389927 ER PT J AU Ponnuswamy, P Ostermeier, E Schrottle, A Chen, J Huang, PL Ertl, G Nieswandt, B Kuhlencordt, PJ AF Ponnuswamy, Padmapriya Ostermeier, Eva Schroettle, Angell Chen, Jiqiu Huang, Paul L. Ertl, Georg Nieswandt, Bernhard Kuhlencordt, Peter J. TI Oxidative Stress and Compartment of Gene Expression Determine Proatherosclerotic Effects of Inducible Nitric Oxide Synthase SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID VASCULAR SMOOTH-MUSCLE; E-DEFICIENT MICE; DIET-INDUCED ATHEROSCLEROSIS; TRAUMATIC BRAIN-INJURY; E-KNOCKOUT MICE; IN-VIVO; SUPEROXIDE GENERATION; NO-SYNTHASE; TETRAHYDROBIOPTERIN; 17-BETA-ESTRADIOL AB Genetic and pharmacological inhibition of inducible nitric oxide synthase (iNOS) decreases atherosclerosis development. Potential proatherogenic effects of iNOS include iNOS mediated oxidative stress and iNOS expression in different cellular compartments. Lesional iNOS can potentially produce nitric oxide radicals (NO), superoxide radicals (O(2)(-)), or both; these radicals may then react to form peroxynitrite. Alternatively, O(2)(-) radicals from oxidases co-expressed with iNOS could react with NO to produce peroxynitrite. Therefore, the expression profiles of the genes that modulate the redox system in different iNOS-expressing cell compartments may determine the role of iNOS in atherosclerosis. We used apoE (apoE(-/-)) and apoE/iNOS double knockout (apoE(-/-)/iNOS(-/-)) mice to assess vascular NO, O(2)(-), and peroxynitrite formation by electron spin resonance spectroscopy, high performance liquid chromatography, and 3-nitrotyrosine staining. The relevance of the iNOS expressing cell compartment was tested by bone marrow transplantation. We show that iNOS significantly contributes to vascular NO production and itself produces O(2)(-), leading to peroxynitrite formation in atherosclerotic lesions. Our bone marrow transplantation experiments show that bone marrow derived cells exclusively mediate the proatherosclerotic effects of iNOS in mates, while both parenchymal and bone marrow derived iNOS equally contribute to atherosclerosis in females. Moreover, iNOS expression affects vascular remodeling. These findings establish for the first time that the proatherosclerotic effects of iNOS vary with sex in addition to the compartment of its expression. (Am J Pathol 2009, 174;2400-2410; DOI: 10.2353/ajpath.2009.080730) C1 [Kuhlencordt, Peter J.] Univ Munich, Med Poliklin, D-80336 Munich, Germany. [Chen, Jiqiu; Huang, Paul L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Nieswandt, Bernhard] Univ Wurzburg, Inst Clin Biochem & Pathobiochem, Wurzburg, Germany. [Ponnuswamy, Padmapriya; Ostermeier, Eva; Schroettle, Angell; Ertl, Georg] Univ Wurzburg, DFG Res Ctr Expt Biomed, Rudolf Virchow Ctr, Herz Kreislaufzentrum,Med Klin 1, Wurzburg, Germany. RP Kuhlencordt, PJ (reprint author), Univ Munich, Med Poliklin, Pettenkoferstr 8A, D-80336 Munich, Germany. EM peter.kuhlencordt@med.uni-muenchen.de FU Deutsche-Forschungsgemeinschaft [KU-1206, 1206]; IZKF-Wurzburg FX Supported by grants from the Deutsche-Forschungsgemeinschaft (KU-1206(1) and 1206(2) and the IZKF-Wurzburg to P.K. NR 55 TC 26 Z9 28 U1 2 U2 8 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2009 VL 174 IS 6 BP 2400 EP 2410 DI 10.2353/ajpath.2009.080730 PG 11 WC Pathology SC Pathology GA 449ZT UT WOS:000266370600042 PM 19465644 ER PT J AU Van Hoek, AN Bouley, R Lu, YX Silberstein, C Brown, D Wax, MB Patil, RV AF Van Hoek, Alfred N. Bouley, Richard Lu, YingXian Silberstein, Claudia Brown, Dennis Wax, Martin B. Patil, Rajkumar V. TI Vasopressin-induced differential stimulation of AQP4 splice variants regulates the in-membrane assembly of orthogonal arrays SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE hydrophobic plasma membrane protein; osmotic water transport ID INSENSITIVE WATER CHANNEL; PLASMA-MEMBRANES; COLLECTING DUCTS; EPITHELIAL-CELLS; M23 ISOFORMS; AQUAPORIN-4; EXPRESSION; KIDNEY; PROTEIN; BRAIN AB Van Hoek AN, Bouley R, Lu YX, Silberstein C, Brown D, Wax MB, Patil RV. Vasopressin-induced differential stimulation of AQP4 splice variants regulates the in-membrane assembly of orthogonal arrays. Am J Physiol Renal Physiol 296: F1396-F1404, 2009. First published March 18, 2009; doi: 10.1152/ajprenal.00018.2009.-Aquaporin-4 (AQP4) is a basolateral water channel in collecting duct principal cells and assembles into orthogonal array particles (OAPs), the size of which appears to depend on relative expression levels of AQP4 splice variants. Because the higher-order organization of AQP4 was perturbed by vasopressin in Brattleboro rats and phosphorylation sites have been identified on AQP4, we investigated whether vasopressin and forskolin (Fk) affect AQP4 assembly and/or expression in LLC-PK1 cells stably transfected with the AQP4 splice variant M23, which is responsible for formation of OAPs, and/or the splice variant M1, which does not form OAPs. Our data show that [lys(8)]-vasopressin (LVP) and Fk treatment led to differential increases in expression levels of M23-AQP4 and M1-AQP4 that varied as a function of incubation time. At early time points (day 1) expression of M1 was significantly stimulated (4.5-fold), over that of M23 (1.6-fold), but after 3 days the expression of M23 became predominant (4.1-fold) over that of M1 (1.9-fold). This pattern of stimulation was dependent on an intact AQP4 residue serine 111 and required protein synthesis. In cells expressing both M1 and M23 (M1/M23 similar to 1), with small sized OAPs at the membrane, the LVP/Fk-induced stimulation of M23 was modified and mimicked that of M1 when expressed alone, suggesting a dominant role for M1. In Brattleboro kidney inner medulla, an 8-day chronic exposure to the vasopressin agonist (dDAVP) led to reduction in M1 and a significant increase in M23 immunoblot staining (M1/M23 = 2/3 -> 1/4). These results indicate that AQP4 organization and expression are regulated by vasopressin in vivo and in vitro and demonstrate that the dominant role for M1 is restricted to a one-to-one interaction between AQP4 splice variants that regulates the membrane expression of OAPs. C1 [Van Hoek, Alfred N.; Bouley, Richard; Lu, YingXian; Brown, Dennis] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Van Hoek, Alfred N.; Bouley, Richard; Lu, YingXian; Brown, Dennis] Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. [Van Hoek, Alfred N.; Bouley, Richard; Lu, YingXian; Brown, Dennis] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Van Hoek, Alfred N.; Bouley, Richard; Lu, YingXian; Brown, Dennis] Harvard Univ, Sch Med, Boston, MA USA. [Silberstein, Claudia] Univ Buenos Aires, Fac Med, Dept Fisiol, Lab Fisiopatogenia, RA-1425 Buenos Aires, DF, Argentina. [Wax, Martin B.; Patil, Rajkumar V